[ CAS No. 558-42-9 ] {[proInfo.proName]}

Name: 558-42-9|1-Chloro-2-methyl-2-propanol|97%
Brand: Ambeed
SKU: A557630
Rating: 92 (30 reviews)

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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 558-42-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 558-42-9 ]

SDS Specification

Alternatived Products of [ 558-42-9 ]

Product Details of [ 558-42-9 ]

CAS No. :	558-42-9	MDL No. :	MFCD00021807
Formula :	C₄H₉ClO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JNOZGFXJZQXOSU-UHFFFAOYSA-N
M.W :	108.57	Pubchem ID :	68409
Synonyms :

Calculated chemistry of [ 558-42-9 ]

Physicochemical Properties

Num. heavy atoms :	6
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	27.34
TPSA :	20.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.43 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.51
Log Po/w (XLOGP3) :	0.75
Log Po/w (WLOGP) :	1.0
Log Po/w (MLOGP) :	1.16
Log Po/w (SILICOS-IT) :	0.78
Consensus Log Po/w :	1.04

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	3.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.92
Solubility :	13.1 mg/ml ; 0.12 mol/l
Class :	Very soluble
Log S (Ali) :	-0.75
Solubility :	19.1 mg/ml ; 0.176 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.08
Solubility :	8.95 mg/ml ; 0.0824 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.77

Safety of [ 558-42-9 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P261-P305+P351+P338	UN#:	1987
Hazard Statements:	H225-H315-H319-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 558-42-9 ]

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

Upstream synthesis route of [ 558-42-9 ]
Downstream synthetic route of [ 558-42-9 ]

[ 558-42-9 ] Synthesis Path-Upstream 1~3

1
[ 558-42-9 ]
[ 3587-64-2 ]

Reference： [1] Patent: US5663200, 1997, A,

2
[ 558-42-9 ]
[ 124-41-4 ]
[ 3587-64-2 ]

Reference： [1] Journal of the American Chemical Society, 1953, vol. 75, p. 155,157

3
[ 558-42-9 ]
[ 28075-29-8 ]
[ 100442-33-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 1998, vol. 33, # 5, p. 399 - 420

[ 558-42-9 ] Synthesis Path-Downstream 1~88

1
[ 109-06-8 ]
[ 558-42-9 ]
[ 18144-09-7 ]
(Ot-bu-Cl)(Ot-bu)SiCl₂ [ No CAS ]

Reference： [1]Patent: US2566363,1946,

2
[ 594-37-6 ]
[ 558-42-9 ]

Reference： [1]Journal of the American Chemical Society,1936,vol. 58,p. 1011
[2]Journal of the American Chemical Society,1936,vol. 58,p. 1011
[3]Journal of the Chemical Society,1956,p. 3337,3342,3344

3
[ 558-42-9 ]
[ 64-17-5 ]
[ 151-50-8 ]
[ 13635-04-6 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1910,vol. 29,p. 59
Chemisches Zentralblatt,1909,vol. 80,p. 1982

4
[ 558-42-9 ]
[ 44855-57-4 ]
(β-hydroxy-isobutyl)-(1-methyl-heptyl)-amine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1943,vol. 65,p. 1222,1223

5
[ 558-42-9 ]
[ 111-26-2 ]
hexylamino-<i>tert</i>-butyl alcohol [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1943,vol. 65,p. 1222,1223

6
[ 558-42-9 ]
[ 111-68-2 ]
heptylamino-<i>tert</i>-butyl alcohol [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1943,vol. 65,p. 1222,1223

7
[ 558-42-9 ]
[ 36776-27-9 ]
[ 856977-04-3 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 1009,1011

8
[ 558-42-9 ]
[ 2218-96-4 ]
[ 856978-60-4 ]

Reference： [1]Journal of the Chemical Society,1951,p. 774,779

9
[ 558-42-9 ]
[ 124-41-4 ]
[ 3587-64-2 ]

Reference： [1]Journal of the American Chemical Society,1953,vol. 75,p. 155,157

10
[ 558-42-9 ]
[ 1074-82-4 ]
[ 167108-05-6 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium iodide; In N,N-dimethyl-formamide;Heating / reflux;	A solution of 1-chloro-2-methyl-2-propanol (2.23 g, 97percent, 0.02 mol), potassium phthalimide (3.780 g, 98percent, 0.02 mol) and sodium iodide (60 mg, 4 mmol) in anhydrous DMF (40 mL) was heated to reflux overnight. The solvent was evaporated under reduced pressure. The resulting product was triturated with a mixture of 3:2 ethyl acetate/hexanes and the ensuing white precipitate was removed by filtration. The yellow filtrate was concentrated under reduced pressure and purified by flash chromatography in a mixture of 2:3 ethyl acetate/hexanes. The impure product thus isolated was triturated with hot hexanes (125 mL) and filtered to remove an insoluble white impurity. After evaporation of the solvent under reduced pressure, the obtained white solid was recrystallized in hexanes. The product was yielded as colorless crystals that were collected by filtration and dried under high vacuum (1.63 g, 37percent yield). m.p.: 104-105° C.; TLC Rf 0.20 (2:3 ethyl acetate/hexanes); FTIR (KBr): 3524, 3456, 3097, 3031, 2973, 2930, 1773, 1698, 1611, 1466, 1427, 1389, 1319, 1190, 1076, 990, 965, 912, 890, 838, 766, 724, 712, 638 cm-1; 1H-NMR(500 MHz, CDCl3): delta 1.26 (s, 6H, 2 CH3), 2.74 (s, 1H, OH), 3.75 (s, 2H, CH2), 7.72 (dd, 2H, Jo=5.44 Hz, Jm=3.04 Hz, 2 Hc),, 7.85 (dd, 2H, Jo=5.42 Hz, Jm=3.06 Hz, 2 Hb); 13C-NMR(126 MHz, CDCl3): delta 27.6 (2 CH3), 49.3 (CH2), 71.6 (CMe2), 123.6 (2 Cb), 132.0 (2 Ca), 134.3 (2 Cc), 169.3 (2 CO).

Reference： [1]Patent: US2008/102028,2008,A1 .Location in patent: Page/Page column 9; 10
[2]Chemische Berichte,1921,vol. 54,p. 3160

11
[ 558-42-9 ]
[ 2624-31-9 ]
palmitic acid-(β-hydroxy-isobutyl ester) [ No CAS ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1943,vol. 63,p. 477,486
Chem.Abstr.,1950,p. 7233

12
[ 558-42-9 ]
[ 151-50-8 ]
[ 13635-04-6 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1910,vol. 29,p. 59
Chemisches Zentralblatt,1909,vol. 80,p. 1982

13
[ 558-42-9 ]
[ 558-30-5 ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 3122 - 3128
[2]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1907,vol. 145,p. 438
[3]Patent: DE199148,
[4]Zhurnal Russkago Fiziko-Khimicheskago Obshchestva,1902,vol. 34,p. 307
Chemisches Zentralblatt,1902,vol. 73,p. 19
[5]Zhurnal Russkago Fiziko-Khimicheskago Obshchestva,1902,vol. 34,p. 307
Chemisches Zentralblatt,1902,vol. 73,p. 19
[6]ChemBioChem,2013,vol. 14,p. 870 - 881

14
[ 558-42-9 ]
[ 2074-80-8 ]

Reference： [1]Chemische Berichte,1958,vol. 91,p. 2130,2140
[2]Journal of Organic Chemistry USSR (English Translation),1965,vol. 1,p. 714 - 718
Zhurnal Organicheskoi Khimii,1965,vol. 1,p. 714 - 718

15
[ 558-42-9 ]
[ 14967-17-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2451

16
[ 558-42-9 ]
[ 78-84-2 ]

Reference： [1]Chemisches Zentralblatt,1902,vol. 73,p. 20
[2]Chemisches Zentralblatt,1902,vol. 73,p. 20
[3]Patent: US2042225,1934,

17
[ 513-37-1 ]
[ 558-42-9 ]

Reference： [1]Industrial and Engineering Chemistry,1941,vol. 33,p. 385
[2]Industrial and Engineering Chemistry,1941,vol. 33,p. 385
[3]Industrial and Engineering Chemistry,1941,vol. 33,p. 385
[4]Industrial and Engineering Chemistry,1941,vol. 33,p. 385
[5]Industrial and Engineering Chemistry,1941,vol. 33,p. 385
[6]Patent: US2042222,1934,
[7]Patent: US2042222,1934,
[8]Patent: US2042222,1934,
[9]Patent: US2042222,1934,
[10]Patent: US2042222,1934,

18
[ 558-42-9 ]
[ 5169-95-9 ]
[ 109042-57-1 ]

Reference： [1]Patent: US2756229,1953,

19
[ 558-42-9 ]
[ 103-71-9 ]
[ 91131-41-8 ]

Reference： [1]Journal of Organic Chemistry,1970,vol. 35,p. 3291 - 3295

20
[ 558-42-9 ]
[ 60-24-2 ]
[ 26475-41-2 ]

Reference： [1]Journal of general chemistry of the USSR,1964,vol. 34,p. 2362 - 2366
Zhurnal Obshchei Khimii,1964,vol. 34,p. 2350 - 2354

21
[ 558-42-9 ]
[ 65567-06-8 ]
[ 110102-84-6 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1987,p. 2273 - 2280

22
[ 558-42-9 ]
[ 42287-37-6 ]

Yield	Reaction Conditions	Operation in experiment
1.98 g	With hydrazine hydrate; In ethanol;Reflux;	A mixture of 1a (20.0 g, 400.0 mmol) and 1b (2.17 g, 20.0 mmol) in ethanol (50 mL) was refluxed overnight, then evaporated under high vacuum. The residue was dissolved in ethanol and the resulting solid was filtered off. The filtrate was concentrated to give crude 1c (1.98 g, 95percent) which was used directly for the next step.
	With hydrazine hydrate; sodium hydroxide; at 95℃;	Step 1: Intermediate 48-b To a mixture of sodium hydroxide (7.37 g, 184.0 mmol) and hydrazine monohydrate (46.10 g, 921.0 mmol) heated to 95°C, was added l-chloro-2- methylpropan-2-ol (20.00 g, 184.0 mmol). The reaction was stirred overnight at 95 °C and then cooled to room temperature. Volatiles were removed under reduced pressure. THF (40 mL) and diethyl ether (40 mL) were added to the residue; a precipitate formed which was removed by filtration. The filtrate was concentrated under reduced pressure to provide intermediate 48-b as a colorless oil.

Reference： [1]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 1529 - 1532
[2]Patent: US2013/72481,2013,A1 .Location in patent: Paragraph 0271-0272
[3]Patent: WO2013/177668,2013,A1 .Location in patent: Page/Page column 80

23
[ 829-95-8 ]
[ 558-42-9 ]
[ 63196-87-2 ]
[ 880-22-8 ]
[ 112425-40-8 ]

Reference： [1]Phosphorus and Sulfur and the Related Elements,1987,vol. 29,p. 265 - 270

24
[ 829-95-8 ]
[ 558-42-9 ]
[ 63196-87-2 ]
[ 112425-40-8 ]
4,4,6-trimethylisothiochroman [ No CAS ]

Reference： [1]Phosphorus and Sulfur and the Related Elements,1987,vol. 29,p. 265 - 270

25
[ 829-95-8 ]
[ 558-42-9 ]
[ 880-22-8 ]
[ 112425-40-8 ]
4,4,6-trimethylisothiochroman [ No CAS ]

Reference： [1]Phosphorus and Sulfur and the Related Elements,1987,vol. 29,p. 265 - 270

26
[ 558-42-9 ]
[ 105-13-5 ]
[ 154044-75-4 ]

Reference： [1]Tetrahedron,1994,vol. 50,p. 10289 - 10298

27
[ 558-42-9 ]
[ 5538-51-2 ]
2-Acetoxy-benzoic acid 2-chloro-1,1-dimethyl-ethyl ester [ No CAS ]
[ 132305-33-0 ]

Reference： [1]Acta Chemica Scandinavica,1990,vol. 44,p. 952 - 956
[2]Acta Chemica Scandinavica,1990,vol. 44,p. 952 - 956

28
[ 558-42-9 ]
[ 2873-29-2 ]
[ 121237-58-9 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 6585 - 6588

29
[ 5463-09-2 ]
[ 558-42-9 ]
1-(6-amino-2-butylamino-purin-9-yl)-2-methyl-propan-2-ol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2088 - 2095

30
[ 305379-28-6 ]
[ 558-42-9 ]
1-(4-{5-[4-(3,4-Dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazin-1-yl)-2-methyl-propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With sodium carbonate; In ethanol;	Example 102 1-(4-{5-[4-(3,4-Dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazin-1-yl)-2-methyl-propan-2-ol: (Reference: Ind. Acad. Sci. 1939, 49, 101-4.) A solution of 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (155 mg, 0.41 mmol), sodium carbonate (66 mg, 0.62 mmol, 1.5 equiv) and 1-chloro-2-methyl-propan-2-ol (51 mul, 53 mg, 0.50 mmol, 1.2 equiv) in 50percent aqueous ethanol (20 ml) under nitrogen atmosphere was heated at reflux overnight.. The reaction mixture was then diluted with brine and extracted with ethyl acetate (3*25 ml).. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and -concentrated in vacuo.. Purification of the residue by flash column chromatography (50percent THF/0.5percent ammonium hydroxide/hexanes) provided the desired product (100 mg, 54percent). MS m/z 446 (M++1).
54%	With sodium carbonate; In ethanol;	EXAMPLE 102 1-(4-{5-[4-(3,4-Dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazin-1-yl)-2-methyl-propan-2-ol: (Reference: Ind. Acad. Sci. 1939, 49,101-4.) A solution of 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (155 mg, 0.41 mmol), sodium carbonate (66 mg, 0.62 mmol, 1.5 equiv) and 1-chloro-2-methyl-propan-2-ol (51 mul, 53 mg, 0.50 mmol, 1.2 equiv) in 50percent aqueous ethanol (20 ml) under nitrogen atmosphere was heated at reflux overnight. The reaction mixture was then diluted with brine and extracted with ethyl acetate (3*25 ml). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (50percent THF/0.5percent ammonium hydroxide/hexanes) provided the desired product (100 mg, 54percent). MS m/z 446 (M++1).

Reference： [1]Patent: US6355635,2002,B1 .Location in patent: Page column 71
[2]Patent: US2001/39277,2001,A1

31
[ 784156-96-3 ]
[ 558-42-9 ]
[ 784156-57-6 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (5S)-N2, N2-bis (tert-butoxycarbonyl)-5- (2, 3-difluorophenyl)-D-lysine (0.569 g, 1.24 MMOL), 1-CHLORO-2-METHYL-2-PROPANOL (0.202 g, 1.86 mmol) and DIISOPROPYLETHYLAMINE (0.529 g, 4.10 mmol) in ETOH (5 mL) was heated at 75 oC overnight. The reaction was concentrated to dryness, diluted with DCM (20 mL) and EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) were added followed by DIISOPROPYLETHYLAMINE (0.650 ML, 3.73 MMOL). After stirring overnight, NAHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (10percent- 35percent EtOAc/ hexanes) to give the title compound (0.21 g). MS 513.1 (M+1). H NMR (500 MHz, CD30D) 5 7.1 (M, 3H), 5.24 (d, J = 10.7 Hz, 1H), 4.02 (M, 1H), 3.69 (d, J = 13.9 Hz, 1H), 3.60 (d, J = 15. 1 Hz, 1H), 3.39 (m, 1H), 3. 24 (d, J = 14.2 Hz, 1H), 2.4 (m, 1H), 2.1 (m, 3H), 1.5 (s, 18H), 1.20 (s, 3H), 1.16 (s, 3H).
		A mixture of (5S)-N2r/V2-bis(/ert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine(0.569 g, 1.24 mmol, described in Intermediate 4), l-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and lambdayV-diisopropylethylamine (0.713 mL, 4.10 mmol) in EtOH (5 mL) was heated at 75 0C for 18 h. The reaction mixture was concentrated to dryness under reduced pressure and the <n="51"/>residue was dissolved in CH2Cl2 (20 mL), then EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) and N^V-diisopropylethylamine (0.650 mL, 3.73 mmol) were added. The resulting mixture was stirred at ambient temperature for 18 h, then aqueous NaHCO3 was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 90:10 to 65:35, to give the title compound. MS: mlz = 513 (M + 1).

Reference： [1]Patent: WO2004/92166,2004,A2 .Location in patent: Page 109
[2]Patent: WO2008/153849,2008,A1 .Location in patent: Page/Page column 49-50

32
[ 784156-96-3 ]
[ 558-42-9 ]
C₂₆H₄₀F₂N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; at 75℃;	INTERMEDIATE 13; (3R.6S)-3-Amino-6-('2.3-difluorophenylVl-(2-hydroxy-2-methylpropyl')azepan-2-one; Step A. Di-fert-butyl r(3R.66f)-6-(;2.3-difluorophenylVl-(;2-hvdroxy-2-methylpropylV2-oxoazepan-3- yl] imidodicarbonate; A solution of (55)-N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.569 g, 1.24 mmol), l-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and diisopropylethylamine (0.529 g, 4.10 mmol) in EtOH (5 mL) was heated at 75 0C overnight. The reaction was concentrated to dryness, diluted with DCM (20 mL) and EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) were added followed by diisopropylethylamine (0.650 mL, 3.73 mmol). After stirring overnight, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (10percent --> 35percent EtOAc / hexanes) to give the title compound (0.21 g). MS 513.1 (M+l). 1HNMR (500 MHz, CD3OD) delta 7.1 (m, 3H), 5.24 (d, J= 10.7 Hz, IH), 4.02 (m, IH), 3.69 (d, J= 13.9 Hz, IH), 3.60 (d, EPO <DP n="74"/>J= 15.1 Hz, IH), 3.39 (m, IH), 3.24 (d, J= 14.2 Hz, IH), 2.4 (m, IH), 2.1 (m, 3H), 1.5 (s, 18H), 1.20 (s, 3H), 1.16 (s, 3H).

Reference： [1]Patent: WO2006/41830,2006,A2 .Location in patent: Page/Page column 72-73

33
[ 558-42-9 ]
[ 33141-66-1 ]
[ 908247-81-4 ]

Yield	Reaction Conditions	Operation in experiment
26%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;	Intermediate 12; Preparation of 4-(3,3-dimethylbut-1-ynyl)-3-(2-hydroxy-2-methylpropxy)benzoic acid; Ethyl 3-(2-hydroxy-2-methylpropoxy)-4-bromobenzoate; Ethyl 4-bromo-3-hydroxybenzoate (1.5 g, 6.12 mmol), potassium carbonate (5.07 g, 36.72 mmol) and 1-chloro-2-methylpropan-2-ol (0.75 mL, 7.34 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under vacuum to an oil. Purification by column chromatography on silica gel using EtOAc/hexane (0-50percent) gave the product (0.5 g, 26percent) as a yellow oil.

Reference： [1]Patent: US2006/194801,2006,A1 .Location in patent: Page/Page column 34

34
[ 121-32-4 ]
[ 558-42-9 ]
3-ethoxy-4-(2-hydroxy-2-methyl-propoxy)-benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		67.1 In analogy to Example 64.1, from 3-ethoxy-4-hydroxy-benzaldehyde and 1-chlor-2-methyl-2-propanol there was obtained 3-ethoxy-4-(2-hydroxy-2-methyl-propoxy)-benzaldehyde.

Reference： [1]Patent: US2001/1799,2001,A1

35
ammonium chloride [ No CAS ]
[ 676-58-4 ]
[ 78-95-5 ]
[ 558-42-9 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; diethyl ether;	a 1-Chloro-2-hydroxy-2-methylpropane A solution of 46.3 g (0.5 mol) of 1-chloro-2-propanone in 50 ml of anhydrous diethyl ether was added dropwise with stirring at 0° to 5° C. to 44.9 g (0.6 mol) of methyl magnesium chloride in the form of a 20percent strength solution in tetrahydrofuran and 200 ml of dry diethyl ether. The mixture was then stirred first at room temperature for one hour and then with boiling under reflux for a further hour, the tertiary alkoxide formed was decomposed by addition of 50percent strength aqueous ammonium chloride solution, the ether phase was separated off and the aqueous phase was extracted by shaking with ether. The combined ethereal extracts were washed successively with aqueous sodium hydrogen sulfite and sodium hydrogen carbonate solution and a little water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the liquid residue was subjected to fractional distillation. Yield: 31.1 g (57.3percent of theory) Boiling point: 125-127° C. C4H9 ClO (MW=108.6) It was also possible to prepare the compound in an analogous manner from methyl or ethyl chloroacetate using twice the molar amount of methyl magnesium chloride in yields of around 60percent of theory.

Reference： [1]Patent: US2002/10333,2002,A1

36
[ 558-42-9 ]
[ 141-43-5 ]
[ 39216-89-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In methanol;	2,2-Dimethylmorpholine hydrochloride 1-Chloro-2-methyl-2-propanol (135 ml) was added dropwise over 10 min to stirred 2-aminoethanol (400 ml) at 10° C. under nitrogen. The cooling bath was then removed and stirring was continued at room temperature for 48 h. A solution of sodium hydroxide (48.8 g) in methanol (440 ml) was added and the resulting white suspension was stirred for 10 min. The mixture was filtered through a pad of kieselguhr and the filtrate was concentrated under reduced pressure. The residual oil was distilled in vacuo to give 1-[(2-hydroxyethyl)amino]-2-methyl-2-propanol (133 g).

Reference： [1]Patent: US5593983,1997,A

37
[ 558-42-9 ]
[ 3587-64-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol;	87a 1-Methoxy-2-methyl-2-propanol 10.8 g (0.1 mol) of 1-chloro-2-methyl-2-propanol (Lancaster Synthesis, Bischheim, France) in 30 ml of methanol is treated, under argon, with 20.4 ml of a solution of sodium methoxide (110 mmol; 1.1 equivalents) in methanol, and the mixture is boiled under reflux for 2.5 h. After the reaction has ended, the precipitate is filtered off and the solvent is distilled off via a Vigreux column, and the residue is distilled at standard pressure, yielding the title compound: 1 -H-NMR (200 MHz; CDCl3)=3.33/s (3H); 3.15/s (2H); 1.13/s (6H). FAB-MS (M+H)+ =105. [see, also Amer., Soc. 75, 155 (1953)].

Reference： [1]Patent: US5663200,1997,A

38
[ 558-42-9 ]
[ 120-80-9 ]
[ 107189-19-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In methanol; water;	EXAMPLE 1 Preparation of 2-(2-hydroxy-2-methylpropoxy)phenol from 1-chloro-2-methyl-2-propanol Catechol (11.0 g, 0.10 mole), sodium carbonate (10.6 g, 0.10 mole) and 100 g methanol were combined in a 250 ml 3-necked round bottom flask equipped with an air stirrer, heating mantle, condenser and thermometer, and heated to reflux (approximately 65° C.). 1-Chloro-2-methyl-2-propanol (10.9 g, 0.10 mole) was added by syringe. The mixture was refluxed for 3 hours, then left standing overnight. Water (40 ml) was added and the mixture was refluxed for 2 hours. After cooling, the water was extracted three times with 100 ml of dichloromethane. The combined dichloromethane layers were washed twice with 100 ml of water, then concentrated to afford 4.40 g (24percent) of waxy yellow solid. Recrystallization from ethyl acetate (10 g) and hexane (50 g) gave a white solid. 1 Hnmr analysis was consistent with the structural formula of 2-(2-hydroxy-2-methylpropoxy)phenol. Analysis: Cald., C 65.91percent, H, 7.74percent; found, C 65.85, 66.05, H 7.66, 7.66.

Reference： [1]Patent: US4639536,1987,A

39
[ 558-42-9 ]
[ 4198-90-7 ]
[ 924300-38-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In ethanol; water; for 24h;Heating / reflux;	To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol) and 1-chloro-2-methyl propan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 mL) was added potassium carbonate (7.5 g, 54 mmol) and water (5 mL). The reaction EPO <DP n="98"/>mixture was stirred at reflux for 24 hours. Cooled to room temperature. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 ml_) and dried over anhydrous Na2SO4. Removal of solvent gave 4-(2-hydroxy-2- methylpropoxy)-3,5-dimethyl benzonitrile (2.9 g, 97percent) as a white solid. To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and tert- butyldimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 days. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solventwas removed under reduced pressure and the crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 10percent ethyl acetate in hexanes as eluent) to give 4-[2-(te/?-butyldimethylsilanyloxy)-2-methylpropoxy]- 3,5-dimethylbenzonitrile (2.24 g, 54percent). n-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-/V- dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 mL) dropwise at - 1O0C over a period of 10 min under nitrogen. The stirring was continued at O0C for 1 hour. The reaction mixture was cooled to -5O0C. A solution of 4-[2-(tert- butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued at room temperature for 1 hour. Aqueous ammonium chloride solution (10 mL) was added. Ethyl acetate (100 mL) was added. The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 0-5percent methanol in CH2CI2 as eluent) to give 3-{4-[2-(terf-butyldimethylsilanyloxy)-2-methylpropoxy]- 3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37percent) of as white solid. The above compound (0.42 g, 0.82 mmol) was dissolved in anhydrous THF (20 mL). Tetrabutyl ammonium fluoride (4.1 mL, 1.0M solution in THF) was added at O0C. The reaction mixture was stirred at O0C for 10 min, then at room temperature for 2 h and then stirred at 7O0C for 24 hours. The mixture was cooled EPO <DP n="99"/>to room temperature. Saturated aqueous ammonium chloride (30 ml_) was added. The organic phase was separated, washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (Silica Gel 230-400 mesh; 0-4percent methanol in CH2CI2 as eluent) to give 3-(4-(2-hydroxy-2-methylpropoxy)-3,5- dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (0.15 g, 46percent) as a white solid. MS (ES) m/z: 398.96 (M+1 ); MP 252-2540C
97%	With potassium carbonate; In ethanol; water; for 24h;Heating / reflux;	To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol) and 1-chloro-2-methyl propan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 mL) was added potassium carbonate (7.5 g, 54 mmol) and water (5 mL). The reaction mixture was stirred at reflux for 24 h and cooled to room temperature. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.9 g, 97percent) as a white solid.To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and tert-butyidimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 d. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2.x.100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4-[2-(tert-butyidimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (2.24 g, 54percent). N-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at -10° C. over a period of 10 min under nitrogen. The stirring was continued at 0° C. for 1 h. The reaction mixture was cooled to -50° C. A solution of 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued at room temperature for 1 h. An aqueous ammonium chloride solution (10 mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5percent methanol in CH2Cl2 as eluent) to give 3-{4-[2-(tert-butyidimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylphenyll-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37percent), as a white solid.The above compound (0.42 g, 0.82 mmol) was dissolved in anhydrous THF (20 mL). Tetrabutylammonium fluoride (4.1 mL, 1.0 M solution in THF) was added at 0° C. The reaction mixture was stirred at 0° C. for 10 min, then at room temperature for 2 h and then stirred at 70° C. for 24 h. The mixture was cooled to room temperature. Saturated aqueous ammonium chloride (30 mL) was added. The organic layer was separated, washed with water, brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh; 0-4percent methanol in CH2Cl2 as eluent) to give 3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (0.15-g, 46percent), as a white solid. Selected data: MS (ES) m/z: 397.98; MP 252-254° C. at decomposition.
97%	With potassium carbonate; In ethanol; water; at 20℃; for 24h;Reflux;	To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol) and 1-chloro-2-methyl propan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 mL) was added potassium carbonate (7.5 g, 54 mmol) and water (5 mL). The reaction mixture was stirred at reflux for 24 h and cooled to room temperature. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.9 g, 97percent) as a white solid.

97%	With potassium carbonate; In ethanol; water; for 24h;Reflux;	4-hydroxy-3,5-dimethyl-benzonitrile (2.00g, 13.5mmol) and 1-chloro-2-methyl-2-ol (8.85g, 81.5mmol) in ethanol(50 mL) of was added potassium carbonate (7.5g,54mmol) and water (5mL). The reaction mixture was stirred at reflux for 24 hours,cooled to room temperature. The precipitated solid was filtered off, washedwith water. The solid was dissolved in ethyl acetate (100 mL) in water (50 mL),brine (50 mL), dried over anhydrous Na 2SO 4dry. The solvent was removed togive 4- (2-hydroxy-propoxy) -3,5-dimethyl-benzonitrile(2.9g, 97percent) as a white solid. 4-(2-hydroxy-2-methyl-propoxy) -3,5-dimethyl-benzonitrile (2.90g, 13.2mmol) wasadded imidazole (2.7g in dry DMF (20mL) in a solution, 40mmol) andtert-butyldimethylsilyl chloride (2.19g, 14.6mmol). At room temperature, thereaction mixture was stirred under nitrogen for 3 days. Was added water(200mL), and the mixture was extracted with ethyl acetate (200mL). The organiclayer was washed with water (2 × 100mL) and brine (100 mL), dried over anhydrousNa 2SO 4dry. The solvent was removed under reduced pressure and the crudecompound was purified by column chromatography to give 4- [2-(tert-butyldimethylsilyloxy) -2-methyl-propoxy] -3,5 methyl-benzonitrile(2.24g, 54percent). At -10 deg.] C, over 10 minutes, under nitrogen n-butyllithium(6.2mL, 6.6mmol, 1.6M solution in hexane) was added dropwise to 2,4-dimethoxy-6-N- dimethyl-benzamide (0.9g, 4.3mmol) in anhydrous THF (10mL) in a solution.Stirring was continued at 0 1 hour. Thereaction mixture was cooledto -50 . Rapidly added 4- [2-(tert-butyldimethylsilyloxy) -2-methyl-propoxy] -3,5-dimethyl-benzonitrile(1.58g, 4.73mmol) in dry THF ( 5mL) was added. The cooling bath was removed andthe reaction mixture was allowed to warm to room temperature. Stirring was continued at room temperaturefor 1 hour. Was added aqueous ammonium chloride solution (10mL), then ethylacetate (100mL). The organic layer was separated, which was washed with water(10 mL), dried (Na 2SO 4). The solvent was removed under reduced pressure, andthe crude compound by column chromatography (silica gel 230-400 mesh; used inCH 2Cl 20-5percent methanol as eluant) to afford a white solid 3- {4- [2-(tert-butyldimethylsilyloxy) -2-methyl propoxy] -3 ,5-dimethyl-6,8-dimethoxy-phenyl} -2H- isoquinolin-1-one (0.82g, 37percent). The abovecompound (0.42g, 0.82mmol) was dissolved in anhydrous THF (20mL) in. At 0 was added tetrabutylammonium fluoride (4.1mL,1.0M solution in THF). At 0 The reactionmixture was stirred for 10 minutes, then stirred at room temperature for 2 hours, then stirred at 70 24 hours. The mixture was cooled to roomtemperature. Saturated ammonium chloride solution (30mL). The organic layer wasseparated, which was washed with water, brine, dried over anhydrous Na 2SO 4dry. The solvent was removed underreduced pressure. The crude product was purified by column chromatography(silica gel 230-400 mesh; used in CH 2Cl 20-4percent methanol as eluant) to afford awhite solid of 3- (4- (2-hydroxy-propoxy) -3,5-dimethylphenyl) -6 , 8--dimethoxy isoquinoline -1 (2H) - one (0.15-g, 46percent). Selected data: MS (ES) m /z: 397.98; MP252-254 ,decomposition.
97%	With potassium carbonate; In ethanol; water; for 24h;Heating / reflux;	To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol) and 1-chloro-2-methyl propan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 mL) was added potassium carbonate (7.5 g, 54 mmol) and water (5 ml_). The reaction mixture was stirred at reflux for 24 h and cooled to RT. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), and dried over anhydrous Na2SCU. Removal of solvent gave 4-(2-hydroxy-2-methylpropoxy)-3,5- dimethyl benzonitrile (2,9 g, 97percent) as a white solid.[0113] To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and terf-butyldimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at RT under nitrogen for 3 d. Water (200 mL) was <n="60"/>added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4-[2-(tert- butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (2.24 g, 54percent). n-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-/v"-dimethylbenzarnide (0,9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at -10°C over a period of 10 rnin under nitrogen. The stirring was continued at 0"C for 1 h. The reaction mixture was cooled to -50°C. A solution of 4-[2-(tert-butyidimethylsilanyloxy)-2-methylpropoxy]-3,5- dimethylbenzonitrile (1.58 g, 4,73 mmol) in anhydrous THF (5 mL) was quickly added. The cooiing bath was removed and the reaction mixture was allowed to warm to RT. The stirring was continued at RT for 1 h. An aqueous ammonium chloride solution (10 mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5percent methanol in CH2CI2 as eluent) to give 3-{4-[2-(tert- butyldimethylsilanyloxy)-2-methylpropoxy]- 3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37percent), as a white solid.[0114] The above compound (0.42 g, 0.82 mmol) was dissolved in anhydrous THF (20 mL). Tetrabutylammonium fluoride (4.1 mL, 1.0 M solution in THF) was added at 0°C. The reaction mixture was stirred at 0°C for 10 min, then at RT for 2 h and then stirred at 70°C for 24 h. The mixture was cooled to RT.Saturated aqueous ammonium chloride (30 mL) was added. The organic layer <n="61"/>was separated, washed with water, brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh; 0-4percent methanol in CH2Cl2 as eluent) to give 3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)- 6,8-dimethoxyisoquinolin-1(2H)-one (0.15-g, 46percent), as a white solid. Selected data: MS (ES) m/z: 397.98; MP 252-254 °C at decomposition.

Reference： [1]Patent: WO2007/16525,2007,A2 .Location in patent: Page/Page column 96-98
[2]Patent: US2008/188467,2008,A1 .Location in patent: Page/Page column 27-28
[3]Patent: US2013/281397,2013,A1 .Location in patent: Paragraph 0456
[4]Patent: CN103319408,2016,B .Location in patent: Paragraph 0396-0401
[5]Patent: WO2008/92231,2008,A1 .Location in patent: Page/Page column 58-60

40
[ 59390-28-2 ]
[ 558-42-9 ]
[ 128780-36-9 ]

Reference： [1]Journal of the American Chemical Society,1990,vol. 112,p. 6411 - 6413

41
[ 558-42-9 ]
[ 682-00-8 ]
[ 35952-62-6 ]

Reference： [1]Journal of Organometallic Chemistry,1972,vol. 35,p. 91 - 104

42
[ 558-42-9 ]
[ 1067-52-3 ]
[ 35952-62-6 ]

Reference： [1]Journal of Organometallic Chemistry,1972,vol. 35,p. 91 - 104

43
[ 558-42-9 ]
[ 18144-09-7 ]
(Ot-bu-Cl)(Ot-bu)SiCl₂ [ No CAS ]

Reference： [1]Patent: US2566363,1946,
[2]Patent: US2566363,1946,

44
[ 558-42-9 ]
[ 853020-95-8 ]
[ 853018-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 75℃; for 130h;	6-Methoxy-l'- (2-phenoxyethyl)-2, 3,4, 9-tetrahydrospiro[beta-carboline-1, 3'-pyrrolidine] (EXAMPLE 10,66 mg, 0.2 mmol, K2CO3 (48 mg, 0.3 mmol), 1-chloro-2-methylpropan-2- ol (28 mg, 0.3 mmol) and acetonitrile (2 mL) were stirred at75 C for 16h. MoreK2CO3 (48 mg, 0.3 mmol), 1-chloro-2-methylpropan-2-ol (28 mg, 0.3 mmol) were added to the reaction and1-chloro-2-methylpropan-2-ol (28 mg, 0.3 mmol) was added again after 24h and 48h. After another 72h, the mixture was filtered and the solvent was removed. The product was purified by preparative HPLC using acetonitrile-water gradients containing 0.1percent trifluoroacetic acid. Yield: 6.96 mg (8percent).HPLC 98percent, RT : 2.099 (10-97percent MeCN over 3 min). 'H NMR (270 MHz, Methanol-d3)8 ppm 1.26 (s, 3 H) 1.35 (s, 3 H) 2.46-2. 53 (m,1 H) 2.84-3. 04 (m,1 H) 3.04-3. 14 (m, 2 H) 3. 47-3. 66 (m,6 H) 3.81 (s,3 H) 3.84 (dd,J=6. 68,3. 22 Hz, 2 H) 4.18-4. 29 (m,1 H) 4.32-4. 35 (m, 2 H) 6.81(dd,J=8. 91,2. 47 Hz, 1 H) 6.95-7. 02 (m, 4 H) 7.23-7. 33 (m,3 H).

Reference： [1]Patent: WO2005/48916,2005,A2 .Location in patent: Page/Page column 62-63

45
[ 110-85-0 ]
[ 558-42-9 ]
[ 156339-46-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	In ethanol; at 110℃; for 6h;	EXAMPLE 122 {4-[2-tert-Butyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazol-4-yl]thiophen-2-yl}-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]methanone (Compound 122) Step 1; Piperazine (6.88 g, 80.0 mmol) was dissolved in ethanol (40 mL), and 1-chloro-2-methyl-2-propanol (2.18 g, 20.0 mmol) was added thereto, and then, the mixture was stirred at 110°C for 6 hours. After the mixture was left to cool to room temperature, the solvent was evaporated. Then, ethyl acetate was added to the residue, and the precipitated solid was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol = 90/10) to give 2-methyl-1-(piperazin-1-yl)propan-2-ol (1.89 g, 11.96 mmol, 60percent).
	at 110℃; for 6h;	Piperazine (6.88 g, 80 mmol) was dissolved in ethanol (40 mL).1-Chloro-2-methyl-2-propanol (2.18 g, 20 mmol) was added. The mixture was stirred at 110°C for 6h. After the mixture was left to cool to room temperature, the solvent was evaporated. Ethyl acetate (40 mL) was added and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure to afford 2-methyl-1-piperazin-1-yl-propan-2-ol (4.1 g, crude) as a white solid, which was used directly to the next step without purification. MS (ESI): m/z =159.3 [M+1]+.

Reference： [1]Patent: EP2090570,2009,A1 .Location in patent: Page/Page column 77
[2]Patent: WO2017/108723,2017,A2 .Location in patent: Page/Page column 455; 456

46
[ 558-42-9 ]
[ 594-37-6 ]

Reference： [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 2790 - 2795

47
[ 558-42-9 ]
[ 86-74-8 ]
[ 1195786-68-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzyltrimethylammonium chloride; sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 16h;	a) 1-(9H-carbazol-9-yl)-2-methylpropan-2-ol To a solution containing carbazole (20 g; 0.12 mol) in DMSO (300 ml) was added 50percent sodium hydroxide solution (300 ml), benzyltrimethylammonium chloride (5.5 g; 0.024 mol) and, dropwise, 2-chloro-2-methylpropan-2-ol (39.1 g; 0.36 mol). The mixture thus obtained was stirred at room temperature for 16 hours. The mixture was poured into H2O and ice (3 L), stirred for 1 hour and filtered, and the solid obtained was crystallized from a hexane/ethyl acetate mixture (9:1) to give 1-(9H-carbazol-9-yl)-2-methylpropan-2-ol (15 g). 1H NMR (300 MHz, DMSO-d6) delta 8.07-8.15 (m, 2H), 7.68 (d, J = 8.33 Hz, 2H), 7.40 (ddd, J = 1.24, 7.13, 8.29 Hz, 2H), 7.13-7.20 (m, 2H), 4.64 (s, 1 H), 4.26 (s, 2H), 1.21 (s, 6H).

Reference： [1]Patent: EP2119705,2009,A1 .Location in patent: Page/Page column 7

48
[ 773837-37-9 ]
[ 558-42-9 ]
[ 13635-04-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	In ethanol; water; for 3h;Reflux;	STEP 1. 3-hydroxy-3-methylbutanenitrileTo a solution of 1-chloro-2-methylpropan-2-ol (17 g, 0.16 mol) in ethanol (320 mL) and water (55 mL) was added sodium cyanide (9.4 g, 0.19 mol) and the mixture was refluxed. After 3 hours, the mixture was cooled to room temperature and concentrated in vacuo. To the residue was added water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give 14 g (90percent) of the title compound.1H-NMR (300 MHz, CDCl3) delta 2.54 (s, 2H), 2.03 (s, 1H), 1.42 (s, 6H).

Reference： [1]Patent: US2009/298811,2009,A1 .Location in patent: Page/Page column 58

49
[ 558-42-9 ]
[ 106-45-6 ]
2-methyl-1-[(4-methylphenyl)sulfanyl]propan-2-ol [ No CAS ]

Reference： [1]Chemical Communications,2009,p. 2700 - 2702

50
[ 558-42-9 ]
[ 54669-43-1 ]
[ 27998-55-6 ]

Yield	Reaction Conditions	Operation in experiment
	sodium bromide; In N,N-dimethyl-formamide; at 50℃; for 18h;	To a mixture of 1-chloro-2-methylpropan-2-ol (2.2 g, 20.26 mmol) and potassium ethanethioate (6.94 g, 60.8 mmol) in DMF (20 mL) was added 100 mg of sodium bromide and the resulting mixture was heated at 50° C. for 18 hours. The mixture was then poured into water and extracted with EtOAc. The acetate layer was washed with water, brine, dried with MgSO4 and concentrated under reduced pressure to provide 3.4 g of the title compound

Reference： [1]Patent: US2010/69348,2010,A1 .Location in patent: Page/Page column 73

51
[ 558-42-9 ]
[ 302-01-2 ]
[ 42287-37-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;Reflux;	Step 1 : A mixture of 5b and 5a in ethanol (50mL) was refluxed overnight, evaporated under high vacuum. The residue was re-dissolved in ethanol and the resulting precipitate was filtered off. The filtrate was concentrated and dried to give crude 5c. The procedure from 5c to 5d was similar to that of Example 1 (1.84g, 61percent from 5a).

Reference： [1]Patent: WO2010/56320,2010,A2 .Location in patent: Page/Page column 57; 58

52
[ 558-42-9 ]
[ 74936-72-4 ]
[ 890045-70-2 ]

Yield	Reaction Conditions	Operation in experiment
58%		Example 1; l-Chloro-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)- 1 -pyridine-3 , 5 -dicarboxylate; 31 g (0.26 moles) of thionyl chloride were added dropwise under stirring to a mixture of 78 g (0.235 moles) of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid, 420 ml methylene dichloride and 110 ml dimethyl formamide kept at temperature of -20C - +2° under nitrogen. After terminating the addition of the thionyl chloride the stirring was continued under nitrogen for a further hour. To the above mixture a solution of 26 g (0.24 moles) of l-chloro-2-methyl-2-propanol in 60 ml methylene dichloride was added dropwise while stirring under nitrogen at a temperature of -50C - O0C. The stirring was continued for 3 EPO <DP n="4"/>hours at O0C, afterwards the mixture was allowed to stand for 24 hours at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in 1200 ml of ethylacetate. The organic solution was washed with saturated solution of sodium chloride and afterwards with a solution of 5percent Na2CO3. The organic layer was separated and dried with Na2SO4. The organic solution was evaporated to 500 ml and allowed to stand at O0C for 24 hours. The l-Chloro-2-methyl-2-prorhoyl methyl 1,4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)-l-pyridine-3,5-dicarboxylate thus obtained was filtered and dried at 5O0C under vacuum. The weight was 58 g ( 58 percent yield) of about 98percent purity as determined by HPLC analysis, shown in Figure 1.The method for performing the HPLC was as follows:HPLC: Merck-Hitachi with autosamplerColumn: Symmetry C 18, 4,6 x 250mm (Waters)Detector: UV 237nmMobile Phase: 60percent Acetonitrile + 40percent buffer pH 4.0Flow rate: lml/minInjection Volume: 20mulTemparature: 3O0CThe buffer pH 4.0 was prepared by dissolving 5.14g potassium di- hydrogen phosphate and 2.4 ml triethylamine in 980 ml water with mixing. The pH of the solution was adjusted to 4.0 with phosphoric acid and distilled water was added to make 1 liter, and the solution was mixed.The product has the following 1H NMR Spectrum (300 MHz, CDCI3): 8.11 (lH,m), 8.04 (lH,m), 7.64 (lH,d, J=7.5Hz), 7.37 (lH,t, J=8.1Hz), 3.64 (3H,s), 2.97 (lH,s) 2.90 (lH,s) 2.35 (3H,s) 2.34 (3H,s), 1.47 (3H,s), 1.44 (3H,s).

Reference： [1]Patent: WO2006/59332,2006,A1 .Location in patent: Example 1

53
[ 3469-69-0 ]
[ 558-42-9 ]
[ 1298032-45-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.666667h;sealed tube; microwave irradiation;	Example A65Preparation of intermediate 65: l-(4-Iodo-pyrazol-l-yl)-2-methyl-propan-2-olA mixture of 4-iodopyrazole (3 g, 15.47 mmol), l-chloro-2-methyl-2-propanol and cesium carbonate (8.06 g, 24.75 mmol) in N,N-dimethylformamide (30 ml) was stirred at 160°C for 40 min in a sealed tube, under microwave irradiation. The mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 20/80 to 40/60). The desired fractions were collected and concentrated in vacuo to yield intermediate 65 (3.98 g, 97percent) as a white solid.
97%	With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.666667h;	Example A65Preparation of intermediate 65: 1-(4-Iodo-pyrazol-1-yl)-2-methyl-propan-2-olA mixture of 4-iodopyrazole (3 g, 15.47 mmol), 1-chloro-2-methyl-2-propanol and cesium carbonate (8.06 g, 24.75 mmol) in N,N-dimethylformamide (30 ml) was stirred at 160° C. for 40 min in a sealed tube, under microwave irradiation.The mixture was diluted with water and extracted with dichloromethane.The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo.The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 20/80 to 40/60).The desired fractions were collected and concentrated in vacuo to yield intermediate 65 (3.98 g, 97percent) as a white solid.

Reference： [1]Patent: WO2011/51342,2011,A1 .Location in patent: Page/Page column 94
[2]Patent: US2011/269752,2011,A1 .Location in patent: Page/Page column 41-42

54
[ 558-42-9 ]
[ 123-08-0 ]
[ 1107662-91-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; for 24h;Reflux;	Example 2A4-(2-Hydroxy-2-methylpropoxy)benzaldehyde5.00 g (40.94 mmol) of 4-hydroxybenzaldehyde, 4.44 g (40.94 mmol) of 1-chloro-2-methyl-2-propanol and 6.08 g (57.32 mmol) of sodium carbonate are initially charged in 50 ml of dry DMF and stirred under reflux for 24 h.After cooling to RT, 20 ml of ethyl acetate and 20 ml of sat. aqueous sodium bicarbonate solution are added.The phases are separated, and the organic phase is dried over magnesium sulfate.After removal of the solvent, the residue is purified by column chromatography on silica gel 60 (mobile phase gradient: cyclohexane/ethyl acetate 5:1?1:1).This gives a reddish solid which is used without further purification for the subsequent step.Yield: 4.40 g (50percent of theory, 90percent purity)LC-MS (method 2): Rt=1.37 min; MS (ESIpos): m/z=195 [M+H]+.
	With sodium carbonate; In N,N-dimethyl-formamide; at 130℃;	5 g (40.94 mmol) of 4-hydroxybenzaldehyde were initially charged in 50 ml of DMF. 4.45 g (40.94 mmol) of 1-chloro-2-methylpropan-2-ol and 6.08 g (57.32 mmol) of sodium carbonate were added, and the mixture was then stirred at 130° C. overnight. Saturated aqueous sodium bicarbonate solution/ethyl acetate were added to the reaction mixture. The precipitate was filtered off and discarded. The two phases were separated from one another, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The residue was purified by column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5/1?1/2). Yield: 8.6 g (82percent of theory, 76percent pure) LC-MS (Method 4): Rt=1.17 min; MS (ESIpos): m/z=195 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta=9.87 (s, 1H), 7.86 (d, 2H), 7.12 (d, 2H), 4.70 (s, 1H), 3.84 (s, 2H), 1.21 (s, 6H).

Reference： [1]Patent: US2011/130377,2011,A1 .Location in patent: Page/Page column 19
[2]Patent: US2013/210795,2013,A1 .Location in patent: Paragraph 0402-0406

55
[ 558-42-9 ]
[ 1315463-39-8 ]
[ 1315463-53-6 ]

Yield	Reaction Conditions	Operation in experiment
31%	With N-ethyl-N,N-diisopropylamine; sodium iodide; In acetonitrile; at 160℃; for 0.5h;Microwaves;	To a solution of 1 -methyl-6-(6-(2-(piperidin-4-yl)ethoxy)-5-(trifluoromethyl)- pyridin-3-yl)-1 H-[1 ,2,3]triazolo[4,5-c]pyridine-4-carbonitrile trifluoroacetate (70 mg) and Lambda/,/V-diisopropylethylamine (85 mg) in acetonitrile (2 ml), 1 -chloro-2-methyl- propan-2-ol (48 mg) and sodium iodide (19 mg) were added and heated in microwave at 160 °C for 0.5h. The reaction mixture was concentrated then diluted with dichloromethane and water, extracted with dichloromethane and separated by hydrophobic frits, concentrated. Purified by Strata Si column (5g,dichloromethane:methanol=1 :0, 25:1 , 15:1 , 12.5:1 to 10:1 ) then passed through Strata SCX column (1 g) to give 20.0mg yellow amorphous as 6-(6-(2-(1 -(2-hydroxy- 2-methylpropyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1 -methyl-1 H- [1 ,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (31 percent).1H NMR (CD3OD-d4)5: 9.16 (s, 1 H), 8.75 (s, 1 H), 8.66 (s, 1 H), 4.59 (t, 2H, J=6.4Hz), 4.46 (s, 3H), 2.98 (t, 2H, J=1 1 .6Hz), 2.30 (s, 2H), 2.23 (d, 2H, J=1 1 .6Hz), 1 .70-1.85 (q+d, 4H), 1 .45-1 .60 (br, 1 H), 1 .38 (dq, 2H, J=12.0Hz, 3.30Hz), 1 .17 (s, 6H). MS m/z: 504 (M+H).

Reference： [1]Patent: WO2011/86125,2011,A1 .Location in patent: Page/Page column 59

56
[ 558-42-9 ]
[ 1346243-08-0 ]
[ 1346243-83-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 72h;	Compound 17 (214mg; 0.53mmol), 1 -chloro-2-methyl-2-propanol (0.13ml 1.28mmol), K2CO3 (147mg; 1.1 mmol) in DMF (9ml_) were heated to 120°C for 72 hours. The reaction mixture was cooled to room temperature, poured into H20/K2C03 and extracted with EtOAc. The organic layer was dried (MgS04), filtered and evaporated to dryness. The residue (277mg) was purified by chromatography over silica gel (Irregular SiOH, 15- 40mueta, 30g; mobile phase, gradient from 100percentDCM to 90percentDCM, 10percentMeOH,0.1 percentNH4OH) The pure fractions were collected and evaporated to dryness. The residue (226mg) was crystallized in diethyl ether, yielding 178mg (90percent) of compound 52.MP=159°C(DSC).

Reference： [1]Patent: WO2011/135376,2011,A1 .Location in patent: Page/Page column 307; 308

57
[ 558-42-9 ]
N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methylpiperazin-1-yl)picolinamide [ No CAS ]
6-((R)-4-(2-hydroxy-2-methylpropyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With potassium carbonate; potassium iodide; In acetonitrile; at 100℃; for 72h;Inert atmosphere;	Example 192: Synthesis of 6-(( R )-4-(2-hydroxy-2-methylpropyl)-2-methylpiperazin-1-yl)- N -(( E )-5-hydroxyadamantan-2-yl)picolinamide [447] [448] N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methylpiperazin-1-yl)picolinamide(60 mg, 0.162 mmol), potassium carbonate (45 mg, 0.324 mmol), and potassium iodide (27 mg, 0.162 mmol) were suspended in acetonitrile (2 ml), followed by addition of 1-chloro-2-methylpropan-2-ol (0.10 ml, 0.972 mmol), and then the resulting liquid was stirred at 100oC under nitrogen stream for 72 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (3percent MeOH/MC), to obtain 10 mg of white solid (14percent). MS (ESI): 443[M+H]+

Reference： [1]Patent: WO2011/139107,2011,A2 .Location in patent: Page/Page column 74-75

58
[ 558-42-9 ]
[ 1350648-42-8 ]
3'-fluoro-5,6'-dimethyl-2,2'-bipyridin-4-amine [ No CAS ]
[ 76-05-1 ]
1-(6-fluoro-7-(3'-fluoro-5,6'-dimethyl-2,2'-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0309] To a solution of 7-chloro-6-fluoro-lH-pyrazolo[4,3-b]pyridine (300 mg, 1.749 mmol) in DMF (5 mL) was added Cs2C03 (855 mg, 2.62 mmol) and 1 -chloro-2-methylpropan-2-ol (209 mg, 1.924 mmol) and the mixture was heated at 110 °C for 2 hours. Water (20 mL) was then added and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and evaporated to give l-(7-chloro-6-fluoro-2H- pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol and l-(7-chloro-6-fluoro-lH- pyrazolo[4,3-b]pyridin-l-yl)-2-methylpropan-2-ol which were used i without further purification. MS [M+H] found 244.2.[0310] To a solution of l-(7-chloro-6-fluoro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2- methylpropan-2-ol and l-(7-chloro-6-fluoro-lH-pyrazolo[4,3-b]pyridin-l-yl)-2- methylpropan-2-ol (150 mg, 0.616 mmol), and 3'-fluoro-5,6'-dimethyl-2,2'-bipyridin-4- amine (134 mg, 0.616 mmol) in t-BuOH (15 mL) was added tri(dibenylideneacetone)dipalladium(O) (56.4 mg, 0.062 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2- yl)phosphine (58.7 mg, 0.123 mmol) and potassium carbonate (340 mg, 2.462 mmol) and the mixture was heated at 100°C for 12 hours. The reaction was then cooled, concentrated, and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to give a residue which was purified by prep-HPLC using a Sunfire Prep 5muiotaeta CI 8, 75 X 30 mm column eluting with a gradient of 20-65percent acetonitrile (containing 0.035percent TFA) in water (containing 0.05percent TFA) to give the title compound as a TFA salt. 1H NMR (400 MHz, DMSO- 6) delta ppm 0.89 (s, 6 H) 2.54 (s, 3 H) 2.57 (s, 3 H) 4.29 (s, 2 H) 7.23 (s, 1 H) 7.57 (dd, J=8.59, 3.54 Hz, 1 H) 7.80 (dd, J=l 1.37, 8.59 Hz, 1 H) 8.51 (s, 1 H) 8.67 - 8.84 (m, 2 H) 10.08 (br. s., 1 H). MS [M+H] found 425.4.

Reference： [1]Patent: WO2011/146287,2011,A1 .Location in patent: Page/Page column 94-95

59
[ 558-42-9 ]
[ 1350648-42-8 ]
[ 1350649-09-0 ]
[ 1350649-10-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 2h;	[0309] To a solution of 7-chloro-6-fluoro-lH-pyrazolo[4,3-b]pyridine (300 mg, 1.749 mmol) in DMF (5 mL) was added Cs2C03 (855 mg, 2.62 mmol) and 1 -chloro-2-methylpropan-2-ol (209 mg, 1.924 mmol) and the mixture was heated at 110 °C for 2 hours. Water (20 mL) was then added and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and evaporated to give l-(7-chloro-6-fluoro-2H- pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol and l-(7-chloro-6-fluoro-lH- pyrazolo[4,3-b]pyridin-l-yl)-2-methylpropan-2-ol which were used i without further purification. MS [M+H] found 244.2.

Reference： [1]Patent: WO2011/146287,2011,A1 .Location in patent: Page/Page column 94-95

60
[ 558-42-9 ]
[ 1350648-20-2 ]
[ 1350648-61-1 ]

Yield	Reaction Conditions	Operation in experiment
43.8%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.5h;Microwave irradiation;	[0157] 7-Iodo-2H-pyrazolo[4,3-b]pyridine (300 mg, 1.224 mmol), l-chloro-2-methylpropan- 2-ol (133 mg, 1.224 mmol) and CS2CO3 (399 mg, 1.224 mmol) were combined in DMF (5 mL). The mixture was heated at 120 °C for 30 minutes using a microwave. The reaction mixture was then purified by preparative HPLC using a Sunfire Prep 5muiotaeta CI 8, 75 X 30 mm column eluting with a gradient of 05 - 25percent acetonitrile (containing 0.035percent TFA) in water (containing 0.05percent> TFA) using basic buffer to afford l-(7-iodo-2H-pyrazolo[4,3-b]pyridin- 2-yl)-2-methylpropan-2-ol (170 mg, 0.536 mmol, 43.8 percent yield). MS [M+H] found 318.

Reference： [1]Patent: WO2011/146287,2011,A1 .Location in patent: Page/Page column 33

61
[ 558-42-9 ]
[ 330473-75-1 ]
[ 1253911-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 3h;Microwave;	Step 1.Preparation of I-(6-amino-pyridin-3-yloxy)-2-methyl-propan-2-olTo a microwave flask containing 6-aminopyridin-3-ol hydrobromide (700 mg, 3.66 mmol) and 1-chloro-2-methyl-2-propanol (597 mg, 5.5 mmol) in anhydrous dimethylformamide (17 ml) was added cesium carbonate (3.7 g, 11.4 mmol) and the material was heated in a microwave oven at 140° C. for 3 hours.The vial was cooled to ambient and the solvent was concentrated in vacuo (rotary evaporator/mechanical pump).The residue was taken up in methylene chloride and filtered to remove insolubles, rinsing well with methylene chloride.The crude material was purified by HPLC on silica gel, eluting with a gradient of 2percent to 10percent methanol/methylene chloride to provide the desired product as a orange-brown viscous oil which solidified on standing (449 mg). MS (H+)=183 m/e.

Reference： [1]Patent: US2012/40949,2012,A1 .Location in patent: Page/Page column 71

62
[ 558-42-9 ]
[ 1360552-22-2 ]
[ 1360552-68-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	To a suspension of 1-47 (336 mg, 0.93 mmol) and potassium carbonate (154 mg, 1.12 mmol) in DMF (6 mL) is added l-chloro-2-methyl-propan-2-ol (100 mu, 0.98 mmol). The reaction mixture is stirred at 80 °C for 16 h then concentrated in vacuo. The residue is extracted with CH2CI2, washed with saturated aqueous NuEta40, dried with Na2S04, filtered and concentrated in vacuo to afford 1-104 (365 mg); m/z 434 [M+H].
365 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	To a suspension of I-47 (336 mg, 0.93 mmol) and potassium carbonate (154 mg, 1.12 mmol) in DMF (6 mL) is added 1-chloro-2-methyl-propan-2-ol (100 muL, 0.98 mmol). The reaction mixture is stirred at 80° C. for 16 h then concentrated in vacuo. The residue is extracted with CH2Cl2, washed with saturated aqueous NH4Cl, dried with Na2SO4, filtered and concentrated in vacuo to afford I-104 (365 mg); m/z 434 [M+H].

Reference： [1]Patent: WO2012/24150,2012,A1 .Location in patent: Page/Page column 154
[2]Patent: US2013/195879,2013,A1 .Location in patent: Paragraph 0359; 0390

63
[ 37622-90-5 ]
[ 558-42-9 ]
[ 1369485-89-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 48h;	Step 1: Synthesis of 1-29R9 (2.00 g, 14.3 mmol) is treated with R25 (3.10 g, 28.5 mmol), K2C03 (2.96 g, 21.4 mmol), and DMF (10 mL) and the reaction is stirred at 80 °C for 48 hours. The resulting mixture is diluted with EtOAc, washed with water and brine, dried over Na2S04, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography (0-5percent methanol in CH2C12) to yield 1-29 (2.55 g); m/z 213 [M+H].

Reference： [1]Patent: WO2012/40137,2012,A1 .Location in patent: Page/Page column 117

64
[ 558-42-9 ]
[ 1369483-64-6 ]
[ 1369483-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 72h;	Method 4: Synthesis of l-r4-(3-{(2R)-2-r6-(2-aminopyrimidin-5-yl)pyridin-3-yll-3- methylbutan-2-yl}-l,2,4-oxadiazol-5-yl)-lH-pyrazol-l-yl1-2-methylpropan-2-ol (Example 38).A solution of Example 43 (2.0 g, 5.14 mmol), K2C03 (1.06 g, 7.71 mmol) and R16 (1.05 mL, 10.28 mmol) in DMF (10.0 mL) is stirred at 80°C for 3 days. K2C03 (355 mg, 2.57 mmol) is added and the reaction mixture is heated for additional 2 hours. The reaction mixture is diluted with EtOAc and washed with water. The water layer is extracted with EtOAc. The organic phase is dried over anhydrous Na2S04 and filtered; the solvent removed under vacuum and the crude purified via silica gel column chromatography (DCM/MeOH) to afford Example 38 (1.99 g).

Reference： [1]Patent: WO2012/40137,2012,A1 .Location in patent: Page/Page column 102-103

65
[ 558-42-9 ]
[ 1369512-62-8 ]
[ 1369512-10-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 60h;	Method 11:Synthesis of l-r4-(3 1 6-(2-aminopyrimidin-5-yl)pyridin-3-yl1cvclobutyl}-l,2,4- oxadiazol-5-yl)-lH-pyrazol-l-yl1-2-methylpropan-2-ol (Example 54, Table 1) Ex. 54Example 90 (5.00 g, 13.9 mmol) is treated with R37 (4.00 g, 36.8 mmol), K2C03 (2.88 g, 20.8 mmol) and DMF (50 mL) and the resulting mixture is heated at 80 °C for 60 hours. The reaction mixture is diluted with ethyl acetate and washed with water and brine. The organic phase is dried over Na2S04, filtered, and the solvent is removed in vacuo. This crude mixture is purified by flash chromatography (Si02, 0-5percent 2M NH3 inmethanol/CH2Cl2) to afford the title compound (2.58 g); m/z 433.4 [M+H].

Reference： [1]Patent: WO2012/40139,2012,A1 .Location in patent: Page/Page column 92-93

66
[ 558-42-9 ]
[ 1332331-08-4 ]
[ 1332331-37-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 185℃; for 17h;Inert atmosphere;	Example 294-[4-(l -benzofuran-5-yl)phenyl]-5- [(35)- 1 -(cyclopropylcarbonyl)-3- pyrrolidinyljmethyl} -2-(2-hydroxy-2-methylpropyl)-2,4-dihydro-3H- 1 ,2,4-triazol-3-a) To a solution of 4-[4-(l-benzofuran-5-yl)phenyl]-5-[(3S)-l-(cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (100 mg, 0.233 mmol) in N,N- dimethylformamide (1 mL) in a 5 mL micro waveable vial was added potassium carbonate (100 mg, 0.724 mmol, 3.1 eq) and l-chloro-2-methyl-2-propanol (50 mg, 0.461 mmol, 2 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80 °C. Analysis by LC/MS displayed no reaction. The solution was then irradiated in the microwave at 185 °C for 60 min. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was poured into a mixture ofdichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3x with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30x50 mm column; 25-55percent acetonitrile w/ 0.1percent TFA/water w/ 0.1percent TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (56 mg, 48percent). MS(ES)+ m/e 501.1 [M+H]+.

Reference： [1]Patent: WO2011/103546,2011,A1 .Location in patent: Page/Page column 71

67
[ 558-42-9 ]
3-butyl-4-(4-cyclohexyloxyphenyl)-6-(piperidin-4-yloxy)pyridazine dihydrochloride [ No CAS ]
1-{4-[6-butyl-5-(4-cyclohexyloxyphenylpyridazin-3-yl)oxy]-piperidin-1-yl}-2-methylpropan-2-ol dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		Example 221-{4-[6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-2-methyl-propan-2-ol dihydrochlorideTo a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (Example 14, 0.2 mmol, 97 mg) in EtOH (2 mL) was added 1-chloro-2-methyl-2- propanol (0.4 mmol, 44 mu), and potassium carbonate (0.6 mmol, 83 mg). And the mixture was stirred at 50°C for 4 hours. It was then diluted with water/EtOAc. The organic layers were combined, dried, and condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM + 10percent MeOH) to give a colorless sticky solid, which was dissolved in DCM (2 mL), 1 N HCI in ether (2 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to yield 1-{4-[6- butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-2-methyl-propan-2-ol dihydrochloride (86 mg, 77percent yield). LCMS: m z 483 [M+1]. 1 H NMR (400 MHz, CD3OD): delta 7.53 and 7.62 (1 H, s), 7.41- 7.46 (2H, m), 7.10 - 7.14 (2H, m), 5.42 - 5.52 (1 H, m), 4.41 - 4.46 (1 H, m), 3.65 - 3.83 (2H, m), 3.25- 3.47 (3H, m), 3.05 - 3.12 (2H, m), 2.22 - 2.55 (5H, m), 1.98 - 2.03 (2H, m), 1.78 - 1.83 (2H, m), 1.40 - 1.63 (7H, m), 1.38 (6H, s), 1.22 - 1.36 (3H, m), 0.81 (3H, t).

Reference： [1]Patent: WO2011/103091,2011,A1 .Location in patent: Page/Page column 82

68
[ 558-42-9 ]
[ 999-97-3 ]
[ 31557-15-0 ]

Reference： [1]Chemistry and biodiversity,2012,vol. 9,p. 1823 - 1828

69
[ 558-42-9 ]
[ 994-30-9 ]
[ 1428776-16-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 4-methyl-morpholine; In dichloromethane; at 20℃; for 36h;	A 250 mL round bottom flask was charged with 1-chloro-2-methylpropan-2-ol (2.0 g, 18 mmol). DCM (60 mL) was added, followed by Et3SiCl (3.4 mL, 20 mmol) and then NMM (3 mL, 27 mmol) and the reaction was stirred at rt for 36 hrs. Water (50 mL) and DCM (50 mL) were added and the aqueous layer extracted with DCM (two×30 mL). The combined organic extracts were washed with water and dried over MgSO4. After filtering, the solvents were removed in vacuo, keeping the bath temperature at 22° C. The intermediate was placed under a 10 mm Hg vacuum for 15 min to provide (ca. 18 mmol, 100percent yield) of ((1-chloro-2-methylpropan-2-yl)oxy)triethylsilane as a pale yellow oil. This material was used as is in the next step.

Reference： [1]Patent: US2013/79324,2013,A1 .Location in patent: Paragraph 0872

70
[ 558-42-9 ]
[ 767-00-0 ]
[ 1182426-00-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In ethanol; water; at 80℃; for 16h;	A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL ), 4-hydroxybenzonitrile (2 g, 16.8 mmol), K2CO3 (9.3 g, 67.3 mmol) in water (6 mL) and ethanol (60 mL) was heated at 80 °C for 16 hours. The reaction mixture was cooled and the solvent was concentrated in vacuo. The residue was diluted with ether (200 mL) and filtered and the filtrate was washed sequentially with water (50 mL) and brine solution (50 mL). The organics were separated and dried over MgSO4 and solvent was removed in vacuo to give a residue which was purified by silica gel column chromatography using (0-100percent) EtOAc/DCM as eluent to give 4-(2-hydroxy- 2-methyl-propoxy)benzonitrile (3.0 g, 94 percent) as a yellow solid. ESI-MS m/z calc. 191.1, found 192.3 (M+1)+; Retention time: 1.05 minutes (3 min run).

Reference： [1]Patent: WO2013/109521,2013,A1 .Location in patent: Paragraph 00303; 00304

71
[ 558-42-9 ]
[ 1052114-80-3 ]
[ 1449301-48-7 ]

Yield	Reaction Conditions	Operation in experiment
57 mg	With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 10h;	Ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (400 mg) was suspended in DMF (5.0 ml). Cesium carbonate (1200 mg), 1-chloro-2-methyl-2-propanol (345 mul) and tetra-n-butylammonium iodide (56 mg) were added sequentially, and the mixture was stirred at 70° C. for 10 hours. A 1 N aqueous hydrochloric acid solution was added at room temperature. The insoluble matter was removed by filtration through celite, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->60:1 (v/v)] to give 57 mg of the title compound as a solid. 1H-NMR (CDCl3) delta: 1.32 (6H, s), 1.37 (3H, t, J=7.1 Hz), 3.43 (1H, s), 3.79 (2H, s), 4.36 (2H, q, J=7.1 Hz), 7.00-7.09 (2H, m), 7.45-7.49 (1H, m), 7.51-7.60 (2H, m), 8.16 (1H, d, J=2.3 Hz). MS (ESI) m/z: 334 (M+H)+.

Reference： [1]Patent: US2013/281428,2013,A1 .Location in patent: Paragraph 0851; 0852; 0853; 0854

72
[ 558-30-5 ]
[ 558-42-9 ]
[ 558-38-3 ]

Reference： [1]ARKIVOC,2012,vol. 2012,p. 120 - 133

73
[ 1018975-06-8 ]
[ 558-42-9 ]
[ 1539313-50-2 ]

Yield	Reaction Conditions	Operation in experiment
42%	With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80 - 120℃; for 8.5h;	A mixture of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.025 g, 0.099mmol) (see, for example, US2008139631A1), Cs2CO3 (0.129 g, 0.396 mmol), potassiumiodide (0.0 165 g, 0.099 mmol) and commercially available 1-chloro-2-methylpropan-2-ol (0.041 mL, 0.396 mmol) in DMF (2 mL) was heated at 80°C for 90 mm and then at 120°C for 1 h. Additional 1-chloro-2-methylpropan-2-ol (0.041 mL, 0.396 mmol), Cs2CO3 (0.129 g, 0.396 mmol) and potassium iodide (0.0165 g, 0.099 mmol) were added, and heating continued at 120°C for another 6 h. Upon cooling, the mixture was partitioned between EtOAc (25 mL) and water (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna column; gradient: 10-90percent MeCN-water with 0.1percent TEA). The fractions with product were concentrated down to the aqueous phase, whichis then partitioned between EtOAc (25 mL) and saturated aqueous NaHCO3 solution (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. This chromatography did not separate product from unreacted starting indole, so the material was chromatographed over silica gel using a 50percent-100percent CH2Cl2- hexanes gradient to give 1-(2-(methylthio)ethyl)-2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0:014 g, 42percent yield) as a white solid: MS (ESI): m/z 325 (M+H).

Reference： [1]Patent: WO2014/13309,2014,A1 .Location in patent: Page/Page column 34; 35

74
[ 558-42-9 ]
[ 1581269-90-0 ]
[ 1581269-96-6 ]

Yield	Reaction Conditions	Operation in experiment
14.83%		To a solution of 6-(tert-butylsulfonyl)-4-chloroquinolin-7-ol (250 mg, 0.834 mmol) in DMF (2756 mu) was added K2C03 (576 mg, 4.17 mmol) followed by l-chloro-2- methylpropan-2-ol (209 mu, 2.502 mmol). After 10 min, LCMS showed no product. Heated reaction to 60 °C. No reaction after 3 hr at this temperature. Added sodium iodide (375 mg, 2.50 mmol) and 2,2-dimethyloxirane (371 mu, 4.17 mmol) and stirred for 2 days at to 60 °C. The crude sample was purified via Biotage normal phase chromatography (25g SNAP column, 0percent - 80percent, 80percent. hex / EtOAc). The pure product containing-fractions were combined and concentrated leading to the product as an off-white solid: \-{{6-{tert- butylsulfonyl)-4-chloroquinolin-7-yl)oxy)-2-methylpropan-2-ol (46 mg, 0.124 mmol, 14.83 percent yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.29 (s, 6 H) 1.33 (s, 9 H) 4.03 (s, 2 H) 4.56 (s, 1 H) 7.72 (s, 1 H) 7.76 (d, J=4.80 Hz, 1 H) 8.64 (s, 1 H) 8.94 (d, J=4.80 Hz, 1 H). MS (m/z) 372.2 (M+H+).

Reference： [1]Patent: WO2014/43437,2014,A1 .Location in patent: Page/Page column 45

75
[ 106-41-2 ]
[ 558-42-9 ]
1-(4-bromophenoxy)-2-methylpropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 48h;	To a solution of 1-chloro-2-methylpropan-2-ol (434.4 mg, 4 mmol) in DMF (10 mL) was added K2CO3 (552 mg, 4 mmol) and 4-bromophenol (346 mg, 2 mmol), the reaction was stirred at 140° C. for 48 hours. About of 10percent 4-bromophenol was remained and the reaction was poured into 30 mL of water, extracted with EA (20 mL*3), washed with 30 mL of water and brine, concentrated and purified on TLC (EA:PE=1:3) to give yellow solid. MS (m/z): 196 (M-50)+

Reference： [1]Patent: US2014/121200,2014,A1 .Location in patent: Paragraph 0242; 0243

76
[ 558-42-9 ]
[ 1579519-21-3 ]
[ 1579512-43-8 ]

Yield	Reaction Conditions	Operation in experiment
103 mg		Example 17 Preparation of 1-(6-{2-[2-(2-hydroxy-2-methyl-propyl)-1,2,3,4-tetrahydro-isoquinolin-6-ylmethoxy]-3-methyl-phenyl}-pyridin-2-yl)-5-methoxy-1H-pyrazole-4-carboxylic acid (33) Intermediate 12-48 (90.0 mg, 0.18 mmol) is dissolved in MeCN (5.0 mL) to which is added Cs2CO3 (117.9 mg, 0.36 mmo) and chloride 17-53 (29.5 mg, 0.27 mmol). The mixture is heated to 50° C. for 10 h. The reaction was cooled, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The resulting material is purified by gradient elution on a 30 g KP-C18 SNAP cartridge (Biotage) using a gradient of 15-65percent MeCN/water+0.1percent TFA to afford the intermediate ester. The ester is dissolved in 5 mL of THF/MeOH/water (2:2:1) and treated with LiOH (25.0 mg, 1.10 mmol). The mixture is then heated to 50° C. for 2 h prior to removal of the solvents in vacuo. The remaining crude residue is purified by gradient elution on a 30 g KP-C18 SNAP cartridge (Biotage) using a gradient of 15-65percent MeCN/water+0.1percent TFA to afford title compound 33 (103.0 mg). MS, electrospray, m/z=543.2 [M+H], RT 0.68 min.

Reference： [1]Patent: US2014/73629,2014,A1 .Location in patent: Paragraph 0189; 0190

77
[ 558-42-9 ]
[ 1421930-35-9 ]
[ 1609976-83-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 70 - 120℃; for 25h;	To a mixture of ?ras-4-[(lR)-l-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4- methyl-2,3'-bipyridin-6'-yl)-l-hydroxyethyl]cyclohexanecarboxylic acid (0.100 g, 0.21 mmol), potassium carbonate (0.057 g, 0.41 mmol), and sodium iodide (6 mg, 0.04 mmol) in DMF (1 mL) was added l-chloro-2-methylpropan-2-ol (0.045 g, 0.41 mmol) at 20 °C. The reaction mixture was heated at 70 °C for 2 hours, after which time analysis by LCMS indicated no conversion of starting material to desired product. The reaction mixture was heated at 100 °C for an additional 16 hours, after which time analysis by LCMS indicated partial conversion to desired product. The reaction mixture was heated at 120 °C for an additional 6 hours. LCMS indicated further conversion to desired product. Additional l-chloro-2-methylpropan-2-ol (0.090 g, 0.83 mmol) and potassium carbonate (0.228 g, 1.66 mmol) were added and the reaction mixture was heated for an additional hour at 120 °C. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 mL). The mixture was washed with water (3 x 20 mL) and brine (1 x 15 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100percent ethyl acetate / hexanes). The purified material was dissolved in acetonitrile (10 mL) and then diluted with water (20 mL). The resulting suspension was frozen and lyophilized to afford 2-hydroxy-2-methylpropyl trans- -[(\R)-\-(6- [ - (difluoromethyl)pyridin-2-yl]amino} -4-methyl-2,3 '-bipyridin-6'-yl)- 1 - hydroxyethyl]cyclohexanecarboxylate. MS ESI calc'd. for C30H37F2 4O4 [M + H]+ 555, found 555. XH NMR (500 MHz, DMSO-d6) delta 10.00 (s, 1H), 9.13 (d, J= 2.0 Hz, 1H), 8.39 - 8.35 (m, 2H), 8.32 (s, 1H), 7.68 (d, J= 8.5 Hz, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 7.09 (t, J= 56 Hz, 1H), 7.02 (d, J= 5.0 Hz, 1H), 5.06 (s, 1H), 4.54 (s, 1H), 3.73 (s, 2H), 2.34 (s, 3H), 2.16 - 2.10 (m, 1H), 1.97 - 1.92 (m, 1H), 1.86 - 1.79 (m, 2H), 1.78 - 1.70 (m, 1H), 1.44 (s, 3H), 1.34 - 1.08 (m, 5H), 1.04 (s, 6H).

Reference： [1]Patent: WO2014/74421,2014,A1 .Location in patent: Page/Page column 52; 53

78
[ 558-42-9 ]
[ 1334167-18-8 ]
[ 1609367-74-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4196 - 4212

79
[ 558-42-9 ]
[(1S,3aR,5aS,6R,11bR,11cS)-10-methoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(iminoethano)-1,5a-epoxynaphtho[1,2-e]indol-3-yl](phenyl)methanone [ No CAS ]
[(1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2-hydroxy-2-methylpropyl)-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(iminoethano)-1,5a-epoxynaphtho[1,2-e]indol-3-yl](phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.7 mg		Under an argon atmosphere, the compound 11 (41.7 mg, 0.10 mmol) was dissolved in DMF (2 mL), the solution was added with 1-chloro-2-methyl-2-propanol (103 muL, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and sodium iodide (249 mg, 1.5 mmol), and the mixture was stirred at 100°C for 12 hours. The reaction mixture was poured into distilled water, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated. Under an argon atmosphere, the obtained crude product was dissolved in dichloromethane (2 mL), the solution was added with a solution of boron tribromide in dichloromethane (1.0 mol/L, 0.5 mL, 0.50 mmol) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with 6 M aqueous ammonia (10 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes, and extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated. The obtained crude product was purified by preparative TLC to give the title compound 29 as white amorphous (29.7 mg, 63percent). [0191] The obtained compound 29 was treated with a 20percent solution of hydrogen chloride in methanol to give the hydrochloride of the compound 29. Compound 29 (free base) 1H NMR (CDCl3, 300MHz): delta 0.63-1.29 (m, 2.2H), 1.15 (s, 6H), 1.43-1.57 (m, 0.8H), 1.60-1.84 (m, 2H), 1.91-2.12 (m, 1H), 2.33-2.73 (m, 4H), 2.92-3.17 (m, 3H), 3.24-3.37 (m, 1H), 3.61 (dd, J=5.7, 12.6Hz, 0.8H), 3.78-3.92 (m, 1H), 4.18-4.29 (m, 0.4H), 4.86-5.00 (m, 1.6H), 5.03 (t, J=6.0Hz, 0.2H), 6.50 (d, J=2.4Hz, 0.2H), 6.60 (dd, J=2.7, 8.4Hz, 0.2H), 6.67 (dd, J=2.4, 8.1Hz, 0.8H), 6.72 (d, J=2.4Hz, 0.8H), 6.90 (d, J=8.1Hz, 0.2H), 6.91 (d, J=8.1Hz, 0.8H), 7.30-7.53 (m, 5H)

Reference： [1]Patent: EP2774926,2014,A1 .Location in patent: Paragraph 0188-0191

80
[ 558-42-9 ]
[ 56174-66-4 ]
2-(Me₂NCH₂)C₆H₄SeCH₂C(Me)2OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.27%		Sulfur powder (0.727 g, 22.71 mmol) was added to a solution of (2-Me2NCH2C6H4)Li (3.20 g, 22.71 mmol) in THF (50 mL) and the reaction mixture was stirred at room temperature for 6 h. Then 1-chloro-2-methyl-2-propanol (2.32 mL, rho = 1.06 g/mL, 22.71 mmol) was added at 0 °C and the reaction mixture was stirred for additional 18 h. The solvent was removed under vacuum and the remained product was treated with toluene. The solid residue was filtered off and the solvent was removed at reduced pressure. The resulting yellow oil was further distilled at a pressure of 2·10-2 mbar and compound 1 was isolated as the fraction separated at 95 °C. Yield: 3.21 g (48.27percent). Anal. Found: C 65.34, H 8.91, N 5.81percent; Calc. for C13H21NOS (M = 239.38): C 65.23, H 8.84, N 5.85percent. 1H NMR (CDCl3): delta 1.21s (6H, CCH3), 2.23s (6H, NCH3), 3.08s (2H, CH2S), 3.56s (2H, CH2N), 6.53s, (br., 1H, OH), 7.10m (3H, H3-5), 7.56d (1H, H6, 3JHH 7.7 Hz). 13C NMR (CDCl3): delta 28.67s (NCH3), 44.73s (CCH3), 52.25s (CH2S), 63.06s (CH2N), 70.26s (COH), 126.92s (C4), 128.97s (C5), 131.15s (C3), 135.14s (C6), 138.93s (C2), 139.19s (C1); 1H NMR (acetone-d6): delta 1.23s (6H, NCH3), 2.22s (6H, CCH3), 3.09s (2H, CH2S), 3.56s (2H, CH2N), 5.11s (1H, OH), 7.16-7.31m (3H, H3-5), 7.56d (1H, H6, 3JHH = 7.6 Hz).

Reference： [1]Journal of Organometallic Chemistry,2014,vol. 768,p. 121 - 127

81
[ 558-42-9 ]
[ 56174-66-4 ]
2-(Me₂NCH₂)C₆H₄SeCH₂C(Me)2OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.21%		General procedure: Sulfur powder (0.727 g, 22.71 mmol) was added to a solution of (2-Me2NCH2C6H4)Li (3.20 g, 22.71 mmol) in THF (50 mL) and the reaction mixture was stirred at room temperature for 6 h. Then 1-chloro-2-methyl-2-propanol (2.32 mL, rho = 1.06 g/mL, 22.71 mmol) was added at 0 °C and the reaction mixture was stirred for additional 18 h. The solvent was removed under vacuum and the remained product was treated with toluene. The solid residue was filtered off and the solvent was removed at reduced pressure. The resulting yellow oil was further distilled at a pressure of 2·10-2 mbar and compound 1 was isolated as the fraction separated at 95 °C. Yield: 3.21 g (48.27percent).

Reference： [1]Journal of Organometallic Chemistry,2014,vol. 768,p. 121 - 127

82
[ 558-42-9 ]
[ 56174-66-4 ]
C₁₃H₂₁NOTe [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44.43%		General procedure: Sulfur powder (0.727 g, 22.71 mmol) was added to a solution of (2-Me2NCH2C6H4)Li (3.20 g, 22.71 mmol) in THF (50 mL) and the reaction mixture was stirred at room temperature for 6 h. Then 1-chloro-2-methyl-2-propanol (2.32 mL, rho = 1.06 g/mL, 22.71 mmol) was added at 0 °C and the reaction mixture was stirred for additional 18 h. The solvent was removed under vacuum and the remained product was treated with toluene. The solid residue was filtered off and the solvent was removed at reduced pressure. The resulting yellow oil was further distilled at a pressure of 2·10-2 mbar and compound 1 was isolated as the fraction separated at 95 °C. Yield: 3.21 g (48.27percent).

Reference： [1]Journal of Organometallic Chemistry,2014,vol. 768,p. 121 - 127

83
[ 558-42-9 ]
[ 133071-22-4 ]
[ 7704-34-9 ]
1-{8-(N(CH₃)2)naphthalen-1-yl}SCH₂C(CH₃)2OH [ No CAS ]

Reference： [1]Dalton Transactions,2014,vol. 43,p. 16459 - 16474

84
[ 558-42-9 ]
methyl 6-chloro-5-hydroxy-pyridine-2-carboxylate [ No CAS ]
methyl 6-chloro-5-(2-hydroxy-2-methyl-propoxy)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium carbonate; In methanol; at 80℃;	[00296j Step 1: methyl 6-chloro-5-(2-hydroxy-2-methyl-propoxy)pyridine-2-carboxylate [00297j A solution of methyl 6-chloro-5 -hydroxy-pyridine-2- carboxylate (1.6 g, 8.3 mmol) in methanol (1.5 mL) was treated with finely ground potassium carbonate (4.6 g, 33.0 mmol). The reaction mixture was heated to 80 °C and1-chloro-2-methyl-propan-2-ol (1.7 mL, 16.5 mmol) was added. The reaction mixture was heated at 80 °C overnight. The reaction mixture was concentrated under reduced pressure. The remaining residue was suspended in water (75 mL) and extracted with ethyl acetate (2 x 75 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified bysilica gel colunm chromatography: 40 gram silica gel column, 0-30percent ethyl acetate/hexane gradient over 25 mm to afford methyl 6-chloro-5-(2-hydroxy-2-methyl- propoxy)pyridine-2-carboxylate (1.2 g, 54percent) was obtained as a colorless solid. ?H NMR (400 MHz, CDC13) oe 8.09 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 2H), 1.41 (s, 6H). ESI-MS mlz calc. 259.1, found 260.2 (M+1)+;Retention time: 0.99 mm (3 mm run).

Reference： [1]Patent: WO2015/6280,2015,A1 .Location in patent: Paragraph 00296; 00297

85
[ 558-42-9 ]
[ 499-76-3 ]
[ 1392466-98-6 ]

Yield	Reaction Conditions	Operation in experiment
75%		[00302j 5-(2-fluoro-2-methyl-propoxy)-6-methoxy-pyridine-2- carboxylic acid [00303j A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL, ), 4- hydroxy-3-methyl-benzoic acid (2.0 g, 13.2 mmol), K2C03 (7.3 g, 52.7 mmol), H20 (6.0 mL) and ethanol (60 mL) was heated at 80 °C overnight. The reaction mixturewas cooled to rt, partitioned between iN NaOH and EtOAc and the layers separated. The organic layer was washed with iN NaOH (2x) and the combined aqueous layers were washed with EtOAc. The combined organics were concentrated under reduced pressure and diluted with EtOH (15 mL). The mixture was treated with H20 (2 mL) and NaOH (1.0 g, 26.3 mmol). The reaction mixture was stirred at 40 °C for 4 h. Thereaction mixture was poured into iN NaOH and extracted with ether (2x). The pH was brought to 2-3 with 6N HC1 and the aqueous material was extracted with EtOAc (3x). The organics were combined, washed with saturated aqueous NaC1, dried (Na2SO4), filtered, and evaporated to dryness. The material was triturated with ether to provide 4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoic acid (2.2 g, 75percent) as a white solid.?H NMR (400 MHz, DMSO) d 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.73 - 7.70 (m, 1H), 6.96 (d, J = 8.6 Hz, 1H), 4.67 (s, 1H, OH), 3.76 (s, 2H), 2.20 (s, 3H), 1.22 (s, 6H). ESI-MS mlz calc. 224.1, found 225.5 (M+1) Retention time: 1.06 mm (3 mm run).

Reference： [1]Patent: WO2015/6280,2015,A1 .Location in patent: Paragraph 00302; 00303

86
[ 558-42-9 ]
[ 3964-57-6 ]
methyl 3-chloro-4-(2-hydroxy-2-methyl-propoxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		[00351j Step 1: methyl 3-chloro-4-(2-hydroxy-2-methylpropoxy)benzoate [00352j A 500 ml 3 neck RB flask was fitted with a mechanical stirrer,a J-Kem temperature probe/controller, an addition funnel, a water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with methyl 3-chloro-4-hydroxy-benzoate (10 g, 53.6 mmol) and methylalcohol (40 ml) which provided a clear pale yellow solution. Stirring was commenced and the pot temperature was recorded at 19 °C. The vessel was then charged with potassium carbonate (30 g, 0.21 mol) added as a solid in one portion which resulted in an exotherm to 23 °C. Note: The potassium carbonate was ground to a fine powder prior to use. The resulting suspension was continued to stir at rt for 15 mm and thentreated with 1-chloro-2-methyl-propan-2-ol (11.6 g, 0.11 mol) added neat dropwise via addition funnel over 10 mm. The resulting reaction mixture/suspension was then heated to 70 °C and stirred for 20 h. The reaction mixture was cooled to rt and diluted with ethyl acetate (250 ml). The mixture was filtered through a glass fit Buchner funnel with a 10 mm layer of Celite. The filter cake was washed with ethyl acetate (2 x100 ml). The filtrate was transferred to a separatory funnel and partitioned with 1 M aqueous NaOH (250 ml). The organic was removed and washed with 1 M aqueous NaOH (2 x 150 ml), saturated aqueous sodium chloride (150 ml), dried over sodium sulfate (250 g) and filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to provide methyl 3-chloro-4-(2-hydroxy-2-methylpropoxy)benzoate (9.0 g, 65percent) as a clear pale yellow oil. The material was used without further purification in the next synthetic step. ESI-MS mlz caic. 258.7, found 259.2 (M+1) Retention time: 1.46 mm (3 mm run).

Reference： [1]Patent: WO2015/6280,2015,A1 .Location in patent: Paragraph 00351; 00352

87
[ 558-42-9 ]
[ 196081-71-7 ]
2-bromo-3-(2-hydroxy-2-methylpropoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.3%	With sodium carbonate; In dimethyl sulfoxide; at 140℃; for 3h;	A solution of 2-bromo-3-hydroxybenzaldehyde (7.5 g, 37.3 mmol), 1- chloro-2-methylpropan-2-ol (9.4 g, 85.6 mmol) and Na2C03 (6.7 g, 63.2 mmol) in 70 mL of DMSO was stirred at 140 °C for 3 hours. Then the mixture was cooled to room temperature, poured into 300 mL of water, extracted with ethyl acetate (600 mL), washed with water (300 mL), brine (50 mL), dried over anhydrous sodium sulfate. The solvent was evaporated at 40 °C under reduced pressure and the residue was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and petroleum ether (1 :3) to give the title compound (9.2 g, 90.3percent) as a colorless oil. 1H NMR (300 MHz, CDCI3): delta 10.43 (s, 1 H), 7.54 (dd, 1 H, J1 =3.0, J2=7.5), 7.40-7.34 (m, 1 H), 7.54 (dd, 1 H, J1 =3, J2=7.5), 3.90 (s, 2H), 1.42 (s, 6H)
90.3%	With sodium carbonate; In dimethyl sulfoxide; at 140℃; for 3h;	[00212] A solution of 2-bromo-3-hydroxybenzaldehyde (7.5 g, 37.3 mmol), 1 - chloro-2-methylpropan-2-ol (9.4 g, 85.6 mmol) and Na2C03 (6.7 g, 63.2 mmol) in 70 mL of DMSO was stirred at 140 °C for 3 hours. Then the mixture was cooled to room temperature, poured into 300 mL of water, extracted with ethyl acetate (600 mL), washed with water (300 mL), brine (50 mL), dried over anhydrous sodium sulfate. The solvent was evaporated at 40 °C under reduced pressure and the residue was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and petroleum ether (1 :3) to give the title compound (9.2 g, 90.3percent) as a colorless oil. 1H NMR (300 MHz, CDCI3): delta 10.43 (s, 1 H), 7.54 (dd, 1 H, J1 =3.0, J2=7.5), 7.40-7.34 (m, 1 H), 7.54 (dd, 1 H, J1 =3, J2=7.5), 3.90 (s, 2H), 1 .42 (s, 6H).

Reference： [1]Patent: WO2015/21396,2015,A2 .Location in patent: Paragraph 00212-00213
[2]Patent: WO2016/128948,2016,A1 .Location in patent: Paragraph 00212

88
[ 558-42-9 ]
[ 1361189-68-5 ]
[ 1361190-12-6 ]

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

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H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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