[ CAS No. 13750-63-5 ] {[proInfo.proName]}

Name: 13750-63-5|(4-Methylthiazol-2-yl)methanol|97%
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Quality Control of [ 13750-63-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 13750-63-5 ]

CAS No. :	13750-63-5	MDL No. :	MFCD08236826
Formula :	C₅H₇NOS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CQMPPPAHJBQCOY-UHFFFAOYSA-N
M.W :	129.18	Pubchem ID :	17750909
Synonyms :

Calculated chemistry of [ 13750-63-5 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.4
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.21
TPSA :	61.36 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.46
Log Po/w (XLOGP3) :	0.5
Log Po/w (WLOGP) :	0.79
Log Po/w (MLOGP) :	-0.47
Log Po/w (SILICOS-IT) :	2.35
Consensus Log Po/w :	0.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.35
Solubility :	5.74 mg/ml ; 0.0444 mol/l
Class :	Very soluble
Log S (Ali) :	-1.36
Solubility :	5.66 mg/ml ; 0.0438 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.47
Solubility :	4.35 mg/ml ; 0.0337 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.17

Safety of [ 13750-63-5 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338	UN#:	1760
Hazard Statements:	H318	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 13750-63-5 ]

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

Upstream synthesis route of [ 13750-63-5 ]
Downstream synthetic route of [ 13750-63-5 ]

[ 13750-63-5 ] Synthesis Path-Upstream 1~1

1
[ 13750-63-5 ]
[ 79-37-8 ]
[ 82294-70-0 ]

Reference： [1] Patent: US6277871, 2001, B1,

[ 13750-63-5 ] Synthesis Path-Downstream 1~79

1
[ 13750-63-5 ]
[ 50398-72-6 ]

Yield	Reaction Conditions	Operation in experiment
88.3%	With thionyl chloride; In dichloromethane; at 0 - 20℃; for 1h;	To a stirred solution <strong>[13750-63-5](4-methylthiazol-2-yl)methanol</strong> (2, 1 g, 7.7 mmol) in DCM (20 mL), was added SOCl2(0.89 mL, 11.55 mmol) drop wise at 0 C and the reaction mixture was stirred at rt for 1 h (Reaction condition b). The reaction mixture was evaporated under vacuum and dried to afford the product as brown oil (3) (1 g, 88.3 %, Yield). NMR (400 MHz, CDC13) delta (ppm): 6.91 (s, 1H), 4.82 (s, 2H), 2.45 (s, 3H).
73%	With methanesulfonyl chloride; triethylamine; In dichloromethane; at 20℃;Inert atmosphere;	A 25-mL round bottom flask equipped with a magnetic stirrer under nitrogen was charged with alcohol 21a (210 mg, 1.67 mmol), CH2Cl2 (4 mL), and triethylamine (0.45 mL, 3.25 mmol). Methanesulfonyl chloride (0.25 mL, 3.2 mmol) was added via a syringe over 5 minutes. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with saturated NaHCO3 (15 ml), dried over Na2SO4, and concentrated under reduced pressure and purified on an ISCO using a maximum gradient of 5% MeOH/DCM affording desired compound (180 mg, 73% yield). 1H NMR (CDCl3, 300 MHz) delta: 6.94 (s, 1H), 4.84 (s, 2H), 2.47 (s, 3H).
56%		To a 0 C solution of (4-methyl-l,3-thiazol-2-yl)methanol (1.70 g, 14.4 mmol) in dichloromethane (25 mL) was added thionyl chloride (2.55 g, 21.6 mmol) dropwise, after which the reaction mixture was allowed to warm up to room temperature and stirred at that temperature for two hours. The reaction mixture was washed by the addition of saturated sodium bicarbonate solution (1 x 40 mL), and the organic layer was separated, dried (sodium sulfate), filtered and concentrated to a residue. Purification was achieved by silica gel chromatography using 20% ethyl acetate in hexanes to afford 2-(chloromethyl)-4-methyl-l,3- thiazole (1.20 g, 8.12 mmol, 56% yield) as pale yellow viscous oil. 1H NMR (300 MHz, CDC13) delta (ppm): 6.87 (s, 1H), 4.76 (s, 2H), 2.40 (s, 3H).

	With thionyl chloride; In dichloromethane; at 0℃; for 2h;	The compound (142 mg) prepared in step 1), and thionyl chloride (1 mL) were added to dichloromethane (3 mL), and stirred at 0C for 2 hrs. The solution was warmed to room temperature, filtered in a vacuum, and subjected to azeotropic distillation with toluene. The distillate was used in a subsequent reaction without purification.
	With thionyl chloride; In dichloromethane; at 0 - 20℃; for 2h;	Step 2 Synthesis of 2-(chloromethyl)-4-methylthiazole To a solution of <strong>[13750-63-5](4-methylthiazol-2-yl)methanol</strong> (0.5 g, 3.87 mmol) in DCM (5 mL) was added thionyl chloride (0.19 ml, 2.6 mmol) at 0 C. The mixture was stirred at room temperature for 2 hour. The reaction was concentrated to give 2-(chloromethyl)-4-methylthiazole (570 mg, crude) as yellow oil, which was used without purification. LCMS retention time 0.895 min; LCMS MH+ 148
	With thionyl chloride; In dichloromethane; at 0 - 20℃; for 2h;	To a solution of <strong>[13750-63-5](4-methylthiazol-2-yl)methanol</strong> (0.5 g, 3.87 mmol) in DCM (5 mL) was added thionyl chloride (0.19 ml, 2.6 mmol) at 0 C. The mixture was stirred at room temperature for 2 hour. The reaction was concentrated to give 2-(chloromethyl)thiazole (570 mg, crude) as yellow oil, which was used without purification. LCMS retention time 0.895 min; LCMS MH+ 148
1 g	With thionyl chloride; In dichloromethane; at 0 - 20℃; for 1h;	To a stirred solution of <strong>[13750-63-5](4-methylthiazol-2-yl)methanol</strong> (2, 0.9 g, 6.97 mmol) in DCM (5 mL), was added SOCl2 (0.83 mL, 11 mmol) drop wise at 0 C and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized using cold NaHC03 (5 mL) solution and extracted with DCM (2 X 25 mL). Organic layer was washed with brine (5mL) solution, dried over anhydrous Na2S04 and evaporated to afford the product as yellow oil. (1 g). MS (ESI): mass calcd.for C5H6CINS , 146.99; m/z found 148.1 (M+H)+.

Reference： [1]Patent: WO2019/77631,2019,A1 .Location in patent: Paragraph 000133; 000331
[2]Patent: WO2013/142712,2013,A1 .Location in patent: Page/Page column 68
[3]Patent: WO2012/88431,2012,A1 .Location in patent: Page/Page column 109
[4]Journal of the Chemical Society,1949,p. Spl. 113
[5]Tetrahedron,2003,vol. 59,p. 1381 - 1387
[6]Patent: WO2014/3483,2014,A1 .Location in patent: Page/Page column 46
[7]Patent: WO2014/143799,2014,A2 .Location in patent: Page/Page column 412; 413
[8]Patent: US2014/275528,2014,A1 .Location in patent: Paragraph 0357; 0358
[9]Patent: WO2019/58393,2019,A1 .Location in patent: Paragraph 000368

2
2-benzoyloxymethyl-4-methyl-thiazole [ No CAS ]
[ 13750-63-5 ]

Reference： [1]Journal of the Chemical Society,1949,p. Spl. 113

3
[ 50-00-0 ]
[ 89602-38-0 ]
[ 13750-63-5 ]

Reference： [1]Acta Chemica Scandinavica (1947),1966,vol. 20,p. 2649 - 2657

Yield	Reaction Conditions	Operation in experiment
		Step 1. To a stirred solution of 2-acetylthiazole (2 g, 16 mmol) in 1:1 THF:MeOH was added sodium borohydride (620 mg, 16 mmol) and stirred overnight. The reaction was filtered and the solvent removed under reduced pressure. The residue was dissolved in 95:5 CH2 Cl2:MeOH and passed through a plug of silica in a Buchner funnel and eluted with same. The solvent was removed under reduced pressure to give alpha-methyl-2-thiazolylmethanol.
		The following hydroxymethyl and halomethyl thiazoles are converted to the corresponding (2-amino-ethyl)thiomethylthiazoles by the procedure of Example 58: 2-hydroxymethyl-4-methylthiazole 4-chloromethyl-2-methylthiazole 2-chloro-4-chloromethylthiazole
663.4 mg (68%)		EXAMPLE 22C 2-hydroxymethyl-4-methyl-thiazole A 50 mL round-bottom flask, under N2 purge, was charged with the product from Example 22B (1.28 g, 7.5 mmol) and ethanol (15 mL). Calcium chloride (1.66 g, 15 mmol) was added and stirred until all the solid had dissolved. Sodium borohydride (1.14 g, 30 mmol) and THF (8 mL) were added. The reaction was stirred at room temperature for approximately 48 hours. The reaction mixture was quenched with 2 mL water. Saturated NaHCO3 was added forming a white precipitate. The mixture was extracted with Et2O (310 mL) and then EtOAc (35 mL). The aqueous layer was stirred overnight with 2M Na2CO3 (25 mL) and combined with the organic layers. The solution was extracted with methylene chloride (3*25 mL) and washed with brine, dried (MgSO4), and concentrated under vacuum to provide 663.4 mg (68%) of the title compound as a pale yellow solid. 1H NMR (300 MHz, CDCl3) delta 8.7, s, 1H; 4.84, s, 2H; 2.45, s, 3H.

500 mg	With sodium tetrahydroborate; water; In methanol; at 0 - 26℃;	General procedure: To a cold solution of 5-((tert-butyldimethylsilyl)oxy)-2-iodobenzaldehyde (5.0 g, 0.0i3 mol) in MeOH (50 mL) was added solution of NaBH4 (i.53 g, 0.0i4 mol in 5 mL water) at 0C. The reaction mixture was stirred at ft for 4-5h.The reaction mixture was quenched withdil.HC1 and extracted with DCM. The organic layers were dried over Na2504 and concentrated to afford 4.2 g of title compound.
		The following hydroxymethyl and halomethyl thiazoles are converted to the corresponding (2-aminoethyl)thiomethylthiazoles by the procedure of Example 1: 2-hydroxymethyl-4-methylthiazole 4-chloromethyl-2-methylthiazole 2-chloro-4-chloromethylthiazole 2-bromomethyl-4,5-dimethylthiazole

5
[ 13750-68-0 ]
[ 13750-63-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0 0C in dichloromethane. The resulting mixture was stirred for 20 minutes followed by quenching with aqueous NH4Cl. Evaporation of the solvent from the organic layer and flash chromatography of the residue afforded the corresponding mesylate as an oil. The mesylate (0.25g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62g, 9.6 mmol) was added. The mixture was heated to reflux for 2 hours followed by cooling and washing with aqueous NH4Cl. Evaporation of the solvent from the organic layer resulted in the corresponding azide. The azide (0.14g, 0.91mmol) was dissolved in ethyl acetate, Pd(OH)2 (0.07g) was added, and the suspension was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through Celite. Evaporation of the solvent and flash chromatography of the residue afforded the desired methylthiazole methylamine as a yellow oil. 1H-NMR: (300 MHz, CDCl3), d: 6.74 (m, 1 H); 4.09 (m, 2 H); 2.37 (s, 3 H).
100%	With methanol; sodium tetrahydroborate; at 0℃; for 0.75h;	[0271] Using an alternative synthetic route, NaBH4 (0.75 g, 19.9 mmol, 1.3 eq) was added to a stirred solution of 4-methylthiazole-2-carbaldehyde (Aldrich, 1.7 ml, 2.0 g, 15.3 mmol, 1 eq) in 30 ml anhydrous MeOH at 0 C. After 45 min the solvent was removed in vacuo. The residue was diluted with saturated aqueous NH4C1 and extracted with EtOAc (x3). The combined organics were washed with brine (xl) and dried over Na2S04. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded (4-methylthiazol-2-yl)methanol in quantitative yield.
100%	With methanol; sodium tetrahydroborate; at 0℃; for 0.75h;	Using an alternative synthetic route, NaBH4 (0.75 g, 19.9 mmol, 1.3 eq) was added to a stirred solution of 4-methylthiazole-2-carbaldehyde (Aldrich, 1.7 ml, 2.0 g, 15.3 mmol, 1 eq) in 30 ml anhydrous MeOH at 0 C. After 45 min the solvent was removed in vacuo. The residue was diluted with saturated aqueous NH4C1 and extracted with EtOAc (x3). The combined organics were washed with brine (xl) and dried over Na2S04. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded (4-methylthiazol-2-yl)methanol in quantitative yield.

98%	With methanol; sodium tetrahydroborate; at 0℃; for 1h;	To a solution of 4-methyl-1,3-thiazole-2-carbaldehyde (10.0 g,79.0 mmol) in MeOH (200 mL) was added sodium borohydride(2.98 g, 79.0 mmol) at 0 C. After being stirred for 1 h at 0 C, the reaction mixture was quenched with aqueous NH4Cl solution at 0 C and then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography(silica gel, eluted with 50% EtOAc in hexane) to give 10.0 g (98%) of 29 as colorless oil. 1H NMR (400 MHz, CDCl3) d2.43 (3H, s), 3.29 (1H, brs), 4.91 (2H, d, J = 6.0 Hz), 6.85 (1H, s)
94%		Preparation 30; (4-Methyl-thiazol-2-yl)-methanolMethod A: Dissolve 4-methyl-thiazole-2-carbaldehyde (prepare in 92% yield according to the procedures essentially as described in Khanna, I.K., et al., /. Med. Chem. (2000) 43, 3168-3185) (15.0 g, 118 mmol) in EtOH (250 mL) and add sodium borohydride (2.23 g, 59.0 mmol). Stir at room temperature for 1 h, then cautiously add aqueous NH4Cl (50 mL) to the reaction mixture. Concentrate in vacuo at 45 0C to remove EtOH. Dilute with water (50 mL) and extract into EtOAc (3 x 10OmL). Dry the combined organic portions (MgSO4), filter, and concentrate in vacuo at 45 0C to give 14.39 g (94%) of the title compound as a yellow oil. MS (ES): 130 (M+l); 1H NMR (CDCl3): delta 6.88 (s, IH), 4.94 (s, 2H), 3.16 (s, IH), 2.46 (s, 3H).
92%	With sodium tetrahydroborate; In ethanol; at 20℃; for 1h;	A 50-mL round bottom flask equipped with a magnetic stirrer was charged commercially available thiazole aldehyde (382 mg, 2.94 mmol), ethanol (95%, 10 mL), NaBH4 (1 12 mg, 2.94 mmol) was added in several portions. The reaction mixture was stirred at room temperature for 1 hour. Acetone (1 mL) was added to the reaction mixture. After 20 minutes, the reaction mixture was concentrated and the residue was partition between EtOAc (50 mL) and 1 N HCl (15 mL). The organic layer was washed with saturated NaHCO3 (15 mL), brine (15 mL), dried over Na2S04, concentrated under reduced pressure and purified on silica gel. Elution with 10%EtOAc/Hexanes afforded the reduced compound (350mg, 92% yield). 1H NMR (CDCl3, 400 MHz) delta: 6.75 (s, 1H), 5.84 (bs, 1H), 4.79 (s, 2H), 2.31 (s, 3H).
90%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 2h;	To the stirred solution of 4-methylthiazole-2-carbaldehyde (1, 1.0 g, 7 mmol) in MeOH (30 mL) at 0 C, was added sodium borohydrate (0.52 g, 14 mmol) lot wise. The reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 X 25 mL). Organic layer was washed with brine (15mL) solution, dried over anhydrous Na2S04 and evaporated. The crude residue was purified by gradient column chromatography using 40-60% EtOAc in Hexane to afford the product as pale yellow gummy. (0.9g, 90%, Yield). MS (ESI): mass calcd.for C5H7NOS, 129.02; m/z found 130.1 (M+H)+.
84%		To a 0 C solution of 4-methyl-l,3-thiazole-2-carbaldehyde (2.00 g, 15.7 mmol) in methanol (20 mL) was added sodium borohydride (0.700 g, 18.9 mmol) portionwise, after which the reaction was warmed to room temperature and stirred at that temperature for two hours. The reaction mixture was then quenched by the addition of water (5 mL), concentrated to a residue, reconstituted in water (40 mL) and extracted with ethyl acetate (2 x 60 mL), (magnesium sulfate), filtered and concentrated to afford (4-methyl-l,3-thiazol-2-yl)methanol (1.70 g, 13.2 mmol, 84% yield) as viscous oil. This material was used in the subsequent step without any purification.
79.5%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;	To the stirred solution of 4-methylthiazole-2-carbaldehyde (1, 1 g, 7.8 mmol) in MeOH (10 mL), was added NaBH4(0.5 g, 15.6 mmol) portion wise at 0 C and stirred at rt for 1 h (Reaction condition a). The reaction mixture was quenched with ice and the MeOH was evaporated. To the resulting crude added water (5 mL) and extracted with EtOAc (2 X 20 mL). Organic layer was washed with brine (5 mL) solution, dried over anhydrous Na2S04and evaporated under vacuum to give the product as brown oil (2) (1 g, 79.5%, Yield). MS (ESI): mass calcd. for C5H7NOS 129.02; m/z found 130.1 (M+H)+.
70%		PREPARATION 115(5-Bromo-4-methyl-thiazol-2-yl)-methanolTo a solution of 4-methyl-thiazole (10 g, 100 mmol) in dry THF (300 mL) was added n- BuLi in hexane (60 mL, 150 mmol, 2.5 M) dropwise at -70C, and the mixture was stirred at -70C for 1.5 hour, DMF (12 mL) was added to the slurry over 15 min, and the mixture was stirred at -70C for 3 hours. TLC (petroleum etherEtOAc 10:1 ) indicated the reaction was completed. The mixture was warmed to 0C, and poured onto wet-ice. The mixture was acidified by 2N HCI to pH ~ 4, and extracted with EtOAc (100 mL chi 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuum to give 4-methyl-thiazole-2-carbaldhyde (10 g, 78.7%) as brown oil.To a solution of 4-methyl-thiazole-2-carbaldhyde (10.0 g, 78 mmol) in dry THF (80 mL) was added NaBH4 (1.49 g, 39 mmol), and the mixture was stirred at room temperature for 2 hours. TLC (petroleum etherEtOAc 2:1 ) indicated the reaction was completed. The mixture was diluted with NH4CI solution (50 mL) and the mixture was filtered. The filtrate was extracted with EtOAc (50 mL chi 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column eluting with petroleum etherEtOAc 3:1 to give (4-Methyl-thiazol-2-yl)-methanol (7 g, 70%) as a yellow oil.To a solution of (4-methyl-thiazol-2-yl)-methanol (7.0 g, 54.3 mmol) in DMF (80 mL) was added NBS (10.6 mg, 59.6 mmol), and the mixture was stirred at 50C overnight. TLC (petroleum etherEtOAc 2:1 ) indicated the reaction was completed. The mixture was diluted with H20 (50 mL) and extracted with EtOAc (50 mL chi 3). The combined organic layers were washed with brine (50 mL 3), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column (petroleum etherEtOAc 10:1 ) to give the title compound (1 1.2 g, 99%) as a brown solid.
	With sodium tetrahydroborate; In tetrahydrofuran; ethanol; at 0 - 20℃;	To a solution of 4-methyl-1,3-thiazole-2-carbaldehyde (300 mg) in THF (3 ml) and EtOH (3 ml) at 0C was added sodiumborohydride (267 mg). The mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue was suspended in CH2Cl2. The suspension was stirred for 2h and the obtained salts were filtered off. The filtrate was concentrated under vacuum to give 252 mg of the title compound as a yellow solid. 1H-NMR (delta, ppm, CDCl3): 7.43 (d, 1 H), 7.37(d, 1 H), 3.94 (s, 3H), 2.53(s, 3H).
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1h;	Example 1: Synthesis of Heterocycle AlcoholsExample 1.1: Methylthiazole Methanol; [0278] Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 0C was treated with n-BuLi (1.6 M, 7.56 niL) for 30 min, DMF (1.4 niL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material was disappeared (by TLC), the reaction mixture was recooled to 0 0C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aquoues NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), delta: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H).
28 g	With methanol; sodium tetrahydroborate; at 0 - 25℃; for 16h;	II. (4-Methylthiazol-2-yl)methanol To a suspension of 4-methylthiazole-2-carbaldehyde (67 g, 0.527 mol) in methanol (800 mL) stirred at 0 C was added NaBH4 (56.7 g, 1.5 mol) portionwise. After all the NaBH4 was added, the reaction mixture was stirred at 25 C for 16 hours. The reaction was quenched by water (800 mL) and extracted with ethyl acetate (500 mL x 3). The organic layers were combined and dried over anhydrous Na2S04 and filtered. The filtrate was concentrated and purified by flash chromatography with PE:EtOAc = 10: 1 to give (4- methylthiazol-2-yl)methanol (28 g, 217 mmol, 41 % yield) as red liquid: H NMR (400 MHz, CD3OD) delta 7.05 (s, 1H), 4.79 (s, 2H), 2.38 (s, 3H).
261 mg	With sodium tetrahydroborate; In methanol; at 0℃; for 3h;	4-Methyl-2-thiazole carboxaldehyde (350 mg) was added to methanol (10 mL), followed by dropwise adding sodium borohydride thereto. The solution was stirred at 0C for 3 hrs. The reaction mixture was extracted with dichloromethane (20 mL, three times) and an aqueous ammonium chloride solution (20 mL). The organic layers were pooled, dried over anhydrous magnesium sulfate, and subjected to vacuum filtration and vacuum distillation to afford the desired compound (261 mg).
1.3 g	With methanol; sodium tetrahydroborate; at -60℃; for 1h;Inert atmosphere;	Step 1 Synthesis of (4-methylthiazol-2-yl)methanol To a solution of 4-methylthiazole (1.0 g, 10.1 mmol) in THF (30 mL) was added n-BuLi (7.56 mL, 13.48 mmol) dropwise under a nitrogen atmosphere at -60 C. The reaction was stirred for 1 h; then DMF (1.4 ml, 18.2 mmol) was added dropwise while maintaining -60 C. The resulting mixture was stirred at this temperature for 30 min. The reaction was quenched with aqueous saturated ammonium chloride (5 mL) and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow oil. This oil was dissolved in methanol (15 ml) and sodium borohydride (460 mg, 12.1 mmol) was added portionwise under nitrogen atmosphere at -60 C. The mixture was stirred at this temperature for 1 h. The reaction mixture was quenched with acetone, warmed to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ ethyl acetate (3 : 1) to give (4-methylthiazol-2-yl)methanol (1 .3 g, 90.3%) as brown oil . LCMS retention time 0.375 min; LCMS MH+ 130.
1.3 g	With sodium tetrahydroborate; In methanol; at -60℃; for 1h;	To a solution of 4-methylthiazole (1.0 g, 10.1 mmol) in tetrahydrofuran (30 mL) was added n-BuLi (7.56 mL, 13.48 mmol) dropwise under a nitrogen atmosphere at -60 C. The reaction was stirred for 1 hour; then DMF (1.4 ml, 18.2 mmol) was added dropwise while maintaining -60 C. The resulting mixture was stirred at this temperature for 30 min. The reaction was quenched with aqueous saturated ammonium chloride (5 mL). The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow oil. This yellow oil was dissolved in methanol (15 ml) and sodium borohydride (460 mg, 12.1 mmol) was added portionwise under nitrogen atmosphere at -60 C. The mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with acetone, warmed to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (3:1) to give thiazol-2-ylmethanol (1.3 g, 90.3%) as brown oil. LCMS retention time 0.375 min; LCMS MH+ 130

Reference： [1]Patent: WO2009/42694,2009,A1 .Location in patent: Page/Page column 65
[2]Patent: WO2011/130383,2011,A1 .Location in patent: Page/Page column 80
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[4]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3098 - 3115
[5]Patent: WO2007/2181,2007,A2 .Location in patent: Page/Page column 134
[6]Patent: WO2013/142712,2013,A1 .Location in patent: Page/Page column 49
[7]Patent: WO2019/58393,2019,A1 .Location in patent: Paragraph 000367
[8]Patent: WO2012/88431,2012,A1 .Location in patent: Page/Page column 108
[9]Patent: WO2019/77631,2019,A1 .Location in patent: Paragraph 000133; 000330
[10]Patent: WO2011/138751,2011,A2 .Location in patent: Page/Page column 119-120
[11]Journal of Medicinal Chemistry,2005,vol. 48,p. 1367 - 1383
[12]Tetrahedron,2003,vol. 59,p. 1381 - 1387
[13]Patent: EP2080761,2009,A1 .Location in patent: Page/Page column 37-38
[14]Patent: WO2006/34277,2006,A1 .Location in patent: Page/Page column 59
[15]Patent: WO2013/149362,2013,A1 .Location in patent: Page/Page column 34
[16]Patent: WO2014/3483,2014,A1 .Location in patent: Page/Page column 46
[17]Patent: WO2014/143799,2014,A2 .Location in patent: Page/Page column 412; 413
[18]Patent: US2014/275528,2014,A1 .Location in patent: Paragraph 0355; 0356

6
[ 13750-63-5 ]
[ 202931-56-4 ]
C₂₂H₂₁N₅OS [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1367 - 1383

7
[ 7210-73-3 ]
[ 13750-63-5 ]

Yield	Reaction Conditions	Operation in experiment
60%		Method B: Alternatively, dissolve 4-methyl-thiazole-2-carboxylic acid ethyl ester (prepare in 27% yield according to the procedures essentially as described in Erlenmeyer, H., et al., HeIv. CHm. Acta (1944), 27, 1437-1438) (1.52 g, 8.88 mmol) in THF (6OmL) and add lithium borohydride (2.0M solution in THF, 9 mL, 17.8 EPO <DP n="136"/>mmol). Heat at reflux temperature for 18 h. Allow to cool to room temperature and dilute the reaction mixture with water (20 mL). Extract into ethyl acetate (3 x 50 mL). Dry the combined organic portions (MgSO4), filter, and concentrate in vacuo at 45 0C. Purify the crude product on silica gel (40 g) with 40 - 80% EtOAc/hexanes to give 690 mg (60%) of the title compound as a colorless oil.

Reference： [1]Patent: WO2007/2181,2007,A2 .Location in patent: Page/Page column 134-145

8
[ 13750-63-5 ]
[ 506-96-7 ]
[ 59311-22-7 ]

Yield	Reaction Conditions	Operation in experiment
53%	at 0 - 20℃; for 18h;	Preparation 37; 2-Bromomethyl-5-chloro-thiopheneCool (5-chloro-thiophen-2-yl)-methanol (Preparation 30) (330 mg, 2.22 mmol) to 0 0C and add acetyl bromide (709 mg, 430 muL, 5.76 mmol). Allow to warm to room temperature over 18 h, dilute with EtOAc (10 mL), and cautiously add saturated aqueous NaHCO3 (3 mL). When the carbon dioxide evolution stops, load the mixture onto a Varian Chem Elut CE1005 solid phase extraction cartridge (Varian part number 12198006). Elute with EtOAc, collect, and concentrate about 50 mL to obtain the crude product. Purify on silica gel (12 g) using 0-15% EtOAc/hexanes to afford 250 mg (53%) of the title compound as a yellow oil. MS (EI): 210,212; 1H NMR (CDCl3): delta 6.92 (d, IH, /=3.5 Hz), 6.78 (d, IH, /=4.0 Hz), 4.66 (s, 2H).

Reference： [1]Patent: WO2007/2181,2007,A2 .Location in patent: Page/Page column 137

9
[ 13750-63-5 ]
(Z)-4-methyl-2-(3-phenyloxiranyl)thiazole [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 1381 - 1387

10
[ 13750-63-5 ]
(E)-4-methyl-2-(3-phenyloxiranyl)thiazole [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 1381 - 1387

11
[ 13750-63-5 ]
4-methyl-2-(1-oxaspiro[2.5]oct-2-yl)thiazole [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 1381 - 1387

12
[ 13750-63-5 ]
(Z)-2-(1,3-diphenylaziridin-2-yl)-4-methylthiazole [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 1381 - 1387

13
[ 13750-63-5 ]
(E)-2-(1,3-diphenylaziridin-2-yl)-4-methylthiazole [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 1381 - 1387

14
[ 13750-63-5 ]
4-(4-methyl-thiazol-2-yl)-3-phenyl-butan-2-one [ No CAS ]

Reference： [1]Journal of the Chemical Society,1949,p. Spl. 113

15
[ 13750-63-5 ]
3-(4-methyl-thiazol-2-yl)-2-phenyl-propionitrile [ No CAS ]

Reference： [1]Journal of the Chemical Society,1949,p. Spl. 113

16
[ 68-12-2 ]
[ 13750-63-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1: Preparation of Selected Beta-Secretase Inhibitor Compounds; Example 1.1: Synthesis of tert-butyl 3-hydroxy-4-(3-methoxybenzylammo)-l- phenylbutan-2-ylcarbamate; [0215] Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 0C was treated with n-BuLi (1.6 M, 7.56 niL) for 30 min, DMF (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material was disappeared (by TLC), the reaction mixture was recooled to 0 0C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), delta: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H).

Reference： [1]Patent: WO2006/110668,2006,A1 .Location in patent: Page/Page column 49

17
[ 13750-63-5 ]
[ 124-63-0 ]
[ 918792-87-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;	Preparation 34; Methanesulfonic acid 4-methyl-thiazol-2-ylmethyl esterCombine 4-methyl-thiazol-2-yl)-methanol (Preparation 30) (1.00 g, 7.74 mmol) and triethylamine (1.25 g, 1.73 mL, 12.4 mmol) in dichloromethane (30 mL) with stirring and cool to 0 0C under nitrogen. Add methanesulfonyl chloride (931 mg, 633 muL, 8.13 mmol) to the reaction mixture and stir at 0 0C for 30 min. Warm to room temperature over 30 min, then dilute with water (40 mL) and dichloromethane (40 mL). Separate the layers, dry the organic portion (MgSO4), filter, and concentrate in vacuo at 40 0C to afford 1.15 g (72%) of the title compound as a brown oil. MS (ES): m/z 208 (M+l); 1H NMR (CDCl3): delta 7.03 (m, IH), 5.48 (s, 2H), 3.11 (s, 3H), 2.50 (d, 3H, 7=0.9 Hz).
	With triethylamine; In dichloromethane; at 0℃; for 0.333333h;	Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0 0C in dichloromethane . The resulting mixture was stirred for 20 minutes followed by quenching with aqueous NH4Cl. Evaporation of the solvent from the organic layer and flash chromatography of the residue afforded the corresponding mesylate as an oil. The mesylate (0.25g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62g, 9.6 mmol) was added. The mixture was heated to reflux for 2 hours followed by cooling and washing with aqueous NH4Cl. Evaporation of the solvent from the organic layer resulted in the corresponding azide. The azide (0.14g, 0.91 mmol) was EPO <DP n="52"/>dissolved in ethyl acetate, Pd(OH)2 (0.07g) was added, and the suspension was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through Celite. Evaporation of the solvent and flash chromatography of the residue afforded methylthiazole methylamine as a yellow oil. 1H-NMR: (300 MHz, CDCl3), delta: 6.74 (m, 1 H); 4.09 (m, 2 H); 2.37 (s, 3 H).
	With triethylamine; In dichloromethane; at 0℃; for 0.333333h;	Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0 0C in dichloromethane. The resulting mixture was stirred for 20 minutes followed by quenching with aqueous NH4Cl. Evaporation of the solvent from the organic layer and flash chromatography of the residue afforded the corresponding mesylate as an oil. The mesylate (0.25g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62g, 9.6 mmol) was added. The mixture was heated to reflux for 2 hours followed by cooling and washing with aqueous NH4Cl. Evaporation of the solvent from the organic layer resulted in the corresponding azide. The azide (0.14g, 0.91mmol) was dissolved in ethyl acetate, Pd(OH)2 (0.07g) was added, and the suspension was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through Celite. Evaporation of the solvent and flash chromatography of the residue afforded methylthiazole methylamine as a yellow oil. 1H-NMR: (300 MHz, CDCl3), d: 6.74 (m, 1 H); 4.09 (m, 2 H); 2.37 (s, 3 H).

	With triethylamine; In dichloromethane; at 0℃; for 0.333333h;	Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0 0C in dichloromethane. The resulting mixture was stirred for 20 minutes followed by quenching with aqueous NH4Cl. Evaporation of the solvent from the organic layer and flash chromatography of the residue afforded the corresponding mesylate as an oil. The mesylate (0.25g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62g, 9.6 mmol) was added. The mixture was heated to reflux for 2 hours followed by cooling and washing with aqueous NH4Cl. Evaporation of the solvent from the organic layer resulted in the corresponding azide. The azide (0.14g, 0.91mmol) was dissolved in ethyl acetate, Pd(OH)2 (0.07g) was added, and the suspension was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through Celite. Evaporation of the solvent and flash chromatography of the residue afforded the desired methylthiazole methylamine as a yellow oil. 1H-NMR: (300 MHz, CDCl3), d: 6.74 (m, 1 H); 4.09 (m, 2 H); 2.37 (s, 3 H).
	With triethylamine; In dichloromethane; at 0℃; for 0.333333h;	[0270] Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0 C in dichloromethane. The resulting mixture was stirred for 20 minutes followed by quenching with aqueous NH4C1. Evaporation of the solvent from the organic layer and flash chromatography of the residue afforded the corresponding mesylate as an oil. The mesylate (0.25g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62g, 9.6 mmol) was added. The mixture was heated to reflux for 2 hours followed by cooling and washing with aqueous NH4C1. Evaporation of the solvent from the organic layer resulted in the corresponding azide. The azide (0.14g, 0.91mmol) was dissolved in ethyl acetate, Pd(OH)2 (0.07g) was added, and the suspension was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through Celite. Evaporation of the solvent and flash chromatography of the residue afforded the desired methylthiazole methylamine as a yellow oil. 1H-NMR: (300 MHz, CDC13), delta: 6.74 (m, 1 H); 4.09 (m, 2 H); 2.37 (s, 3 H).
	With triethylamine; In dichloromethane; at 0℃; for 0.333333h;	Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0 C in dichloromethane. The resulting mixture was stirred for 20 minutes followed by quenching with aqueous NH4C1. Evaporation of the solvent from the organic layer and flash chromatography of the residue afforded the corresponding mesylate as an oil. The mesylate (0.25g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62g, 9.6 mmol) was added. The mixture was heated to reflux for 2 hours followed by cooling and washing with aqueous NH4C1. Evaporation of the solvent from the organic layer resulted in the corresponding azide. The azide (0.14g, 0.91mmol) was dissolved in ethyl acetate, Pd(OH)2 (0.07g) was added, and the suspension was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through Celite. Evaporation of the solvent and flash chromatography of the residue afforded the desired methylthiazole methylamine as a yellow oil. 1H-NMR: (300 MHz, CDC13), delta: 6.74 (m, 1 H); 4.09 (m, 2 H); 2.37 (s, 3 H).
	With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;	III. Methanesulfonic acid 4-methyl-thiazol-2-ylmethyl ester To a stirred solution of <strong>[13750-63-5](4-methyl-thiazol-2-yl)-methanol</strong> (1.5 g, 11.6 mmol) and Et3N (4.85 mL, 34.8 mmol) in DCM (50 mL) was added MsCl (2.7 mL, 34.8 mmol) in dropwise at 0C. After the additional, the mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched by water (15 mL), extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over Na2S04, filtered and concentrated in vacuum to give the crude product methanesulfonic acid 4-methyl-thiazol-2- ylmethyl ester (2.4 g, 100% yield): lR NMR (400 MHz, CDC13) delta 7.01 (s, 1H), 5.43 (s, 2H), 3.13 (s, 3H), 2.46 (s, 3H).

Reference： [1]Patent: WO2007/2181,2007,A2 .Location in patent: Page/Page column 136
[2]Patent: WO2006/110668,2006,A1 .Location in patent: Page/Page column 49-50
[3]Patent: WO2009/15369,2009,A2 .Location in patent: Page/Page column 75
[4]Patent: WO2009/42694,2009,A1 .Location in patent: Page/Page column 65
[5]Patent: WO2011/130383,2011,A1 .Location in patent: Page/Page column 79
[6]Patent: WO2012/54510,2012,A1 .Location in patent: Page/Page column 81-82
[7]Patent: WO2013/149362,2013,A1 .Location in patent: Page/Page column 34-35
[8]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 668 - 672

18
[ 13750-63-5 ]
[ 156-57-0 ]
[ 55904-83-1 ]
3-methoxy-4-{2-[(4-methylthiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;	EXAMPLE 39 When 2-chloromethyl-4-methyltriazole [prepared by the reaction of thionyl chloride and 2-hydroxymethyl-4-methylthiazole, which itself is prepared according to the procedure of J. Chem. Soc., (Suppl. Issue No. 1), S106-111 (1966) or Acta Chem. Scand., 20, 2649 (1966)] is reacted with cysteamine hydrochloride and about two equivalents of a strong base such as sodium methoxide, and the resultant amine is treated with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide, there is produced 3-methoxy-4-{2-[(4-methylthiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide.
	With thionyl chloride;	EXAMPLE 39 When 2-chloromethyl-4-methylthiazole [prepared by the reaction of thionyl chloride and 2-hydroxymethyl-4-methylthiazole, which itself is prepared according to the procedure of J. Chem. Soc., (Suppl. Issue No. 1), S106-111 (1966) or Acta Chem. Scand., 20, 2649 (1966)] is reacted with cysteamine hydrochloride and about two equivalents of a strong base such as sodium methoxide, and the resultant amine is treated with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide, there is produced 3-methoxy-4-{2-[(4-methylthiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide.

Reference： [1]Patent: US4471122,1984,A
[2]Patent: US4510309,1985,A

19
[ 13750-63-5 ]
[ 156-57-0 ]
[ 13623-94-4 ]
1-nitro-2-methylthio-2-{2-[(4-methylthiazol-2-yl)methylthio]ethylamino}ethylene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;	EXAMPLE 15 When 2-chloromethyl-4-methylthiazole [prepared by the reaction of thionyl chloride and 2-hydroxymethyl-4-methylthiazole, which itself is prepared according to the procedure of J. Chem. Soc., (Suppl. Issue No. 1), S106-111 (1966) or Acta Chem. Scand., 20, 2649 (1966)] is reacted with cysteamine hydrochloride and about two equivalents of a strong base such as sodium methoxide, and the resultant amine is treated with 1,1-bis(methylthio)-2-nitroethylene, there is produced 1-nitro-2-methylthio-2-{2-[(4-methylthiazol-2-yl)methylthio]ethylamino}ethylene.

Reference： [1]Patent: US4200578,1980,A

20
[ 50398-72-6 ]
[ 13750-63-5 ]
[ 156-57-0 ]
[ 10191-60-3 ]
N-cyano-N'-{2-[(4-methylthiazol-2-yl)methylthio]ethyl}-S-methylisothiourea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;	EXAMPLE 16 When 2-chloromethyl-4-methylthiazole [prepared from 2-hydroxymethyl-4-methylthiazole and thionyl chloride] is reacted with cysteamine hydrochloride and about two equivalents of a strong base such as sodium methoxide and the resultant amine treated with dimethyl cyanodithioimidocarbonate there is produced N-cyano-N'-{2-[(4-methylthiazol-2-yl)methylthio]ethyl}-S-methylisothiourea.

Reference： [1]Patent: US4200578,1980,A

21
[ 13750-63-5 ]
[ 79-37-8 ]
[ 82294-70-0 ]

Yield	Reaction Conditions	Operation in experiment
461.0 mg (87%)	In dichloromethane; dimethyl sulfoxide;	EXAMPLE 22D 4-methylthiazole-5-carboxaldehyde A 3-neck, 100 mL round-bottom flask was charged with anhydrous CH2Cl2 (15 mL) and oxalyl chloride (0.54 mL, 6.24 mmol) under N2 atmosphere. The mixture was cooled to -78 C. Anhydrous DMSO (0.59 mL, 8.32 mmol) was slowly added. The reaction was allowed to stir for 30 minutes. The product from Example 22C (537.5 mg, 4.16 mmol) in CH2Cl2 (5 mL) was slowly added. The reaction was allowed to stir for approximately 3 hours, until TLC (1:1 EtOAc/hexanes) showed no starting material. The reaction was quenched with triethylamine (2.4 mL, 16.64 mmol) and stirred for 10 minutes before warming to room temperature. The reaction was poured into Et2O (100 mL) and extracted with water (2*25 mL). The organic phase was washed with NaHCO3 (25 mL) and brine. The organic phase was dried (MgSO4) and concentrated under vacuum. The crude product was stored in the freezer to provide 461.0 mg (87%) of the title compound as an orange crystalline solid. 1H NMR (300 MHz, CDCl3) delta 10.15, s, 1H; 8.9, s, 1H; 2.8, s, 3H.

Reference： [1]Patent: US6277871,2001,B1

22
[ 693-95-8 ]
[ 68-12-2 ]
[ 13750-63-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1Synthesis of Heterocycle AlcoholsExample 1.1; Methylthiazole Methanol Methylthiazole (1.0 g, 10.1 mmol) in THF at -78 C. was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material was disappeared (by TLC), the reaction mixture was recooled to 0 C. and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqeuous NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), delta: 6.89 (s, 1H); 4.95 (s, 2H); 2.48 (s, 3H).
		Example 1.1: Synthesis of Amine Building Blocks.; Example 1.1.1: (4-methylthiazol-2-yl)methanamine; Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 0C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 rnL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 0C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), d: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H).
		[0269] Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4C1, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2S04, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDC13), delta: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H).

Methylthiazole (1.0 g, 10.1 mmol) in tetrahydrofuran (THF) at - 78 C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, dimethylformamide (DMF) (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 C and lithium aluminum hydride (LAH) (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4C1, diluted with ethyl acetate (EtOAc). The organic solution was separated, extracted twice with EtOAc, dried with Na2S04, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDC13), delta: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H).

Reference： [1]Patent: US2008/125467,2008,A1 .Location in patent: Page/Page column 19
[2]Patent: WO2009/42694,2009,A1 .Location in patent: Page/Page column 64-65
[3]Patent: WO2011/130383,2011,A1 .Location in patent: Page/Page column 79
[4]Patent: WO2012/54510,2012,A1 .Location in patent: Page/Page column 81

23
[ 13750-63-5 ]
[ 74124-79-1 ]
[ 881009-02-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine; In acetonitrile; at 20℃; for 15h;	Example 2.8Synthesis of Heterocycle Mixed Carbonate; To a stirred solution of 4-methyl thiazole methanol (0.47 g, 3.6 mmol) in CH3CN (15 mL) was added triethylamine (1.5 mL, 11 mmol) and N,N'-disuccinnimidyl carbonate (1.12 g, 4.4 mmol). The resulting mixture was stirred at room temperature for 15 h and was concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide mixed carbonate 8e (955 mg, 97%) which was used for next step without further purification.

Reference： [1]Patent: US2008/125467,2008,A1 .Location in patent: Page/Page column 24

24
[ 693-95-8 ]
[ 13750-63-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1.1: Synthesis of Amine Building Blocks.; Example 1.1.1: (4-methylthiazol-2-yl)methanamine; Methylthiazole (1.0 g, 10.1 mmol) in THF at - 78 0C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, DMF (1.4 rnL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 0C and LAH (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH4Cl, diluted with EtOAc. The organic solution was separated, extracted twice with EtOAc, dried with Na2SO4, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDCl3), d: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H).

Reference： [1]Patent: WO2009/15369,2009,A2 .Location in patent: Page/Page column 75

25
[ 13750-63-5 ]
[ 1137879-81-2 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene;Product distribution / selectivity;	Diphenylphosphoryl azide (DPPA) (1.2 eq) and l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (1.2 eq) were added to a stirred solution of <strong>[13750-63-5](4-methylthiazol-2-yl)methanol</strong> (1 eq) in 7 ml anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo. Purification via flash chromatography yielded2-(azidomethyl)-4-methylthiazole.
	With diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene;Inert atmosphere;	0272] Diphenylphosphoryl azide (DPPA) (1.2 eq) and l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (1.2 eq) were added to a stirred solution of <strong>[13750-63-5](4-methylthiazol-2-yl)methanol</strong> (1 eq) in 7 ml anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo.Purification via flash chromatography yielded2-(azidomethyl)-4-methylthiazole.
	With diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene;Inert atmosphere;	Diphenylphosphoryl azide (DPPA) (1.2 eq) and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.2 eq) were added to a stirred solution of <strong>[13750-63-5](4-methylthiazol-2-yl)methanol</strong> (1 eq) in 7 ml anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo.Purification via flash chromatography yielded2-(azidomethyl)-4-methylthiazole.

Reference： [1]Patent: WO2009/42694,2009,A1 .Location in patent: Page/Page column 65
[2]Patent: WO2011/130383,2011,A1 .Location in patent: Page/Page column 80
[3]Patent: WO2011/130383,2011,A1
[4]Patent: WO2012/54510,2012,A1
[5]Patent: WO2012/54510,2012,A1 .Location in patent: Page/Page column 82

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Yield	Reaction Conditions	Operation in experiment
99%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 50℃;	PREPARATION 115(5-Bromo-4-methyl-thiazol-2-yl)-methanolTo a solution of 4-methyl-thiazole (10 g, 100 mmol) in dry THF (300 mL) was added n- BuLi in hexane (60 mL, 150 mmol, 2.5 M) dropwise at -70C, and the mixture was stirred at -70C for 1.5 hour, DMF (12 mL) was added to the slurry over 15 min, and the mixture was stirred at -70C for 3 hours. TLC (petroleum etherEtOAc 10:1 ) indicated the reaction was completed. The mixture was warmed to 0C, and poured onto wet-ice. The mixture was acidified by 2N HCI to pH ~ 4, and extracted with EtOAc (100 mL chi 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuum to give 4-methyl-thiazole-2-carbaldhyde (10 g, 78.7%) as brown oil.To a solution of 4-methyl-thiazole-2-carbaldhyde (10.0 g, 78 mmol) in dry THF (80 mL) was added NaBH4 (1.49 g, 39 mmol), and the mixture was stirred at room temperature for 2 hours. TLC (petroleum etherEtOAc 2:1 ) indicated the reaction was completed. The mixture was diluted with NH4CI solution (50 mL) and the mixture was filtered. The filtrate was extracted with EtOAc (50 mL chi 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column eluting with petroleum etherEtOAc 3:1 to give (4-Methyl-thiazol-2-yl)-methanol (7 g, 70%) as a yellow oil.To a solution of <strong>[13750-63-5](4-methyl-thiazol-2-yl)-methanol</strong> (7.0 g, 54.3 mmol) in DMF (80 mL) was added NBS (10.6 mg, 59.6 mmol), and the mixture was stirred at 50C overnight. TLC (petroleum etherEtOAc 2:1 ) indicated the reaction was completed. The mixture was diluted with H20 (50 mL) and extracted with EtOAc (50 mL chi 3). The combined organic layers were washed with brine (50 mL 3), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column (petroleum etherEtOAc 10:1 ) to give the title compound (1 1.2 g, 99%) as a brown solid.
78%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 2h;	To a solution of 29 (10.0 g, 77 mmol) in MeCN (387 mL) was added NBS (13.8 g, 77.0 mmol) at room temperature. After being stirred for 2 h at room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with saturated aqueous NH4Cl solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 33% EtOAc in hexane) to give 12.6 g (78%) of 30 as yellow solid. 1H NMR (400 MHz, CDCl3)d 2.37 (3H, s), 2.74 (1H, brs), 4.85 (2H, s).
75%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 50℃; for 2h;	To a solution of thiazole 21a (720 mg, 5.58 mmol) in DMF (15 mL) was added NBS (1.1 g, 6.14 mmol) and the mixture was stirred at 50C for 2 hours. After the completion of the reaction, the mixture was diluted with water and was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue which was purified in ISCO max gradient 40% EtOAc/hexane to give the pure product (870 mg, 75% yield). 1H NMR (CDCl3, 400 MHz) 8: 4.83 (s, 2H), 4.01 (bs, 1H), 2.36 (s, 3H).

With N-Bromosuccinimide; In N,N-dimethyl-formamide;Reflux;

To a solution of Intermediate 53 (252 mg) in DMF was added N-bromosuccinimide (385 mg). The mixture was heated under reflux overnight. The solvent was evaporated under vacuum and the residue obtained was purified by column chromatography on silica gel using hexane/EtOAc as eluent to give 95 mg of the title compound as a brown solid. 1H-NMR (delta, ppm, CDCl3): 4.86 (s, 2H), 2.38 (s, 3H).

Reference： [1]Patent: WO2011/138751,2011,A2 .Location in patent: Page/Page column 119-120
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3098 - 3115
[3]Patent: WO2013/142712,2013,A1 .Location in patent: Page/Page column 49
[4]Patent: EP2080761,2009,A1 .Location in patent: Page/Page column 38

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Reference： [1]Patent: WO2011/130383,2011,A1
[2]Patent: WO2011/130383,2011,A1
[3]Patent: WO2012/54510,2012,A1
[4]Patent: WO2012/54510,2012,A1

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