[ CAS No. 16545-68-9 ] {[proInfo.proName]}

Name: 16545-68-9|Cyclopropanol|95%
Brand: Ambeed
SKU: A740969
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Quality Control of [ 16545-68-9 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 16545-68-9 ]

CAS No. :	16545-68-9	MDL No. :	MFCD19707103
Formula :	C₃H₆O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YOXHCYXIAVIFCZ-UHFFFAOYSA-N
M.W :	58.08	Pubchem ID :	123361
Synonyms :

Calculated chemistry of [ 16545-68-9 ]

Physicochemical Properties

Num. heavy atoms :	4
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	15.58
TPSA :	20.23 Å²

Pharmacokinetics

GI absorption :	Low
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) :	-6.58 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.12
Log Po/w (XLOGP3) :	0.1
Log Po/w (WLOGP) :	0.08
Log Po/w (MLOGP) :	-0.1
Log Po/w (SILICOS-IT) :	0.82
Consensus Log Po/w :	0.4

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.26
Solubility :	31.7 mg/ml ; 0.546 mol/l
Class :	Very soluble
Log S (Ali) :	-0.08
Solubility :	48.3 mg/ml ; 0.832 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.28
Solubility :	110.0 mg/ml ; 1.89 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 16545-68-9 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P210-P233-P240-P241-P242-P243-P261-P264-P271-P280-P303+P361+P353-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P370+P378-P403+P233+P235-P405-P501	UN#:	1993
Hazard Statements:	H225-H315-H319-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 16545-68-9 ]

* 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 [ 16545-68-9 ]
Downstream synthetic route of [ 16545-68-9 ]

[ 16545-68-9 ] Synthesis Path-Upstream 1~10

1
[ 411235-57-9 ]
[ 16545-68-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	With dihydrogen peroxide; sodium hydroxide In water at 5℃; for 1 h;	Step 1: cyclopropanol (0104) (0105) Cyclopropylboronic acid (10g, 0.116mol), sodium hydroxide aqueous solution (8.37g, 0.209mol, added to 100ml water) were added into a 1L reaction flask, and hydrogen peroxide (34percent, 80mL) was slowly dropped thereinto under ice bath and the temperature was kept not higher than 5°Cduring the process of dropping. After adding, the mixture was stirred at 5°C for 1 hour. After completion of the reaction, a saturated sodium thiosulfate aqueous solution was slowly dropped to terminate the reaction until the potassium iodide-starch test paper does not change color. The reaction solution was extracted with diethyl ether for three times and the combined organic phase was washed with saturated brine, dried, filtered and concentrated at 0°C to obtain the title compound (colorless oil, 4g, 60percent), which may be used directly for the subsequent reaction. (MS: [M+1] none)
43%	With dihydrogen peroxide; sodium hydroxide In water at 0℃; for 1 h;	A solution of aqueous hydrogen peroxide (30percent, 84 equiv) was added drop-wise to a stirring solution of cyclopropylboronic acid (1 equiv) in aqueous 10percent sodium hydroxide (1 equiv) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate pentahydrate and extracted with diethyl ether. The combined organic were dried over sodium sulfate, filtered, and concentrated in vacuo at 0° C. to give cyclopropanol (43percent yield) as clear oil. ¹H NMR (400 MHz, CHLOROFORM-d₁) δ ppm 3.49-3.53 (m, 1H) 2.22 (br. s., 1H) 0.52-0.60 (m, 2H) 0.42-0.52 (m, 2H).
36.4%	at 0℃; for 1.5 h;	To a solution of cyclopropylboronic acid (0.65 g, 7.57 mmol) in 10percent NaOH (5.0mL) at 0 °C was added a solution of 30percent hydrogen peroxide (21.44 mL, 189 mmol)dropwise. The reaction mixture was stirred at 0 °C for 1.5 h. The reaction mixture was diluted with diethyl ether, quenched with saturated NaHSO3 (15 mL) at 0 °C. After stirring for 15 mm, the organic layer was collected, washed with brine, dried over sodium sulfate and concentrated at 0 °C to give Intermediate 33A (0.16 g, 2.75 mmol, 36.4 percentyield) as colorless liquid. It was used for the next step without further purification. ‘H NMR (400MHz, chloroform-d) ö 3.62-3.41 (m, 1H), 0.69-0.40 (m, 4H).

33%

With dihydrogen peroxide; sodium hydroxide In water at 0℃; for 1 h;

A solution of aqueous H₂O₂(30percent, 20 mL, 200 mmol) was added dropwise with continuous stirring at 0° C. to a suspension of cyclopropyl boronic acid (0.62 g, 7.2 mmol) in 10percent aqueous NaOH (5 mL). The resulting mixture was stirred for 1 hour at 0° C. The reaction mixture was quenched with saturated aqueous Na₂S₂O₃and extracted with Et₂O. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo at 0° C. The material was dissolved in Et₂O (15 ml), 4 Molecular sieves were added and it was left overnight at room temperature to yield the title compound as pale yellow oil (140 mg, 33percent):¹H NMR (400 MHz, CDCl₃): δ 0.43 (m, 4H), 3.36 (m, 1H).

Reference： [1] Patent: EP3150592, 2017, A1, . Location in patent: Paragraph 0103; 0104; 0105
[2] Patent: US2014/200206, 2014, A1, . Location in patent: Paragraph 0319
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8989 - 9002
[4] Patent: WO2018/13774, 2018, A1, . Location in patent: Page/Page column 356
[5] Patent: US2012/10183, 2012, A1, . Location in patent: Page/Page column 54
[6] Patent: TW2016/2093, 2016, A, . Location in patent: Paragraph 0322
[7] Patent: WO2017/7701, 2017, A1, . Location in patent: Page/Page column 36-37
[8] Patent: US2016/194302, 2016, A1, . Location in patent: Paragraph 0411; 0412

2
[ 75-19-4 ]
[ 16545-68-9 ]

Reference： [1] Journal of the Chemical Society, Chemical Communications, 1981, # 10, p. 482 - 483
[2] Patent: US2004/171614, 2004, A1,
[3] Patent: US2005/85506, 2005, A1,

3
[ 7732-18-5 ]
[ 411235-57-9 ]
[ 16545-68-9 ]

Reference： [1] Patent: WO2015/65937, 2015, A1, . Location in patent: Paragraph 000295

4
[ 7722-84-1 ]
[ 411235-57-9 ]
[ 16545-68-9 ]

Reference： [1] Patent: US2015/166505, 2015, A1, . Location in patent: Paragraph 0328; 0329; 0330

5
[ 13837-45-1 ]
[ 16545-68-9 ]

Reference： [1] Journal of Organic Chemistry, 1980, vol. 45, # 21, p. 4129 - 4135

6
[ 4606-06-8 ]
[ 16545-68-9 ]
[ 64-19-7 ]

Reference： [1] Tetrahedron Letters, 1987, vol. 28, # 24, p. 2767 - 2768

7
[ 7393-45-5 ]
[ 16545-68-9 ]

Reference： [1] Journal of the American Chemical Society, 1951, vol. 73, p. 3176,3178

8
[ 74592-24-8 ]
[ 16545-68-9 ]

Reference： [1] Journal of Organic Chemistry, 1980, vol. 45, # 21, p. 4129 - 4135
[2] Journal of Organic Chemistry, 1980, vol. 45, # 21, p. 4129 - 4135

9
[ 106-89-8 ]
[ 16545-68-9 ]

Reference： [1] Journal of the American Chemical Society, 1972, vol. 94, p. 125 - 133

10
[ 358-23-6 ]
[ 16545-68-9 ]
[ 25354-42-1 ]

Reference： [1] Chemische Berichte, 1985, vol. 118, # 4, p. 1564 - 1574
[2] Journal of the American Chemical Society, 1972, vol. 94, p. 125 - 133

[ 16545-68-9 ] Synthesis Path-Downstream 1~88

1
[ 110-86-1 ]
[ 16545-68-9 ]
[ 99-33-2 ]
3,5-dinitro-benzoic acid cyclopropyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1943,vol. 65,p. 1782

2
[ 420-05-3 ]
[ 16545-68-9 ]
allophanic acid cyclopropyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1943,vol. 65,p. 1782

3
[ 7393-45-5 ]
[ 16545-68-9 ]

Reference： [1]Journal of the American Chemical Society,1951,vol. 73,p. 3176,3178

4
[ 16545-68-9 ]
(4-nitro-phenyl)-carbamic acid cyclopropyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1943,vol. 65,p. 1782

5
[ 358-23-6 ]
[ 16545-68-9 ]
[ 25354-42-1 ]

Reference： [1]Chemische Berichte,1985,vol. 118,p. 1564 - 1574
[2]Journal of the American Chemical Society,1972,vol. 94,p. 125 - 133

6
[ 16545-68-9 ]
[ 1656-44-6 ]
[ 36342-21-9 ]

Reference： [1]Journal of the American Chemical Society,1972,vol. 94,p. 125 - 133

7
[ 16545-68-9 ]
[ 542-78-9 ]

Reference： [1]Journal of the American Chemical Society,1975,vol. 97,p. 6502 - 6510

8
[ 16545-68-9 ]
[ 2134-29-4 ]

Reference： [1]Journal of the American Chemical Society,1975,vol. 97,p. 6502 - 6510

9
[ 16545-68-9 ]
[ 98-74-8 ]
[ 36342-20-8 ]

Reference： [1]Journal of the American Chemical Society,1972,vol. 94,p. 125 - 133

10
[ 106-89-8 ]
[ 16545-68-9 ]

Reference： [1]Journal of the American Chemical Society,1972,vol. 94,p. 125 - 133

11
[ 16545-68-9 ]
[ 57199-00-5 ]
[ 97674-05-0 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 3255 - 3260

12
[ 16545-68-9 ]
[ 184921-12-8 ]
(4-Cyclopropoxymethyl-piperidin-1-yl)-phenyl-methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4344 - 4361

13
[ 4606-06-8 ]
[ 16545-68-9 ]
[ 64-19-7 ]

Reference： [1]Tetrahedron Letters,1987,vol. 28,p. 2767 - 2768

14
[ 13837-45-1 ]
[ 16545-68-9 ]

Reference： [1]Journal of Organic Chemistry,1980,vol. 45,p. 4129 - 4135

15
[ 74592-24-8 ]
[ 16545-68-9 ]

Reference： [1]Journal of Organic Chemistry,1980,vol. 45,p. 4129 - 4135
[2]Journal of Organic Chemistry,1980,vol. 45,p. 4129 - 4135

16
4-Nitro-benzenecarboperoxoic acid 1-cyclopropyl-1-methyl-ethyl ester [ No CAS ]
[ 16545-68-9 ]
[ 67-64-1 ]
[ 62-23-7 ]

Reference： [1]Tetrahedron Letters,1981,vol. 22,p. 3389 - 3392

17
[ 75-19-4 ]
[ 16545-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	With LiOH; citric acid; In tetrahydrofuran; methanol; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	Step 2: To a solution of 60 mg of Compound 25 in 2 ml of THF was added a solution of 40 mg of LiOH in 0.3 ml of water. The mixture was stirred vigorously over a period of 4 hr, diluted with a few ml of 20% citric acid and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated, the residue was passed through a silica gel plug using 10% of MeOH in DCM as solvent to yield 40 mg of Compound 26.
	With LiOH; citric acid; In tetrahydrofuran; methanol; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	Step 2 To a solution of 60 mg of Compound 25 in 2 mL of THF was added a solution of 40 mg of LiOH in 0.3 mL of water. The mixture was stirred vigorously over a period of 4 hr, diluted with a few mL of 20% citric acid and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated, the residue was passed through a silica gel plug using 10% of MeOH in DCM as solvent to yield 40 mg of Compound 26.

Reference： [1]Journal of the Chemical Society. Chemical communications,1981,p. 482 - 483
[2]Patent: US2004/171614,2004,A1
[3]Patent: US2005/85506,2005,A1

18
[ 16545-68-9 ]
[ 98-58-8 ]
[ 97311-65-4 ]

Reference： [1]Chemische Berichte,1985,vol. 118,p. 1564 - 1574

19
[ 16545-68-9 ]
[ 189949-97-1 ]
3β-(4'-chlorophenyl)tropane-2β-carboxylic acid cyclopropyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 379 - 388

20
[ 16545-68-9 ]
[ 204071-17-0 ]
(1R,2S,3S,5S)-8-Methyl-3-p-tolyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid cyclopropyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 379 - 388

21
[ 16545-68-9 ]
[ 180057-11-8 ]
3β-(4'-iodophenyl)tropane-2β-carboxylic acid cyclopropyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 379 - 388

Yield	Reaction Conditions	Operation in experiment
92%		EXAMPLE VI Synthesis of (+,-)-cis-2-Ethylcyclopropylacetic Acid (15) Synthesis of (+,-)-cis-2-ethylcyclopropylacetic acid (15) was accomplished as illustrated in scheme 1. First the cis-3-hexen-1-ol was reacted with diethyl zinc in presence of chloroiodomethane (Scott E. Denmark and James P. Edwards J. Org. Chem. 1991, 56, 6974-6981) in dichloromethane at 0 C. to give the desired cyclopropyl alcohol 14 in 92% yield.

23
[ 16545-68-9 ]
[ 151397-81-8 ]
[ 53017-62-2 ]

Yield	Reaction Conditions	Operation in experiment
	In 5,5-dimethyl-1,3-cyclohexadiene; acetone;	EXAMPLE 28 1-(N-gamma-Hydroxypropyl)-aminomethyl-2,2-diphenyl cyclopropane hydrochloride (Formula V R = R1 = H, A = CH2 CH2 CH2) A mixture of 0.5 mole of 1-aminomethyl-2,2-diphenyl cyclopropane, 0.52 mole of gamma-<strong>[16545-68-9]cyclopropanol</strong> and 100 cc of xylene is heated with stirring to reflux temperature over a period of 7 hours. The mixture is then allowed to return to ambient temperature and 400 cc of acetone added to it. The product is then stirred for 3 hours, filtered, washed with 100 cc of acetone and dried.

Reference： [1]Patent: US3941833,1976,A

24
[ 919354-27-1 ]
[ 16545-68-9 ]
[ 919354-28-2 ]

Yield	Reaction Conditions	Operation in experiment
23%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	beta-Chloro-S-cyano-l-methylnicotinoyl chloride (2.00 g, 9.30 mmol), <strong>[16545-68-9]cyclopropanol</strong> (0.54 mL, 9.30 mmol) and DIPEA (1.62 mL, 9.30 mmol), were suspended in DCM (40 mL) and stirred at r.t for 16 h. Water (40 mL) was added to the solution and stirred for 5 minutes. The layers were separated and the organics were washed with water (2 x 40 mL), dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a solid. Flash chromatography (40% DCM in Hexanes) afforded cyclopropyl 6-chloro-5-cyano-2~ methyhiicotinate as a solid. Yield: 0.500 g (23 %). 1HNMR (400 MHz, CDC]3): delta 0.85-0.92 (4H, m), 2.90 (3H, s), 4.38-4.45 (IH, m), 8.41 (IH, s).

Reference： [1]Patent: WO2007/8140,2007,A1 .Location in patent: Page/Page column 142

25
C₁₆H₂₀ClNO₂ [ No CAS ]
[ 16545-68-9 ]
[ 1093117-88-4 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 8048 - 8056

26
[ 1203655-88-2 ]
[ 16545-68-9 ]
[ 1203652-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1,2-dimethoxyethane; at 20℃;	A mixture of (R)-4-(1-(4-{1 H-benzo[d][1 ,2,3JMaZOJ-I -yloxy)-6-(4- fluorophenyl)pyrido[3,2-d]pyrimidin-2-ylamino)ethyt)benzenesulfonamide (80 mg), cyciopropanoi (0.1 ml) and CsCO3 (94 mg) in DME (3 ml) was stirred at room temperature over the weekend. The reaction mixture was concentrated and purified by reverse phase HPLC (eiuting with ACN/H2O + 0,1% TFA) to give the title compound, which was characterized by its NMR and mass spectrum as follows: 1H NMR (CD3OD): d 0.83-1.04 (m, 4H), 1.66-1.70 (m, 3H). 4.50-4.58 (m, 1 H), 5.40-5.49 (m, 1 H), 7.19 (t, 2H)1 7.61-7.88 (m, 4H), 7.99-8.02 (m, 1 H), 8.08-8.13 (m, 2H), 8.30 (s, 1H); MS (m/z): 480.3 ([M+H]+, 100).

Reference： [1]Patent: WO2010/2998,2010,A1 .Location in patent: Page/Page column 82; 84

27
[ 16545-68-9 ]
[ 5451-40-1 ]
[ 1236968-90-3 ]

Yield	Reaction Conditions	Operation in experiment
35%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere;	2,6-dichloro-9-cyclopropylpurine2,6-Dichloropurine (1 mmol), triphenylphosphine (1.3 mmol), tetrahydrofurane (5 ml) and <strong>[16545-68-9]cyclopropanol</strong> (5 mmol) were stirred at it under nitrogen to give clear yellowish solution, which was then cooled to 0 C and diisopropyldiazadicarboxylate (DIAD; 1.3 mmol) was added via syringe. The reaction mixture was then stirred at rt for 12 h. After evaporation of the solvents the product was extracted with diethylether and purified by column chromatography (silicagel, 1% MeOH in CHCl3). Crystallization from methanol gave the product in yield 35 %, mp 121-124 C.

Reference： [1]Patent: WO2010/139289,2010,A1 .Location in patent: Page/Page column 25

28
[ 1118566-69-0 ]
[ 16545-68-9 ]
[ 1118567-45-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4465 - 4470

29
[ 766-11-0 ]
[ 16545-68-9 ]
[ 1243318-10-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 0℃; for 0.5h;	[000296j Compounds 5-bromo-2-fluoropyridine (25.0 g, 0.12 mol) and <strong>[16545-68-9]cyclopropanol</strong> (02, 10.4 g, 0.18 mol) were dissolved in NMP (100 mL) and treated with potassium tertbutoxide (180 mL, lMsolution in THF, 0.18 mol) at 0 C. The solution became dark and cloudy, and warmed. After 30 mm, the reaction mixture was partitioned between ethyl acetate and petroleum ether (500 mL, 1/1 v/v) and water (500 mL). The organic layer was separated, washed with water and 5% aq. LiC1, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 03. ?H-NMR (CDC13, 400 MHz) major characteristic peaks: (5(ppm) 0.74-0.81 (m, 4H), 4.13-4.18 (m, 1H), 6.88 (d, J= 8.8 Hz, 1H), 7.66 (dd, J 8.8, 2.4 Hz, 1H), 8.26 (d, J 2.4 Hz, 1H).

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 715 - 719
[2]Patent: WO2015/65937,2015,A1 .Location in patent: Paragraph 000296

30
[ 411235-57-9 ]
[ 16545-68-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	With dihydrogen peroxide; sodium hydroxide; In water; at 5℃; for 1h;	Step 1: cyclopropanol (0104) (0105) Cyclopropylboronic acid (10g, 0.116mol), sodium hydroxide aqueous solution (8.37g, 0.209mol, added to 100ml water) were added into a 1L reaction flask, and hydrogen peroxide (34%, 80mL) was slowly dropped thereinto under ice bath and the temperature was kept not higher than 5Cduring the process of dropping. After adding, the mixture was stirred at 5C for 1 hour. After completion of the reaction, a saturated sodium thiosulfate aqueous solution was slowly dropped to terminate the reaction until the potassium iodide-starch test paper does not change color. The reaction solution was extracted with diethyl ether for three times and the combined organic phase was washed with saturated brine, dried, filtered and concentrated at 0C to obtain the title compound (colorless oil, 4g, 60%), which may be used directly for the subsequent reaction. (MS: [M+1] none)
53%	With dihydrogen peroxide; sodium hydroxide; In water; at 0℃; for 3h;	A suspension of cyclopropyl boronic acid (1.00 g, 11.6 mol) in water (8 mL) was treated at 0 C with NaOH (1.02 g, 25.6 mmol), and stirred for 5 min until a homogeneous solution formed. A solution of 30% aqueous H2O2 (6.54 mL, 64.0 mmol) was added dropwise, and stirring was continued for 3 h at 0 C. The reaction mixture was extracted with Et20 (3 x 5 mL), and the combined organic layers were dried (Na2S04), filtered, and concentrated in vacuo at 0 C to afford cyclopropanol (0.36 g, 53%) as a colorless oil: NMR (500 MHz, CDCL) d 3.52-3.48 (m, 1 H), 0.57-0.46 (m, 4 H). The compound was dissolved in dry CH2CI2 (10 mL) and stored refrigerated over 4 A molecular sieves for 1 d before usage.
43%	With dihydrogen peroxide; sodium hydroxide; In water; at 0℃; for 1h;	A solution of aqueous hydrogen peroxide (30%, 84 equiv) was added drop-wise to a stirring solution of cyclopropylboronic acid (1 equiv) in aqueous 10% sodium hydroxide (1 equiv) at 0 C. The resulting mixture was stirred at 0 C. for 1 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate pentahydrate and extracted with diethyl ether. The combined organic were dried over sodium sulfate, filtered, and concentrated in vacuo at 0 C. to give cyclopropanol (43% yield) as clear oil. 1H NMR (400 MHz, CHLOROFORM-d1) delta ppm 3.49-3.53 (m, 1H) 2.22 (br. s., 1H) 0.52-0.60 (m, 2H) 0.42-0.52 (m, 2H).

36.4%	With dihydrogen peroxide; sodium hydroxide; at 0℃; for 1.5h;	To a solution of cyclopropylboronic acid (0.65 g, 7.57 mmol) in 10% NaOH (5.0mL) at 0 C was added a solution of 30% hydrogen peroxide (21.44 mL, 189 mmol)dropwise. The reaction mixture was stirred at 0 C for 1.5 h. The reaction mixture was diluted with diethyl ether, quenched with saturated NaHSO3 (15 mL) at 0 C. After stirring for 15 mm, the organic layer was collected, washed with brine, dried over sodium sulfate and concentrated at 0 C to give Intermediate 33A (0.16 g, 2.75 mmol, 36.4 %yield) as colorless liquid. It was used for the next step without further purification. ?H NMR (400MHz, chloroform-d) oe 3.62-3.41 (m, 1H), 0.69-0.40 (m, 4H).
33%	With dihydrogen peroxide; sodium hydroxide; In water; at 0℃; for 1h;	A solution of aqueous H2O2 (30%, 20 mL, 200 mmol) was added dropwise with continuous stirring at 0 C. to a suspension of cyclopropyl boronic acid (0.62 g, 7.2 mmol) in 10% aqueous NaOH (5 mL). The resulting mixture was stirred for 1 hour at 0 C. The reaction mixture was quenched with saturated aqueous Na2S2O3 and extracted with Et2O. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo at 0 C. The material was dissolved in Et2O (15 ml), 4 Molecular sieves were added and it was left overnight at room temperature to yield the title compound as pale yellow oil (140 mg, 33%):1H NMR (400 MHz, CDCl3): delta 0.43 (m, 4H), 3.36 (m, 1H).
	With dihydrogen peroxide; sodium hydroxide; In water; at 0℃; for 1h;	An aqueous solution of sodium hydroxide (10%, 1.29 mL, 3.49 mmol) and an aqueous solution of hydrogen peroxide (30%, 9.90 mL, 87.0 mmol) were added to cyclopropylboronic acid (0.300 g, 3.49 mmol) at 0 C., and the reaction liquid was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium thiosulfate was added to the reaction liquid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of cyclopropanol.
	With water; dihydrogen peroxide; sodium hydroxide; at 0℃; for 1h;	To a suspension of cyclopropyl boronic acid (6.2 g, 72 mmol) in 10% aqueous NaOH (50 mL) was added a solution of aqueous H2O2 (30%, 20 mL, 200 mmol) dropwise with continuous stirring at 0 C. After 1 hour at 0 C, the reaction mixture was quenched with saturated aqueous Na2S203 (30 mL, exothermic) and neutralized with 6 N HCl. The resulting solution was extracted with DCM (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered.
	With dihydrogen peroxide; sodium hydroxide; In water; at 0℃; for 1h;	Reference Example 24 Synthesis of crude cyclopropanol (0411) (0412) An aqueous solution of sodium hydroxide (10%, 1.29 mL, 3.49 mmol) and an aqueous solution of hydrogen peroxide (30%, 9.90 mL, 87.0 mmol) were added to cyclopropylboronic acid (0.300 g, 3.49 mmol) at 0 C., and the reaction liquid was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium thiosulfate was added to the reaction liquid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of cyclopropanol.

Reference： [1]Patent: EP3150592,2017,A1 .Location in patent: Paragraph 0103; 0104; 0105
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 929 - 935
[3]Patent: WO2019/203951,2019,A1 .Location in patent: Page/Page column 32-33
[4]Patent: US2014/200206,2014,A1 .Location in patent: Paragraph 0319
[5]Journal of Medicinal Chemistry,2017,vol. 60,p. 8989 - 9002
[6]Patent: WO2018/13774,2018,A1 .Location in patent: Page/Page column 356
[7]Patent: US2012/10183,2012,A1 .Location in patent: Page/Page column 54
[8]Patent: TW2016/2093,2016,A .Location in patent: Paragraph 0322
[9]Patent: WO2017/7701,2017,A1 .Location in patent: Page/Page column 36-37
[10]Patent: US2016/194302,2016,A1 .Location in patent: Paragraph 0411; 0412

31
[ 75-44-5 ]
[ 16545-68-9 ]
cyclopropyl carbonochloridate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dichloromethane; toluene; at 0℃; for 2h;	Step c) Cyclopropyl chloroformiate (BB8)The product of the previous step (50 mg, 0.86 mmol) was dissolved in DCM (1 mL) and cooled to 0 C. Phosgene (20% wt in toluene, 452 mu, 0.86 mmol) was added followed by K2C03 (357 mg, 2.58 mmol). The reaction was stirred vigorously for 2 h and the product was used as a solution in the next step (i.e. Step c, Method 2).
	With potassium carbonate; In dichloromethane; toluene; at 0 - 20℃;Inert atmosphere;	A solution of <strong>[16545-68-9]cyclopropanol</strong> (0.060 g, 1.03 mmol) in CH2CI2 (2 mL) was cooled to 0 C, treated with K2CO3 (0.43 g, 3.10 mmol) followed by phosgene (20% wt in toluene, 0.54 mL, 1.03 mmol), and stirred vigorously overnight at 0 C to room temperature. Unreacted phosgene was removed by purging the solution with N2 gas (passed through a KOH solution to dry) for 30 min. The reaction mixture was filtered through anhydrous MgS04, and concentrated at 0 C to afford cyclopropyl chloroformate as a colorless oil (~0.3 mL) that was used directly as a toluene solution for the next step (cyclopropyl chloroformate/<strong>[16545-68-9]cyclopropanol</strong> = 1:0.19, theoretical concentration = 2.8 M). 1 H NMR (400 MHz, CDCL) d 4.41-3.36 (m, 1 H), 0.98-0.82 (m, 4 H); 13C NMR (100 MHz, CDCL) d 151.3, 56.2, 5.49.

Reference： [1]Patent: WO2012/172473,2012,A1 .Location in patent: Page/Page column 29
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 929 - 935
[3]Patent: WO2019/203951,2019,A1 .Location in patent: Page/Page column 33

32
cyclopropyl benzoate [ No CAS ]
[ 16545-68-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step b) Cyclopropyl alcohol (BB8-b)The ester from the previous step (1 .09 g, 6.72 mmol) was suspended in phosphate buffer (0.1 M, pH 7.2, 40 mL), and Et20 (0.5 mL) was added. Candida lipase B (Novozym 435) immobilised on acrylic beads (0.5 g) was added and the mixture was shaken on a planar shaker for 48 h. 1 M aq NaOH (600 mu) solution was added after 12 h to adjust the pH from 6 to 7. The mixture was filtered through celite and diluted with H20 (50 mL). The solution was washed with hexane (40 mL), and the organic phase was discarded. The aqueous phase was saturated with NaCI and extracted with 5 X 20 mL Et20. The combined organic phases were washed with a 9:1 mixture of brine and aq sat NaHC03 (3 X 20 mL). The product was further purified by distillation at 200 mBar, 95 C. This gave 245 mg of the title compound with some minor impurities, and the product was used as such in the next step.

Reference： [1]Patent: WO2012/172473,2012,A1 .Location in patent: Page/Page column 29

33
[ 4684-94-0 ]
[ 16545-68-9 ]
[ 1248077-05-5 ]

Reference： [1]Patent: US2013/40936,2013,A1 .Location in patent: Paragraph 0230; 0231

34
[ 16545-68-9 ]
[ 271798-12-0 ]
[ 149674-61-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With 60percent of zinc oxide, 20percent of aluminum oxide, 15percent of stannous oxide, 2.5percent of lanthanum oxide and 2.5percent of cerium oxide; reducing by hydrogen; at 140℃; under 3750.38 Torr; for 2h;Large scale;	II. Ester exchange reaction [0104] Adding 1kg 1,4-pentanediol carbonate and 6.7kg <strong>[16545-68-9]cyclopropanol</strong> in a tubular ester exchange reactor; then adding 154g metal-rare earth oxide composite catalyst prepared by the embodiment 3, uniformly mixing and performing an ester exchange reaction, distilling the reaction product to obtain di<strong>[16545-68-9]cyclopropanol</strong> carbonate, wherein the mole ratio of 1,4-pentanediol carbonate to <strong>[16545-68-9]cyclopropanol</strong> is 1: 15, and the weight ratio of the metal-rare earth oxide composite catalyst to the total weight of 1,4-pentanediol carbonate and <strong>[16545-68-9]cyclopropanol</strong> is 2: 100; the ester exchange reaction is performed at a temperature of 140C and under an absolute pressure of 0.5MPa for 120 minutes; in the ester exchange reaction, the conversion rate of 1,4-pentanediol carbonate is 99%, and yield of the di<strong>[16545-68-9]cyclopropanol</strong> carbonate is 93%.

Reference： [1]Patent: EP2664608,2013,A1 .Location in patent: Paragraph 0104

35
[ 3939-09-1 ]
[ 16545-68-9 ]
[ 1243481-96-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 52 Preparation of Compound 52 (2S,5R,13aS)-N-(2-cyclopropoxy-4-fluorobenzyl)-8-hydroxy-7,9-dioxo- 2,3,4,5,7,9,13 ,13a-octahydro-2,5-methanopyrido[ ,2':4,5]pyrazino[2,l - b] [ 1 ,3]oxazepine- 10-earboxamide Step 1 A solution eyelopropanoi (1 ,9 g, 29 mmol) in 20 ml. dioxane was added dropwise to a 0 C solution of Sodium hydride (60% dispersion in mineral oil, 1 .04 g, 26 mmol) in 80 mL dioxane. The reaction mixture was allowed to warm to room temperature, 2,4-difluorobenzonitrile (3.48 g, 25 mmol) was added portionwise, and reaction temperature raised to 95 C. The reaction solution was cooled to room temperature after stirring for 18 hours, diluted with ethyl acetate, washed twice with water and twice with brine, dried over MgS04, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (0-10% EtO Ac/hex an es) afforded 2- cyclopropoxy-4-fluorobenzonitrile. iH~NMR (400 MHz, Chloroform-* ) 6 7.52 (dd, J :::: 8.6, 6.2 Hz, IH), 7.05 (dd, J = 10.5, 2.3 Hz, H), 6.73 (id, J = 8.2, 2.3 Hz, 1 H), 3.87 - 3.76 (m, IH), 0.87 (m, 4H).

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 113-114

36
[ 16545-68-9 ]
[ 1618663-21-0 ]
[ 1618663-61-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium t-butanolate; In 1,4-dioxane; at 25℃;	6-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), <strong>[16545-68-9]cyclopropanol</strong> (2 equiv), sodium tert-butoxide (2 equiv), 1,4-dioxane (0.03 M) were combined and stirred at 25 C. The reaction mixture was loaded directly onto a silica gel column and purified using flash chromatography (0-50% ethyl acetate in hexane) column, to give the title compound (80% yield) as clear oil. MS (ESI) m/z 471.5 [M+1]+.

Reference： [1]Patent: US2014/200206,2014,A1 .Location in patent: Paragraph 0320
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 8989 - 9002

37
[ 16545-68-9 ]
[ 33332-25-1 ]
methyl 5-(cyclopropoxy)pyrazine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 39h;	Methyl 5-(cyclopropoxy)pyrazine-2-carboxylate Cyclopropanol (542 muL, 8.69 mmol) is added to a suspension of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and potassium carbonate (1.60 g, 11.59 mmol) in dimethylformamide (11.6 mL). The reaction mixture is stirred for 15 hours at room temperature then for 24 hours at 50 C. The reaction is cooled to ambient temperature, diluted with water, and extracted with ethyl acetate (3 times). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The crude product is purified by silica gel flash chromatography, eluting with ethyl acetate/hexane (0:100) to ethyl acetate/hexane (35:65) to give the title compound (610 mg, 54%). ES/MS (m/e): 195.0 (M+1).

Reference： [1]Patent: US2014/371212,2014,A1 .Location in patent: Paragraph 0168; 0169

38
[ 16545-68-9 ]
C₂₆H₂₈N₄O₄ [ No CAS ]
4-(4-(cyclopropoxy(pyridin-2-yl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		4-(4-(Cyclopropoxy(pyridin-2-yl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (32 mg, 0.09 mmol) was dissolved in 5 ml DCM, to the solution was added SOCl2 (42 mg, 0.36 mmol), stirred at RT for 10 mins. Then to the reaction mixture was added <strong>[16545-68-9]cyclopropanol</strong> (41 mg, 0.7 mmol) at RT. Reaction completed instantly and was quenched with aq. NaHCO3, evaporated organic solvent, the residue was purified with Prep HPLC to afford 4-(4-(cyclopropoxy(pyridin-2-yl)methyl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole. C24H24N4O2. 401.1 (M+1). 1H NMR (400 MHz, CD3OD) delta 8.82-8.81 (m, 1H), 7.90-7.88 (m, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.66-7.64 (m, 1H), 7.50-7.47 (m, 2H), 6.66 (s, 1H), 3.98-3.87 (m, 1H), 2.40-2.38 (m, 1H), 2.32 (s, 3H), 2.15 (s, 3H), 2.16-2.10 (m, 2H), 1.35-1.24 (m, 8H)

Reference： [1]Patent: US2014/336190,2014,A1 .Location in patent: Paragraph 1177; 1178; 1179

39
[ 7732-18-5 ]
[ 411235-57-9 ]
[ 16545-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; sodium hydroxide; In diethyl ether; at 0 - 20℃;Molecular sieve;	[000295j A solution of aqueous H202 (30%, 400 mL, 4.00 mol) was added dropwise with continuous stirring at 0 C. To a suspension of cyclopropyl boronic acid Compound 01 (62.0 g, 0.72 1 mol) in 10% aqueous NaOH (500 mL). The resulting mixture was stirred for 1 h at 0 C. The reaction mixture was quenched with saturated aqueous Na2S2O3 and extracted with Et20. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo at 0C. The mixture was dissolved in Et20 (400 mL), 4 A molecular sieves were added and it was left overnight at room temperature to yield Compound 02. ?H-NMR (CDC13, 400 MHz) major characteristic peaks: (5(ppm) 0.49-0.57 (m, 4H), 3.48-3.50 (m, 1H).

Reference： [1]Patent: WO2015/65937,2015,A1 .Location in patent: Paragraph 000295

40
[ 16545-68-9 ]
[ 128071-98-7 ]
4-bromo-2-(cyclopropyloxy)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 20℃; for 0.5h;Inert atmosphere;	[000598j To a mixture of <strong>[16545-68-9]cyclopropanol</strong> (1.5 g, 25.8 mmol) and Compound 56A (3.0 g, 17.2 mmol) in N-methyl-2-pyrrolidone (20 mL) was added potassium tert-butoxide (2.9 g,25.8 mmol) in tetrahydrofuran (25 mL) dropwise and the resultant mixture was stirred at room temperature for 0.5 h under nitrogen protection. Then it was diluted with ethyl acetate (50 mL) and petroleum ether (50 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, evaporated and purified with flash column chromatography on silica gel (petroleum ether, 100% v/v) to furnish Compound 56B. LC-MS: (mlz) 216 [M+2] ?H-NMR (DMSO-d6, 400 MHz) 5 Qpm) 0.66-0.69 (m, 2H), 0.75-0.78 (m, 2H), 4.19-4.22 (m, 1H), 7.16 (m, 1H), 7.26-7.28 (m, 1H), 8.11-8.12 (d,J= 5.2 Hz,1H).
	With sodium t-butanolate; In 1-methyl-pyrrolidin-2-one; for 0.833333h;	To a solution of 4-bromo-2-fluoropyridine (3000 mg, 17.05 mmol) and <strong>[16545-68-9]cyclopropanol</strong> (1287 mg, 22.16 mmol) in NMP (22.6 mL) was added sodium tert-butoxide (22.7 mL, 22.67 mmol) . After 50 min, the reaction mixture was partitioned between ethyl acetate and water (100 mL) . The organic layer was separated, washed with water, brine, dried over Na2SO4,filtered and concentrated. The resulting residue was purified by a flash column chromatography on silica gel (ISCO 40g SiO2column, eluting with 0-25% EtOAc/hexanes) to afford the title compound.

Reference： [1]Patent: WO2015/65937,2015,A1 .Location in patent: Paragraph 000598
[2]Patent: WO2018/107415,2018,A1 .Location in patent: Page/Page column 84

41
[ 7722-84-1 ]
[ 411235-57-9 ]
[ 16545-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; at 0℃; for 1h;	Step 1: [0330] To a suspension of cyclopropylboronic acid (2.5 g, 29.0 mmol) in 10% aqueous NaOH (20 mL) was added drop-wise 30% H2O2 (80 mL) at 0 C. and the RM was stirred at same temperature for 1 h. The RM was quenched with Na2S2O3 solution and was extracted with Et2O. The combined organic layers were dried over CaCl2 and the mixture was filtered to obtain a solution which was used in next step (Note: this step was done in two parallel batches on 2.5 g scale and the combined solutions were used in the next step).

Reference： [1]Patent: US2015/166505,2015,A1 .Location in patent: Paragraph 0328; 0329; 0330

42
[ 864830-16-0 ]
[ 16545-68-9 ]
5-bromo-2-cyclopropyl-4-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.3 g		The solution obtained in step-I (200 mL) was diluted with NMP (50 mL) and was cooled to 0 C. NaH (2.59 g, 64.7 mmol) was added and the mixture was stirred for 20 min. 5-Bromo-2-fluoro-4-methyl-pyridine (2.05 g, 10.77 mmol, 0.55 eq.) was added and the RM was stirred at RT for 16 h. The RM was diluted with cold water and the layers were separated. The organic layer was washed with brine, was dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (SiO2CH2Cl2/Hex) to yield the desired compound (1.3 g, 19% over 2 steps). [0333] LC-MS (Method 3): m/z [M+H]+=228.3 (MW calc. 228.09); Rt=3.82 min.

Reference： [1]Patent: US2015/166505,2015,A1 .Location in patent: Paragraph 0328; 0331; 0332; 0333

43
[ 16545-68-9 ]
5-bromo-4-methoxy-2-nitro-pyridine [ No CAS ]
5-bromo-2-cyclopropoxy-4-methoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		A crude <strong>[16545-68-9]cyclopropanol</strong> solution in Et2O (50 mL, synthesized from 3.13 g of cyclopropyl boronic acid and H2O2) was diluted with NMP (15 mL) and cooled to 0 C. NaH (60% in mineral oil, 721 mg, 18.02 mmol) was added at 0 C. and the RM was stirred at same temperature for 10 min. A solution of 5-bromo-4-methoxy-2-nitro-pyridine (700 mg, 3.0 mmol) in NMP (15 mL) was added dropwise and the RM was stirred at RT for 30 min. The RM was quenched with cold water and extracted with 20% EtOAc/Hex. The organic layer was dried and concentrated under reduced pressure to give the crude product which was purified by CC (SiO2; 2% EtOAc/Hex) to yield 5-bromo-2-cyclopropoxy-4-methoxy-pyridine (BB-31, 300 mg, 40%). [0437] LC-MS (Method 4): m/z [M+1]+=244.0 and 246.0 (MW calc. 244.09); Rt=3.37 min

Reference： [1]Patent: US2015/166505,2015,A1 .Location in patent: Paragraph 0428; 0435; 0436; 0437

44
[ 64695-96-1 ]
[ 16545-68-9 ]
1-bromo-5-cyclopropyloxy-2-methyl-4-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium t-butanolate; In tetrahydrofuran; at 60℃; for 16h;	To a solution of <strong>[16545-68-9]cyclopropanol</strong> (1.3 mL, 26 mmol) and 1-bromo-5-fluoro-2-methyl-4- nitrobenzene (3 .Og, 13 mmol) in tetrahydrofuran (50 mL) was added sodium tert-butoxide (1.5 g, 15 mmol). The mixture was stirred at 60 C for 16 h, after which it was filtered and concentrated. The crude product was purified by flash column chromatography (5% ethyl acetate in petroleum ether) to give 1 -bromo-5-(cyclopropoxy)-2-methyl-4-nitro-benzene (3.2 g, 12 mmol, 92% yield) as a yellow solid.
78 g	With sodium t-butanolate; In N,N-dimethyl-formamide; at 0℃; for 1.5h;	Step 1: 1-bromo-5-cyclopropyloxy-2-methyl-4-nitrobenzene 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (70g , 0.3mol), freshly prepared <strong>[16545-68-9]cyclopropanol</strong> diethyl ether complex (23g, ?0.4mol) and N, N- dimethylformamide (260mL) were added into a 500mL reaction flask. Sodium tert-butoxide (35g, 0.36mol) was added slowly thereinto at 0Cand the reaction mixture was stirred at 0C for 1.5 hours. After completion of the reaction, the reaction mixture was poured into ice water slowly, and the precipitated solid was filtered to obtain the crude product. The filter cake was then washed with a lot of water and dried through air to obtain the title compound (yellow solid, 78g, 96%), which may be used directly for the subsequent reaction. (MS: [M+1] none)

Reference： [1]Patent: WO2018/234345,2018,A1 .Location in patent: Page/Page column 193; 194
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3738 - 3743
[3]Patent: EP3150592,2017,A1 .Location in patent: Paragraph 0112; 0113; 0114

45
[ 16545-68-9 ]
7-amino-2-benzyl-4-methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo-[3,4-c]pyridine-6-carboxylic acid [ No CAS ]
cyclopropyl 7-Amino-2-benzyl-4-methyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9371 - 9381

46
[ 16545-68-9 ]
isopropyl (5-(2-iodoacetyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbamate [ No CAS ]
isopropyl (5-(2-cyclopropoxyacetyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.5%		1005981 Cyclopropanol (113 mg, 1.94 mmol) was added to NaHMDS (1 M, 2.07 mL, 2.07 mmol) at 0 C under nitrogen. The mixture was stirred at 0 C for 0.5 hour. Isopropyl (5-(2- iodoacetyl)- 10,11 -dihydro-5H-dibenzo [b,J] azepin-3 -yl)carbamate (300 mg, 646 .imol) in THF (3 mL) was then added dropwise. The mixture was stirred at 25C for 1 hour. TLC showed that starting material was depleted. The reaction was quenched with aqueous saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 3), and washed with brine (20 mL x 2). The organic layer was dried with anhydrous sodium sulfate and concentrated to give a residue. The residue was dissolved in acetonitrile (3 mL) and purified by preparative HPLC to give compound 33 (82 mg, 208 .imol, 32.2% yield, 98.6%purity). ?H NMR (400 MHz, chloroform-cl) oe (ppm) 7.38-7.86 (m, 7H), 5.32 (br, s, 1H), 4.5 1-4.65 (m, 1H), 4.13-4.24 (m, 1H), 3.68-3.84 (m, 4H), 3.08-3.15 (m, 2H), 1.61 (d, J= 4.0 Hz,6H), 0.88 (br, s, 2H), 0.74-0.75 (m, 2H). ESI-TOF HRMS: m/z 395.1974 (C23H26N204 + Hrequires 395.1973).
32.2%		Cyclopropanol (113 mg,1.94 mmol) was added to NaHMDS (1 M,2.07 mL, 2.07 mmol) at 0 C under nitrogen. The mixture wasstirred at 0 C for 0.5 h. Compound 76 (300 mg, 646 mmol) in THF(3 mL) was then added dropwise. The mixture was stirred at 25 Cfor 1 h. TLC showed that starting material 76 was depleted. Thereaction was quenched with aqueous saturated ammonium chloride solution, extracted with ethyl acetate (20 mL 3), and washedwith brine (20 mL 2). The organic layer was dried with anhydroussodium sulfate and concentrated to give a residue. The residue wasdissolved in acetonitrile (3 mL) and purified by preparative HPLC togive compound 61 (82 mg, 208 mmol, 32.2% yield, 98.6% purity). 1HNMR (400 MHz, chloroform-d) d (ppm) 7.38e7.86 (m, 7H), 5.32 (br,s, 1H), 4.51e4.65 (m, 1H), 4.13e4.24 (m, 1H), 3.68e3.84 (m, 4H),3.08e3.15 (m, 2H),1.61 (d, J 4.0 Hz, 6H), 0.88 (br, s, 2H), 0.74e0.75(m, 2H). 13C NMR (126 MHz, DMSO-d6) d (ppm) 168.34, 153.56,140.90, 140.77, 140.59, 137.94, 135.48, 131.21, 130.97, 130.75, 130.55,129.25, 128.99, 128.83, 127.92, 127.71, 126.78, 119.09, 118.30, 118.08,117.55, 68.82, 68.11, 67.95, 53.75, 30.61, 30.02, 29.95, 29.39, 22.41,5.79, 5.76. ESI-TOF HRMS: m/z 395.1974 (C23H26N2O4 H requires395.1973).

Reference： [1]Patent: WO2016/64682,2016,A1 .Location in patent: Paragraph 00598
[2]European Journal of Medicinal Chemistry,2016,vol. 108,p. 505 - 528

47
[ 16545-68-9 ]
[ 105783-77-5 ]
3-cyclopropoxy-1,2,4-triazine [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2016,vol. 2016,p. 2842 - 2850
[2]Journal of Medicinal Chemistry,2019

48
[ 16545-68-9 ]
2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetic acid [ No CAS ]
cyclopropyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.061 g	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 16h;	Diisopropylethylamine (0.142 mL, 0.811 mmol), HBTU (0.184 g, 0.486 mmol), and crude <strong>[16545-68-9]cyclopropanol</strong> (0.0470 g, 0.811 mmol) were added to a solution of 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetic acid (0.100 g, 0.324 mmol) in chloroform (6.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 16 hours. Hydrochloric acid (1.0 N) was added to the reaction liquid, and then the reaction liquid was back-extracted. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained aqueous layer for neutralization, and then the resulting mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain cyclopropyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0.0610 g, 0.175 mmol, 54%) (hereinafter referred to as a ?compound of Example 44?) as a colorless oil.
0.061 g	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 16h;	Example 44 Synthesis of cyclopropyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0608) (0609) Diisopropylethylamine (0.142 mL, 0.811 mmol), HBTU (0.184 g, 0.486 mmol), and crude <strong>[16545-68-9]cyclopropanol</strong> (0.0470 g, 0.811 mmol) were added to a solution of 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetic acid (0.100 g, 0.324 mmol) in chloroform (6.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 16 hours. Hydrochloric acid (1.0 N) was added to the reaction liquid, and then the reaction liquid was back-extracted. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained aqueous layer for neutralization, and then the resulting mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain cyclopropyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0.0610 g, 0.175 mmol, 54%) (hereinafter referred to as a ?compound of Example 44?) as a colorless oil. (0610) 1H-NMR (400 MHz, CDCl3) delta: 0.70-0.78 (4H, m), 1.25-1.45 (2H, m), 1.78-1.87 (2H, m), 2.25-2.38 (7H, m), 2.52-2.62 (1H, m), 2.88-3.05 (5H, m), 3.94-4.04 (1H, m), 4.18-4.26 (1H, m), 4.54-4.62 (1H, m), 4.73 (2H, s), 6.80 (1H, brs), 6.96 (1H, brs). (0611) ESI-MS: m/z=349 (M+H)+.

Reference： [1]Patent: TW2016/2093,2016,A .Location in patent: Paragraph 0374
[2]Patent: US2016/194302,2016,A1 .Location in patent: Paragraph 0608; 0609; 0610; 0611

49
[ 16545-68-9 ]
[ 872367-64-1 ]
C₁₀H₁₁FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With 18-crown-6 ether; potassium carbonate; In tetrahydrofuran; at 60℃; for 3h;	Cyclopropanol (340mg, 5.85mmol) dissolved in tetrahydrofuran (10 mL), compound a87 (1,00g, 5.32mmol), potassium carbonate (1.62g, 11.7mmol)And 18-crown ether -6 (4.22g, 16.0mmol) was added, and the mixture was stirred for 3 h at 60C . Water and 1.0mol / L hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography - (hexane-ethyl acetate) to give the compound a88 (254mg, 21% yield).

Reference： [1]Patent: JP2016/79168,2016,A .Location in patent: Paragraph 0235

50
[ 16545-68-9 ]
C₁₁H₁₄F₂N₂O₂ [ No CAS ]
C₁₄H₁₉FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; for 3.5h;Cooling with ice;	Cyclopropanol (105mg, 1.80mmol) was dissolved in THF (5.0mL), compound a71 (400mg, 1.64mmol) was added. Tertiary butoxy potassium in the reaction solution (239mg, 2.12mmol) was added thereto under ice-cooling, and the mixture was stirred for three and a half hours under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound a72 the (440mg) as a crude product.
	With potassium tert-butylate; In tetrahydrofuran; for 3.5h;Cooling with ice;	Step 2 Preparation of Compound c72 (0552) Cyclopropanol (105mg, 1.80mmol) was dissolved in THF (5.0mL) and Compound c71 (400mg, 1 .64mmol) was added to the mixture. Tertiary butoxy potassium (239mg, 2.12mmol) was added to the reaction mixture under ice-cooling and the mixture was stirred for 3.5 hours under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound c72 a (440mg) as a crude product. [M + H] = 283.30, Method Condition 3: retention time 2.18 min

Reference： [1]Patent: JP2016/79168,2016,A .Location in patent: Paragraph 0233
[2]Patent: EP3059225,2016,A1 .Location in patent: Paragraph 0552

51
[ 16545-68-9 ]
C₆H₅Cl₂N₃O₂ [ No CAS ]
C₉H₁₀ClN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With 18-crown-6 ether; caesium carbonate; In tetrahydrofuran; for 7h;Reflux;	Compound a2 (400mg, 1.802mmol) in THF (4mL) solution of cyclo-propanol (157mg, 2.70mmol), 18-crown-6 (714mg, 2.70mmol) and cesium carbonate (1.761g, 5.40mmol ), and the mixture was heated to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate (20ml), filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the compound a3 a (140 mg, 32%) as a yellow solid.
32%	With 18-crown-6 ether; caesium carbonate; In tetrahydrofuran; for 7h;Reflux;	Step 3 Preparation of Compound c3 (0472) (0473) Cyclopropanol (157mg, 2.70mmol), 18-crown-6 (714mg, 2.70mmol) and cesium carbonate (1.761g, 5.40mmol) were added to the THF solution (4mL) of Compound c2 (400mg, 1.802mmol), and the mixture was refluxed for 7 hours. The mixture was diluted with ethyl acetate (20mL) and filtered through celite. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 5 : 1) to afford Compound c3 (140mg, yield 32%) as yellow solid. 1H-NMR (CDCl3) delta: 0.82-0.85 (m, 4H), 3.33 (d, J = 5.5 Hz, 3H), 4.40-4.45 (m, 1H), 7.84 (br s, 1H), 8.86 (s, 1H).

Reference： [1]Patent: JP2016/79168,2016,A .Location in patent: Paragraph 0223
[2]Patent: EP3059225,2016,A1 .Location in patent: Paragraph 0473

52
[ 16545-68-9 ]
2-(4-fluoro-2-methoxyphenyl)-3-methyloxirane [ No CAS ]
(1S,2S)-1-cyclopropoxy-1-(4-fluoro-2-methoxyphenyl)propan-2-ol [ No CAS ]
(1R,2S)-1-cyclopropoxy-1-(4-fluoro-2-methoxyphenyl)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%; 49%	With sulfuric acid; at 0℃; for 0.166667h;	To a solution of (2,S',3)S)-2-(4-fluoro-2-methoxyphenyl)-3-methyloxirane (50 mg, 0.274 mmol), in <strong>[16545-68-9]cyclopropanol</strong> (1.37 mL) was added sulfuric (1 drop). The reaction mixture was stirred at 0 C for 10 min then quenched by addition of solid K2C03. Volatiles were removed under a gentle stream of N2 and the resulting residue was purified via flash chromatography (Si02, 5- 30% acetone in hexanes) to yield the title compounds as two diastereomers: Major (1S,2S) (32 mg, 49%): 1H MR (400 MHz, CDC13) delta 7.31 (dd, J= 8.4, 6.9 Hz, 1H), 6.69 (td, J= 8.3, 2.4 Hz, 1H), 6.62 (dd, J= 10.9, 2.4 Hz, 1H), 4.62 (d, J= 7.5 Hz, 1H), 3.82 (s, 3H), 3.78 (dt, J= 13.2, 4.6 Hz, 1H), 3.16 (dq, J= 9.1, 3.0 Hz, 1H), 2.62 (s, 1H), 0.99 (d, J= 6.4 Hz, 3H), 0.66 - 0.50 (m, 2H), 0.40 (dddd, J= 16.3, 14.5, 10.4, 6.2 Hz, 2H); 19F NMR (376 MHz, CDC13) delta -112.05 (s); ESIMS m/z 263 ([M+Na]+). Minor (1R,2S) (18 mg, 27%): 1H NMR (400 MHz, CDC13) delta 7.38 (dd, J = 8.4, 7.0 Hz, 1H), 6.70 (td, J = 8.4, 2.4 Hz, 1H), 6.61 (dd, J = 10.9, 2.4 Hz, 1H), 4.83 (d, J = 4.2 Hz, 1H), 4.00 - 3.91 (m, 1H), 3.82 (s, 3H), 3.24 (dq, J = 9.2, 3.0 Hz, 1H), 1.94 (d, J = 6.2 Hz, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.70 - 0.63 (m, 1H), 0.59 - 0.52 (m, 1H), 0.51- 0.43 (m, 1H), 0.42 - 0.35 (m, 1H); 19F NMR (376 MHz, CDC13) delta -112.65 (s); ESIMS m/z 263 ([M+Na]+).

Reference： [1]Patent: WO2016/109305,2016,A1 .Location in patent: Paragraph 00115

53
[ 16545-68-9 ]
ethyl 5-bromo-2-(chloromethyl)nicotinate [ No CAS ]
5-bromo-2-(cyclopropoxymethyl)nicotinic acid [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 919 - 923

54
[ 392-63-2 ]
[ 16545-68-9 ]
2,3,3,3-tetrafluoropropionic acid cyclopropyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sulfuric acid; In water; at 130℃; for 12h;	Water (300 ml),Cyclopropanol (500 ml),N, N-diethyl-2,3,3,3-tetrafluoropropanamide (900 g, 4.47 mol),98% sulfuric acid (600 ml) was placed in the reaction flask,The temperature was raised to 130 C and refluxed for 12 hours.Reaction completed,Atmospheric distillation,Fractions of around 127 C were collected to give cyclopropyl 2,3,3,3-tetrafluoropropionate,The yield was 90%Purity 98.6%.

Reference： [1]Patent: CN106278887,2017,A .Location in patent: Paragraph 0047; 0048

55
[ 16545-68-9 ]
[ 2106-49-2 ]
1-chloro-2-cyclopropoxy-3-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		To a stirred suspension of NaH (0.91 g, 22.8 mmol) in THF (30 mL) was added <strong>[16545-68-9]cyclopropanol</strong> (1.08 mL, 17.1 mmol) in an inert atmosphere at 0C and the reaction mixture was stirred at same temperature for 30 min. A solution of 1-chloro-2-fluoro-3-nitrobenzene (2.00 g, 11.4 mmol) in THF (10 mL) was added drop wise at 0C and the reaction mixture was heated at 75C for 3h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled at room temperature, poured in to crushed ice and extracted with EtOAc (2 * 80 mL). The organic layer was separated, washed with H2O (60 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 10% EtOAc in hexanes) to afford 1-chloro-2-cyclopropoxy-3-nitrobenzene XI-2a (1.20 g) as a pale yellow oil. Yield: 49%. 1H NMR (400 MHz, DMSO-d6) delta 0.60-0.66 (m, 2H), 0.72-0.77 (m, 2H), 4.28-4.33 (m, 1H), 7.35-7.39 (m, 1H), 7.85-7.92 (m, 2H).
		To a solution of NaH (60% dispersion in mineral oil, 319 mg, 7.98 mmol) in THF (10 mL) was slowly added <strong>[16545-68-9]cyclopropyl alcohol</strong> (0.35 mL, 5.58 mmol). After 15 minutes of stirring, 1-chloro-2- fluoro-3-nitrobenzene (700 mg, 3.99 mmol) was added and the resulting solution heated to 75 C for 1 hour. The reaction mixture was cooled to room temperature,quenched with water (5 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine (5 mL), dried over MgSO4 and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product.
		l-chloro-2-cyclopropoxy-3-nitrobenzene : To a solution of NaH (60% dispersion in mineral oil, 319 mg, 7.98 mmol) in THF (10 mL) was slowly added <strong>[16545-68-9]cyclopropyl alcohol</strong> (0.35 mL, 5.58 mmol). After 15 minutes of stirring, l-chloro-2- fluoro-3-nitrobenzene (700 mg, 3.99 mmol) was added and the resulting solution heated to 75 C for 1 hour. The reaction mixture was cooled to room temperature, quenched with water (5 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine (5 mL), dried over MgS04 and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product.

Reference： [1]Patent: EP3584244,2019,A1 .Location in patent: Paragraph 0195; 0197-0198
[2]Patent: WO2017/7694,2017,A1 .Location in patent: Page/Page column 112; 113
[3]Patent: WO2017/7689,2017,A1 .Location in patent: Page/Page column 113; 114

56
[ 16545-68-9 ]
[ 3744-87-4 ]
(R)-cyclopropyl 2-((tert-butoxycarbonyl)amino)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; at 20℃; for 16h;	To the filtration were added (R)-2-((tert-butoxycarbonyl)amino)propanoic acid (6.6 g, 34.9 mmol), HATU (13.3 g, 34.9 mmol) and Et3N (3.8 g, 34.9 mmol). The resulting mixture was stirred for 16 h at ambient temperature. The reaction was quenched by water (10 mL) and washed with a solution of saturated aqueous solution of NaHC03 (3 x 200 mL). The organic layer was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (50: 1) to provide the title compound: LC/MS: [(M+l)]+ = 230.0.

Reference： [1]Patent: WO2017/7701,2017,A1 .Location in patent: Page/Page column 36-37

57
[ 32315-10-9 ]
[ 16545-68-9 ]
C₁₉H₁₉FN₄O₃ [ No CAS ]
C₂₃H₂₃FN₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%		To a solution of <strong>[16545-68-9]cyclopropanol</strong> (58 mg, 1.0 mmol), TEA (606 mg, 6.0 mmol) in DCM (10 mL) was added triphosgene (297 mg, 1 mmol) under ice bath. The solution was warmed to room temperature and stirred for 1 h. TEA (202 mg, 2.0 mmol) and 120-2 (370 mg, 1.0 mmol) were then added. The resulting solution was heated at 50 C for 1 h. After cooling to room temperature, the solution was diluted with DCM. The resulting solution was washed with brine. The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 50 : 1~ 20 : 1) to give 158-1 (150 mg, 33 %) as a gray solid.

Reference： [1]Patent: WO2017/7755,2017,A1 .Location in patent: Paragraph 252

58
[ 16545-68-9 ]
(2S,4R)-1-(2-(3-acetyl-5-isocyanato-1H-indol-1-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide [ No CAS ]
cyclopropyl (3-acetyl-1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indol-5-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 24h;	Compound 98 was dissolved in a mixture of THF (7 mL), ACN (3 mL), and <strong>[16545-68-9]cyclopropanol</strong> (35mg, 2 equiv), followed by the addition of Et3 (76 mu^, 2 equiv) at 0 C. The reaction mixture was then stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by flash column chromatography (silica gel eluted with DCM/CH3OH) to afford the product cyclopropyl (3 -acetyl- 1 -(2-((2S,4R)-2-((3 - chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-l-yl)-2-oxoethyl)-lH-indol-5-yl)carbamate (14). 1H MR (400 MHz, DMSO-i): (major rotamer) delta 0.68-0.72 (m, 4H), 2.00-2.17 (m, 1H), 2.40 (s, 3H), 2.49-2.56 (m, 1H), 3.89 (ddd, J = 22.8, 9.6, 2.8 Hz, 1H), 4.05-4.14 (m, 1 H), 4.32 (dd, J = 20.8, 6.0 Hz, 1H), 4.42-4.49 (m, 2H), 5.12 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 17.2 Hz, 1H), 5.50 (d, J= 52.8 Hz, 1H), 6.97-7.01 (m, 1H), 7.15-7.45 (m, 4H), 8.18 (s, 1 H), 8.31 (s, 1H), 8.59 (t, J = 5.6 Hz, 1H), 9.49 (s, 1H). 19F MR (376 MHz, DMSO-i): (major rotamer) delta -121.8, -176.1. LC (method 1): fe = 1.78 min. LC/MS (EI) mlz: [M + H]+ calcd for C28H27CIF2N4O5, 573; found, 573.

Reference： [1]Patent: WO2017/35349,2017,A1 .Location in patent: Paragraph 0532

59
[ 16545-68-9 ]
7-fluoro-2-methyl-6-nitro-1,2,3 ,4-tetrahydroisoquinoline [ No CAS ]
N-methyl-7-cyclopropoxy-6-nitro-1,2,3,4-tetrahydroisoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		Step 6: N-methyl-7-cyclopropoxy-6-nitro-1,2,3,4-tetrahydroisoquinoline N-methyl-7-fluoro-6-nitro-1,2,3,4-tetrahydroisoquinoline (150mg, 0.72mmol), sodium tert-butoxide (83mg, 0.86mmol) and N, N-dimethylformamide (5mL) were added to a 25ml reaction flask under nitrogen protection. The reaction was stirred for 10 minutes at 0C, and added with <strong>[16545-68-9]cyclopropanol</strong> (54mg, 0.93mmol) in N, N-dimethylformamide (5mL) solution. The reaction was stirred and reacted for 1 hour at 0C. After completion of the reaction, ethyl acetate and water were added to the reaction solution, and the reaction solution was extracted with ethyl acetate twice additionally. The combined organic phase was washed with saturated brine, dried and concentrated. The obtained crude product was separated and purified by column chromatography (silica gel column, eluent: ethyl acetate/petroleum ether, gradient: 0?50%) to obtain the title compound (140mg, 79%). (MS: [M+1] 249.1)

Reference： [1]Patent: EP3150592,2017,A1 .Location in patent: Paragraph 0329; 0340; 0341

60
[ 16545-68-9 ]
2-bromo-4-fluoro-5-nitro-benzonitrile [ No CAS ]
2-bromo-4-cyclopropyloxy-5-nitrobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%		Step 2: 2-bromo-4-cyclopropyloxy-5-nitrobenzonitrile 2-bromo-4-fluoro-5-nitrobenzonitrile (660mg, 2.7mmol), N, N-dimethylformamide (10mL) were added to a 250mL reaction flask. Sodium tert-butoxide (285mg, 2.97mmol) was added slowly at 0C. After the reaction mixture was stirred for 10 minutes, <strong>[16545-68-9]cyclopropanol</strong> (313mg, 5.4mmol) was added slowly into the reaction system. The reaction mixture was stirred for 30 minutes at 0C. After completion of the reaction, the reaction mixture was poured into ethyl acetate and the organic phase was washed with saturated aqueous lithium chloride solution and saturated aqueous sodium chloride solution, dried, concentrated and purified by column chromatography (eluent: ethyl acetate/petroleum ether=1:10) to obtain the title compound (yellow solid, 201mg, 26%). (MS: [M+1] none)

Reference： [1]Patent: EP3150592,2017,A1 .Location in patent: Paragraph 0121; 0124; 0125

61
[ 16545-68-9 ]
[ 100948-84-3 ]
1-chloro-2-cyclopropoxy-4-methoxy-5-nitrobenzene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3383 - 3404

62
[ 697-18-7 ]
[ 16545-68-9 ]
cyclopropyl 2,2-difluoro-2-(fluorosulfonyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 0 - 20℃;	Cyclopropanol (58 mg) was added to dichloromethane (10 mL)A perfluorosulfonate (1 mL) was added dropwise under ice-cooling,Drop finished, naturally rise to room temperature,After completion of the reaction, the water quenching reaction,Washed with dichloromethane (100 mL x 2), washed with water (10 mL x 2), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under pressure,To obtain crude fumigant 15 (2,2-difluoro-2- (sulfonylfluoro) acetic acid cyclopropyl ester), molar yield 90%

Reference： [1]Patent: CN106973901,2017,A .Location in patent: Paragraph 0053-0055

63
[ 16545-68-9 ]
[ 10314-98-4 ]
C₁₇H₂₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
190 mg		To a solution of 1-benzyloxycarbonylpiperidin-4-carboxylic acid (400 mg) in toluene (3 mL) were added TEA (0.85 mL) and diphenylphosphoryl azide (627 mg), and the mixture was stirred at 90 C for 3h. Then, <strong>[16545-68-9]cyclopropanol</strong> (132 mg) (which was prepared analogous to the method described in, for example, US 2012/0010183) was added thereto, and the mixture was stirred at 80 C overnight. The reaction mixture was diluted with ethyl acetate, separated by adding saturated aqueous sodium bicarbonate solution, and the aqueous layer was further extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (190 mg). MS (m/z): 319 [M+H]+

Reference： [1]Patent: EP3190116,2017,A1 .Location in patent: Paragraph 0146

64
2,4-difluoro-N-methyl-5-nitro-benzamide [ No CAS ]
[ 16545-68-9 ]
C₂₁H₂₇ClN₄OSi [ No CAS ]
C₃₂H₃₉FN₆O₃Si [ No CAS ]
C₃₂H₃₉FN₆O₃Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%; 39%		A mixture of intermediate 425 (1.15 g; 5.32 mmol), <strong>[16545-68-9]cyclopropanol</strong> (337 jiL; 5.32mmol) and cesium carbonate (3.5 g; 10.64 mmol) in 1,4-dioxane (15 mL) was heated at80C for 1 hour. The reaction mixture was cooled to room temperature, and dilutedwith DCM. The organic layer was washed with water, filtered through chromabond and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 50g; mobile phase: gradient from 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane). The fractions containing the products were collected andevaporated to dryness yielding 860 mg (63%) of a mixture of intermediates 426 and427 directly used in the next step without any further purification.A mixture of intermediate 426 and 427 (860 mg; 3.38 mmol), iron pownder (945 mg;16.91 mmol) and ammonium chloride (724 mg; 13.53 mmol) in ethanol (22 mL) andwater (5.6 mL) was heated at 70C for 1 hour. The reaction mixture was cooled down to room temperature, diluted with DCM, filtered over Celite and basified with a 10%aqueous solution of K2C03. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness yielding 791 mg of a mixture of intermediates 428 and 429 directly engaged in the next step.In a sealed tube, a mixture of intermediate 7R (936 mg; 2.25 mmol) in 1,4-dioxane (25 mL) was purged with N2. A mixture of intermediates 428 and 429 (758 mg; 3.38 mmol) and cesium carbonate (1.47 g; 4.51 mmol) were successively added and the suspension was degassed after each addition. Then, Pd(OAc)2 (51 mg; 0.226 mmol) and BNAP(140 mg; 0.226 mmol) were added. The flask was sealed, the reaction mixture was degassed with N2 and stirred at 120C (pre-heated bath) for 4 hours.The reaction mixture was cooled to room temperature, poured onto water and extracted with DCM. The organic layer was decanted, dried over MgSO4, filtered over celite and evaporated to dryness. The residue was purified by chromatography over silica gel(irregular SiOH, 80g; mobile phase: gradient from 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane). The pure fractions were collected and evaporated to dryness yielding 451 mg (33%) of intermediate 430 (33%) and 530 mg (39%) of intermediate431.

Reference： [1]Patent: WO2017/125530,2017,A1 .Location in patent: Page/Page column 149; 150; 310; 311

65
2,4-difluoro-N-methyl-5-nitro-benzamide [ No CAS ]
[ 16545-68-9 ]
C₁₁H₁₁FN₂O₄ [ No CAS ]
C₁₁H₁₁FN₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1,4-dioxane; at 80℃; for 1h;	A mixture of intermediate 425 (1.15 g; 5.32 mmol), <strong>[16545-68-9]cyclopropanol</strong> (337 jiL; 5.32mmol) and cesium carbonate (3.5 g; 10.64 mmol) in 1,4-dioxane (15 mL) was heated at80C for 1 hour. The reaction mixture was cooled to room temperature, and dilutedwith DCM. The organic layer was washed with water, filtered through chromabond and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 50g; mobile phase: gradient from 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane). The fractions containing the products were collected andevaporated to dryness yielding 860 mg (63%) of a mixture of intermediates 426 and427 directly used in the next step without any further purification.

Reference： [1]Patent: WO2017/125530,2017,A1 .Location in patent: Page/Page column 310

66
2,4-difluoro-N-methyl-5-nitro-benzamide [ No CAS ]
[ 16545-68-9 ]
C₁₁H₁₃FN₂O₂ [ No CAS ]
C₁₁H₁₃FN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of intermediate 425 (1.15 g; 5.32 mmol), <strong>[16545-68-9]cyclopropanol</strong> (337 jiL; 5.32mmol) and cesium carbonate (3.5 g; 10.64 mmol) in 1,4-dioxane (15 mL) was heated at80C for 1 hour. The reaction mixture was cooled to room temperature, and dilutedwith DCM. The organic layer was washed with water, filtered through chromabond and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 50g; mobile phase: gradient from 20% EtOAc, 80% heptane to 40% EtOAc, 60% heptane). The fractions containing the products were collected andevaporated to dryness yielding 860 mg (63%) of a mixture of intermediates 426 and427 directly used in the next step without any further purification.A mixture of intermediate 426 and 427 (860 mg; 3.38 mmol), iron pownder (945 mg;16.91 mmol) and ammonium chloride (724 mg; 13.53 mmol) in ethanol (22 mL) andwater (5.6 mL) was heated at 70C for 1 hour. The reaction mixture was cooled down to room temperature, diluted with DCM, filtered over Celite and basified with a 10%aqueous solution of K2C03. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness yielding 791 mg of a mixture of intermediates 428 and 429 directly engaged in the next step.

Reference： [1]Patent: WO2017/125530,2017,A1 .Location in patent: Page/Page column 310; 311

67
[ 16545-68-9 ]
C₁₃H₁₉F₂NO₃Si [ No CAS ]
C₁₆H₂₄FNO₄Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With caesium carbonate; In 1,4-dioxane; at 100℃;	A mixture of intermediate 525 (858 mg; 2.83 mmol), <strong>[16545-68-9]cyclopropanol</strong> (717 jiL; 11.3mmol) and cesium carbonate (1.84 g; 5.66 mmol) in 1,4-dioxane (9.5 mL) was heatedat 100C for 2h. The reaction mixture was heated at 100C overnight, cooled to roomtemperature and diluted with DCM. Water was added and the reaction mixture was extracted with DCM (three times). The combined organic layers were washed withwater, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 40 g; mobile phase: gradient from10% EtOAc, 90% heptane to 20% EtOAc, 80% heptane). The pure fractions were collected and evaporated to dryness yielding 581 mg (60%) of intermediate 526.

Reference： [1]Patent: WO2017/125530,2017,A1 .Location in patent: Page/Page column 323

68
[ 16545-68-9 ]
[ 112-76-5 ]
[ 737813-07-9 ]

Yield	Reaction Conditions	Operation in experiment
Ca.85%	With triethylamine; In dichloromethane; at 0 - 4℃; for 2h;	7 mmol of <strong>[16545-68-9]cyclopropanol</strong>, dissolved in 20 ml of anhydrous dichloromethane, were placed in a 100 ml round bottom flask and added of 1.5 ml of triethylamine. To this solution have been added, drop-wise, through a loading funnel, 7 mmol of stearoyl chloride dissolved in anhydrous dichloromethane. The reaction has been maintained at 0-4C under continuos stirring and 2 hrs later the reaction was stopped. Solvent was removed, under reduced pressure, using a rotary evaporator. The residue was purified using a home-made silica chromatographic column eluted with chloroform. Fractions containing cyclopropyl-stearate were collected and the solvent was removed, under reduced pressure, using a rotary evaporator. (0091) The reaction yield has been approximately 85%. Physico-chemical properties of cyclopropyl-stearate: [tabl0022-en] appearance colourless liquid formula C21H42O2 molecular weight 326.57 elemental analysis C = 77.50% ; H = 12.98 ; O = 9.52 solubility in organic solvents >10 mg/ml in DMSO and in chloroform solubility in water scarcely soluble melting point < 20C TLC eluent: chloroform; Rf = 0.75

Reference： [1]Patent: EP1592418,2017,B1 .Location in patent: Paragraph 0090-0092

69
[ 16545-68-9 ]
[ 112-67-4 ]
[ 60128-91-8 ]

Yield	Reaction Conditions	Operation in experiment
Ca.80%	With triethylamine; In dichloromethane; at 0 - 4℃; for 2h;	10 mmol of <strong>[16545-68-9]cyclopropanol</strong>, dissolved in 20 ml of anhydrous dichloromethane, were placed in a 100 ml round bottom flask and added of 1.5 ml of triethylamine. To this solution have been added, drop-wise, through a loading funnel, 10 mmol of palmitoyl chloride dissolved in anhydrous dichloromethane. The reaction has been maintained at 0-4C under continuos stirring and 2 hrs later the reaction was stopped. Solvent was removed, under reduced pressure, using a rotary evaporator. The residue was purified using a home-made silica chromatographic column eluted with chloroform. Fractions containing cyclopropyl-palmitate were collected and the solvent was removed, under reduced pressure, using a rotary evaporator. (0088) The reaction yield has been approximately 80%. Physico-chemical properties of cyclopropyl-palmitate: [tabl0021-en] appearance colourless liquid formula C19H38O2 molecular weight 298.51 elemental analysis C = 75.80% ; H = 12.80 ; O = 11.40 solubility in organic solvents >10 mg/ml in DMSO and in chloroform solubility in water scarcely soluble melting point < 20C TLC eluent: chloroform; Rf = 0.78

Reference： [1]Patent: EP1592418,2017,B1 .Location in patent: Paragraph 0087-0089

70
[ 16545-68-9 ]
[ 350-46-9 ]
1-cyclopropoxy-4-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
460 mg		To a stirred solution of <strong>[16545-68-9]cyclopropanol</strong> (0.122 mL) in DMF (8 mL) at 0 C was carefully added NaH (191 mg). The reaction mixture was stirred at 0 C for 30 min. 1 -Fluoro-4-nitrobenzene (450 mg) was then added slowly. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with ice water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (460 mg). GCMS m/z 179.1 (M+).

Reference： [1]Patent: WO2017/153952,2017,A1 .Location in patent: Page/Page column 157

71
[ 144100-07-2 ]
[ 16545-68-9 ]
2-bromo-6-cyclopropoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium tert-butylate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 0 - 20℃; for 2h;	A mixture of 2-bromo-6-fluoropyridine (371 mg, 2.1 mmol) and <strong>[16545-68-9]cyclopropanol</strong> (350 mg, 6.0 mmol) in NMP (6 mL) was stirred for 5 minutes at 0 oC. Then to the solution was added dropwise a solution of t-BuOK in THF (1M, 0.6 mL, 0.6 mmol) at 0 oC. After addition, the reaction mixture was warmed to RT and stirred for 2 h. The reaction mixture was poured into a mixed solvent of PE/EA/water (50 mL/50mL/100 mL). The organic layer was separated, washed with 5% of LiCl aqueous solution (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column (5% ~ 10% EA/PE) to afford 2-bromo-6-cyclopropoxypyridine (374 mg, 83%) as a colorless oil. LC- MS m/z: 216&218 [M+H]+. Purity (214 nm): 99.6%.
	With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 12h;	2-Bromo-6-fluoropyridine (3.00 g, 17.05 mmol) and <strong>[16545-68-9]cyclopropanol</strong> (1.09 g, 18.76 mmol) were dissolved in 30 mL THF, potassium tert-butoxide (2.47 g, 22.01 mmol) was added at 0C, then stirred at 0C for 12 h. 50 mL water was added into, then extracted by 100 mL EA, the organic phase was washed by 100 mL brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to give 50-1. MS m/z: 216.0 [M+H]+

Reference： [1]Patent: WO2017/176961,2017,A1 .Location in patent: Paragraph 00663
[2]Patent: EP3572413,2019,A1 .Location in patent: Paragraph 0335-0337

72
[ 16545-68-9 ]
[ 42098-25-9 ]
C₇H₉N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium tert-butylate; In acetonitrile; at 20℃; for 3h;	KO'Bu (938 mg, 8.36 mmol) was added to a stirred solution of 5-chloro-l-methyl-4- nitro-lH-pyrazole (900 mg, 5.57 mmol) and <strong>[16545-68-9]cyclopropanol</strong> (970.713 mg, 16.713 mmol) in MeCN (7.27 mL) at rt. Addition was done portionwise. The mixture was stirred at rt for 3hours. Water was added and the mixture acidified with 3N HCl(aq). The reaction mixture was extracted with DCM, dried over MgS04, filtered and evaporated. A purification was performed via preparative LC (Stationary phase: irregular SiOH 15- 40muiotaeta 80g GraceResolv, Mobile phase: gradient from 100% DCM to 98% DCM, 2% MeOH, 0, 1% NH4OH) to afford intermediate 620 (470 mg, yield 46 %).

Reference： [1]Patent: WO2018/2217,2018,A1 .Location in patent: Page/Page column 336

73
[ 16545-68-9 ]
[ 35852-77-8 ]
C₆H₇N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%		At 0C and under nitrogen flux, NaH (60% dispersion in mineral oil) (0.510 g; 12.8 mmol) was added portionwise to a solution of <strong>[16545-68-9]cyclopropanol</strong> (0.64 mL, 12.74 mmol) in Me-THF (24mL). The reaction was stirred at room temperature for 10 minutes. (1844) At -78C, the above described suspension was added dropwise to a solution of 1,4- dinitro-lH-pyrazole (3.00 g; 18.98 mmol) in Me-THF (6.50 mL, 64.9 mmol). The reaction mixture was stirred at -78C for 1 h then allowed to stir at rt for 5 hours. The reaction mixture was poured out onto water, made acidic with 3N HCl(aq), extracted with DCM, dried over MgS04, filtered and evaporated. The crude was purified via preparative LC (Stationary phase irregular SiOH 15-40muiotaeta 24g GraceResolv, Mobile phase: gradient from 80% Heptane, 20% EtOAc to 40% heptane, 60% EtOAc). The pure fractions were collected and the solvent was evaporated to give 466 mg of intermediate 746 (22%).

Reference： [1]Patent: WO2018/2217,2018,A1 .Location in patent: Page/Page column 344

74
[ 16545-68-9 ]
[ 7693-46-1 ]
cyclopropyl (4-nitrophenyl) carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With pyridine; In dichloromethane; at 0℃; for 1.5h;	To a solution of 1.5 g (7.44 mmol, 1.0 eq.) of 4-nitrophenyl chloroformate in 25 mL ofmethylene chloride at 0C was added 0.5 g (8.61 mmol, 1.16 eq.) of <strong>[16545-68-9]cyclopropanol</strong> followedby 0.63 g (8.05 mmol, 1.08 eq) of pyridine. The resulting solution was stirred at 0 C for 1.5 h. The mixture was diluted with 5 mL of methylene chloride and 10 mL of 0.1 M aqueous sulfuric acid. The organic phase was then washed with 10 mL of sat. NaHCO3, 10 mL of water and 10 mL of brine. The organic phase was dried (Na2SO4), filtered and concentratedto a volume of approximately 5 mL, and 10 mL of cyclohexane was added. The resulting yellow solid was removed, and the filtrate was evaporated to provide 0.8 g (3.58 mmol, 48%) of cyclopropyl (4-nitrophenyl) carbonate. ?H NMR (400 MHz, CDC13): 8.26-8.19 (m, 2H), 7.34-7.25 (m, 2H), 4.25-4.19 (m, 1H), 0.85-0.69 (m, 4H).
	With pyridine; In dichloromethane; at 20℃; for 1h;	To a solution of <strong>[16545-68-9]cyclopropanol</strong> (100.00 mg, 1.72 mmol, 1.00 eq) and pyridine (4008.16 mg, 5.16 mmol, 416.49 jiL3.00 eq) in DCM (5.00 mL) was added (4-nitrophenyl)carbonochloridate(346.68 mg, 1.72 mmol, 1.00 eq). The mixture was stirred at 20 C for 1 h. TLC (PE: EtOAc =3:1) showed that reactant (4-nitrophenyl)carbonochloridate was consumed completely and one main new spot formed. The mixture was diluted with 10 mL of DCM and washed with HC1 (1N, 30 mL* 1), saturated NaHCO3 solution (30 mL) and brine (20 mL* 1). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give cyclopropyl (4-nitrophenyl)carbonate (4000.00 mg, crude) as white solid and directly used in the next step.

Reference： [1]Patent: WO2018/172852,2018,A1 .Location in patent: Page/Page column 110; 176
[2]Patent: WO2018/5881,2018,A1 .Location in patent: Page/Page column 331

75
[ 16545-68-9 ]
tert-butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate [ No CAS ]
tert-butyl 3-cyclopropoxy-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 20 - 110℃; for 5.5h;	To a solution of <strong>[16545-68-9]cyclopropanol</strong> (30.8 mg, 0.531 mmol), butetyrlt- 2,3-dihydro-3-oxopyrazole-l-carboxylate (97.7 mg, 0.531 mmol) and triphenylphosphine (139.3 mg, 0.531 mmol) in anhydrous toluene (2 mL) was added di-tert-butyl azodicarboxylate (122.2 mg, 0.531 mmol). The solution was purged with argon for 1 minute, and stirred at ambient temperature for 30 minutes. Then the reaction solution was heated at 110 C for additional 5 hours before it cooled to ambient temperature. The solution was diluted with ether (50 mL), washed with NaOH aqueous solution, brine, dried over sodium sulfate, filtered and concentrated under the reduced pressure. Residue obtained was purified by silica gel chromatography (hexane and ethyl acetate, 0 to 10% ethyl acetate gradient) to afford bteurtyt-l 3-cyclopropoxy-lH-pyrazole-l-carboxylate (52mg, 46%) as a white solid. ESI-MS m/z calc. 224.116, found 225.0 (M+l)+; Retention time: 4.38 minutes. lH NMR (250 MHz, CDC13) delta (ppm) 7.86 (d, J = 2.8Hz, 1H), 5.93 (d, J = 2.8Hz, 1H), 4.20-4.15 (m, 1H), 1.61 (s, 9H), 0.85-0.72 (m, 4H).

Reference： [1]Patent: WO2018/64632,2018,A1 .Location in patent: Paragraph 00635; 00636

76
[ 16545-68-9 ]
tournefolic acid A [ No CAS ]
cyclopropyl (E)-3-(2-(3,4-dihydroxyphenyl)-7-hydroxybenzofuran-4-yl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		Take an appropriate amount of <strong>[16545-68-9]cyclopropanol</strong> and cool it in an ice bath for 15 minutes.Was slowly added dropwise 2eq SOCl2, the reaction was cooled 30min,Then compound Tournefolic acid A(2)(1eq) was added and placed at room temperature.The reaction was continuously monitored by TLC (chloroform/methanol/formic acid 8:1:1, v/v/v) until the starting point disappeared.The reaction product is concentrated under reduced pressure,The crude product was isolated and purified by silica gel column chromatography (chloroform/methanol/formic acid 15:1:0.1-7:1:0.1, v/v/v) to give the target compound 8 (yield 78%).

Reference： [1]Patent: CN107586284,2018,A .Location in patent: Paragraph 0103; 0104; 0105; 0106; 0107; 0108; 0109-0111

77
[ 16545-68-9 ]
4-bromo-3-chloro-2-fluoropyridine [ No CAS ]
4-bromo-3-chloro-2-cyclopropoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.1%	With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 1.5h;Sealed tube;	To a suspension of 4-bromo-3-chloro-2-fluoropyridine (200 mg, 950 muetaiotaomicron) in DMSO (1 mL) was added <strong>[16545-68-9]cyclopropanol</strong> (82.4 mg, 1.42 mmol) and cesium carbonate (619 mg, 1.90 mmol). Reaction mixture was stirred in a capped vial at 100 C for 90 minutes. The resulting reaction mixture was diluted with EtOAc and H20. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography 0-25% EtOAc/Heptane to yield the desired product 4-bromo-3-chloro-2-cyclopropoxypyridine (50.0 mg, 201 muiotaetaomicron, 21.1%). LC-MS (ESI) m/z: [M + H] calculated for C8H7BrClNO: 247.94; found 249.0.

Reference： [1]Patent: WO2018/13597,2018,A1 .Location in patent: Paragraph 0650

78
[ 16545-68-9 ]
N-(2-((2-(2-cyclopropoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.6 mg	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.416667h;	To 60% sodium hydride (15.66 mg, 0.392 mmol) was added Intermediate 33A(37.9 mg, 0.653 mmol) in DMF (0.5 mL). The reaction mixture was stirred at roomtemperature for 15 mm. A solution of Intermediate 30A (15 mg, 0.026 mmol) in DMF (1.0 mL) was added. The reaction mixture was stirred at room temperature for 25 mm.LCMS indicated a completion of the reaction. The reaction mixture was diluted with EtOAc, quenched with 0.5 N HC1. The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated. The crude was dissolved in DMF/acetonitrile (1:1, 2.2 mL) and purified via preparative LC/MS (method D, 60-100% B over 10minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 33 (8.6 mg). ?H NMR (500MHz, DMSO-d6) 8.67 (s, 1H), 8.59 (s, 1H), 7.90 (dd, J=8.5, 5.2 Hz, 2H), 7.83 (s, 1H), 7.45-7.40 (m, 3H), 6.85 (s, 1H), 4.53-4.49 (m, 1H), 4.05 (t, J5.4 Hz, 2H), 3.22 (t, J5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H), 0.93-0.88 (m, 2H), 0.87-0.82 (m, 2H); LC-MS:method A, RT = 2.67 mm, MS (ESI) m/z: 565.1(M+H)t Analytical HPLC purity (method B): 100%.

Reference： [1]Patent: WO2018/13774,2018,A1 .Location in patent: Page/Page column 356; 357

79
[ 16545-68-9 ]
C₂₁H₁₃ClFN₃O [ No CAS ]
(S)-cyclopropyl-8-ethynyl-6-(2-fluorophenyl)-4-methyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.16 g	With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	General procedure: A mixture of the acid SH-053-2'F-S-CH3-acid 6 (200 mg, 0.56 mmol), thionyl chloride (0.407 mL, 5.6 mmol) and dry DCM (20 mL) wasplaced in an oven dried round bottom flask under argon. This suspension, which formed, was allowed to refluxat 60 C for 1 h under argon. The absence of the starting material was confirmed on analysis by TLC (silica gel).The organic solvent and excess thionyl chloride were removed under reduced pressure on a rotovapor. Thisprocedure was repeated five times with dry DCM (15 mL). The yellow residue, which remained was dissolvedin dry DCM (20 mL) and cooled to 0 C for 10 min under argon. Then the appropriate nucleophilicalcohol/thiol/amine (5.6 mmol), followed by triethylamine (0.78 mL, 5.6 mmol) was added to the reactionmixture at 0C and the mixture individually was then allowed to warm to rt and stirred for 1-2 h. After thecompletion of the reaction by TLC (silica gel), the solvent was removed under reduced pressure. The residuewas treated with ice cold water (15 mL) and extracted with DCM (3 x 20 mL). The combined organic layer waswashed with brine (20 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and theresidue was purified by column chromatography to yield the corresponding pure esters, thioesters or amidesdescribed below.

Reference： [1]Arkivoc,2018,vol. 2018,p. 158 - 182

80
[ 16545-68-9 ]
methyl 2-([5-(4-bromothien-2-yl)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate [ No CAS ]
methyl 2-([1-[(2-chlorophenyl)methyl]-5-(4-cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With C51H41ClNOP2Pd; caesium carbonate; In 1,4-dioxane; at 85℃; for 1h;Microwave irradiation;	Methyl 2-([1-[(2-chlorophenyl)methyl]-5-(4-cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate To a solution of the product from the previous step (350 mg, 0.72 mmol, 1.00 equiv) in dioxane (10 mL) was added stepwise Cs2CO3 (473 mg, 1.45 mmol, 2.00 equiv), 2nd Generation XantPhos precatalyst (322 mg, 0.36 mmol, 0.50 equiv), and <strong>[16545-68-9]cyclopropanol</strong> (168 mg, 2.89 mmol, 4.00 equiv). The final reaction mixture was irradiated with microwave radiation for 1 h at 85 C. The resulting solution was diluted with 100 mL of EtOAc. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/petroleum ether (1:2). This resulted in the title compound as a yellow oil (150 mg, 45%).

Reference： [1]Patent: US2018/162822,2018,A1 .Location in patent: Paragraph 0651; 0654

81
[ 16545-68-9 ]
C₁₈H₁₅Cl₂F₃N₆O [ No CAS ]
C₂₁H₂₀ClF₃N₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride; In N,N-dimethyl-formamide; at 110℃; for 2h;Microwave irradiation;	Cesium fluoride (577 mg, 3.8 mmol) was added to a solution of compound 71 (436 mg, 0.95 mmol) in DMF (7.35 mL) and the resulting mixture was stirred and degassed for 15 minutes. Cyclopropanol (0.072 mL, 1.14 mmol) was added and the RM was heated at 110 C for 2 h under microwave irradiation. The solvent was removed in vacuo, then the resulting residue was dissolved in a 1 : 1 mixture of DCM/water (20 mL). The resulting biphasic mixture was separated, then the aqueous layer was extracted with DCM (2x 10 mL). The combined organic layers were dried over MgS04, filtered and the solvent removed under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, using as eluent a gradient DCM/MeOH, 100/0 to 99/1, to provide compound 393 (308 mg) as an impure material, which was used as such in the next step

Reference： [1]Patent: WO2018/83098,2018,A1 .Location in patent: Page/Page column 127

82
[ 16545-68-9 ]
tert-butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate [ No CAS ]
tert-butyl 2,3-dihydro-3-oxopyrazole-1-carboxylate [ No CAS ]
tert-butyl 3-cyclopropoxy-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 20 - 110℃; for 5.5h;	To a solution of <strong>[16545-68-9]cyclopropanol</strong> (30.8 mg, 0.531 mmol), tert-butyl 2,3-dihydro-3- oxopyrazole-1-carboxylate (97.7 mg, 0.531 mmol) and triphenylphosphine (139.3 mg, 0.531 mmol) in anhydrous toluene (2 mL) was added di-tert-butyl azodicarboxylate (122.2 mg, 0.531 mmol). The solution was purged with argon for 1 minute, and stirred at ambient temperature for 30 minutes. Then the reaction solution was heated at 110 C for additional 5 hours before it was cooled to ambient temperature. The solution was diluted with ether (50 mL), washed with NaOH aqueous solution, brine, dried over sodium sulfate, filtered and concentrated under the reduced pressure. Residue obtained was purified by silica gel chromatography (hexane and ethyl acetate, 0 to 10% ethyl acetate gradient) to afford tert-butyl 3-cyclopropoxy-1H-pyrazole-1-carboxylate (52 mg, 46%) as a white solid. ESI-MS m/z calc.224.116, found 225.0 (M+1)+; Retention time: 4.38 minutes.1H NMR (250 MHz, CDCl3) delta (ppm) 7.86 (d, J = 2.8Hz, 1H), 5.93 (d, J = 2.8Hz, 1H), 4.20-4.15 (m, 1H), 1.61 (s, 9H), 0.85-0.72 (m, 4H).

Reference： [1]Patent: WO2018/107100,2018,A1 .Location in patent: Page/Page column 235; 236

83
[ 16545-68-9 ]
ethyl (R)-2-bromo-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetate [ No CAS ]
ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-cyclopropoxyacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-cyclopropoxyacetate Two reactions were carried out in parallel. A mixture of ethyl (R)-2-bromo-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetate (20 g, 39.7 mmol, 1 eq) and <strong>[16545-68-9]cyclopropanol</strong> (6.9 g, 119 mmol, 3 eq) in DCE (300 ml, freshly distilled from P2O5) was stirred with 4 A molecular sieves (15 g) for 0.5 hr at 15 C. To a suspension of AgOTf (30.6 g, 119 mmol, 3 eq) in DCE (300 ml, freshly distilled from P2O5) was added 4 A molecular sieves (15 g). The mixture was stirred at 15 C. for 0.5 hr in dark. The two mixtures were mixed together and stirred at 80 C. in dark for 1.5 hrs. LC-MS showed the reaction was complete. Two reactions were combined for workup. The reaction mixture was filtered, concentrated in vacuo. The residue was purified by silica gel chromatography eluted with Petroleum ether: Ethyl acetate (20:1) to give pure product. To the solid was added Petroleum ether (70 mL). The mixture was stirred at 15 C. for 0.5 hr. The mixture was filtered. The solid was dried in vacuo to afford ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-cyclopropoxyacetate. LCMS-ESI+: calc'd for C21H20BrClNO3S: 480.0 (M+H)+; found: 480.0 (M+H)+. Individual enantiomers were separated using chiral SFC (OJ (250 mm*30 mm, 5 um); Neu-MeOH) to give ethyl (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-cyclopropoxyacetate (peak 1, [alpha]D20 -103.59 (c 1.0, CHCl3)) and ethyl (R)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-cyclopropoxyacetate (peak 2, [alpha]D20 +98.22 (c 1.0, CHCl3)).

Reference： [1]Patent: US2018/118734,2018,A1 .Location in patent: Paragraph 0315; 0317

84
[ 31309-08-7 ]
[ 16545-68-9 ]
2-cyclopropoxy-5-nitronicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; at 20℃;	2-Chloro-5-nitronicotinonitrile (300 mg, 1.64 mmol) and <strong>[16545-68-9]cyclopropanol</strong> (380 mg, 6.54 mmol) were added to potassium carbonate (339 mg, 2.45 mmol), and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and dissolved in ethyl acetate (5 mL). Water (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL*3). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated to dryness to give crude compound 41a. The crude product was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 60/40) to afford compound 41a as a yellow solid (310 mg, 92%). 1H NMR (400 MHz, DMSO-d6) delta ppm 0.85-0.90 (m, 4H), 4.52-4.58 (m, 1H), 9.18 (d, J=2.76 Hz, 1H), 9.35 (d, J=2.76 Hz, 1H).

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 126; 1127

85
[ 22353-40-8 ]
[ 16545-68-9 ]
3-chloro-2-cyclopropoxy-5-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		Cyclopropanol (4.304 g, 74.10 mmol) was slowly added to a mixture of NaH (4.042 g, 101.0 mmol) in THF (30 mL) at room temperature. The mixture was stirred at 40 C. for 1 h. 2,3-Dichloro-5-nitropyridine in THF (20 mL) was added to the mixture at 0 C. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (50 mL). The mixture was extracted with ethyl acetate (200 mL*3). The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 90/10) to afford 3-chloro-2-cyclopropoxy-5-nitropyridine, 18a (9 g, 53%) as a yellow solid.

Reference： [1]Patent: US2018/170909,2018,A1 .Location in patent: Paragraph 0944; 0945

86
[ 350-30-1 ]
[ 16545-68-9 ]
2-chloro-1-cyclopropoxy-4-nitrobenzene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 6724 - 6735

87
[ 74124-79-1 ]
[ 16545-68-9 ]
[ 63038-27-7 ]
(S)-2-((cyclopropoxycarbonyl) amino)-3,3-dimethylbutanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To asolution of <strong>[16545-68-9]cyclopropanol</strong> (0.4 ml, 6.37 mmol) in CH3CN (18 mL) at 0C, was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (DSC) (3.26 g, 12.74 mmol) followed by Et3N (2.66 ml, 19.11 mmol). The reaction mixture was warmed up to 40C and stirred overnight. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue triturated with DCM, the solid filtered, and the filtrated was purified by silica column chromatography (10% - 100%EtOAc/hexanes). The product (663 mg, 3.33 mmol) was dissolved5 in THF (5 mL) and L-tert-leucine methyl ester hydrochloride (0.91 g, 5 mmol) and Et3N (1.39 ml, 0.01 mol) were added, the reaction was warmed up to 40C for 18h, then at room temperature for 48 h, diluted with EtOAc, washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure and the residue (760 mg, 3.31 mmol) was dissolved in a mixture of Methanol (4 mL) / water (2 mL), lithium hydroxide, monohydrate10 (0.56 g, 0.01 mol) was added. After 16 h, the mixture was concentrated, diluted with EtOAc, washed with brine, the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford A5 1HNMR (400 MHz, Chloroform-d) oe 4.19 (d, J 9.6 Hz, 1H), 1.02 (s, 11H), 0.68 (d, J= 4.8 Hz, 5H).

Reference： [1]Patent: WO2018/145021,2018,A1 .Location in patent: Page/Page column 130; 131

88
[ 16545-68-9 ]
[ 1493-27-2 ]
1-(cyclopropyloxy)-2-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.6%	With caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 6h;Inert atmosphere;	1) Under a nitrogen atmosphere, 0.30 g (2.20 mmol) of 2-fluoronitrobenzene, 3.0 mL of N,N-dimethylformamide (analytical grade) and 0.19 g of <strong>[16545-68-9]cyclopropanol</strong> (3.30 mmol) were placed in a 25 mL single port. In a flask, 1.07 g (3.30 mmol) of cesium carbonate was added in two portions under magnetic stirring, so that the temperature in the flask did not exceed 75 C. The mixture was heated to 75 C in a water bath and magnetically stirred for 6 h.2) After the reaction time is reached, the reaction liquid obtained in the step 1) is quenched with 15 mL of water, extracted with ethyl acetate (4 mL×3), washed with saturated brine (4 mL×3), dried over sodium sulfate (1.5 g) After filtration, the obtained filtrate was concentrated by rotary evaporation to give ethyl acetate.The crude product is purified by a silica gel column. The purification is specifically: 2.5 g of column chromatography silica gel containing 200-300 mesh sieve in a column, and the crude product is dissolved in 1.0 mL of ethyl acetate and 0.5 g of the above silica gel. After mixing, the mixture was injected into a silica gel column, and a mixture of ethyl acetate and petroleum ether = 1:100 volume ratio was used as a detergent, and the amount was 300 mL; the eluate which satisfies the pure point of TLC detection was collected; After treatment, a pale yellow oily liquid was obtained, which was found to be 1-(cyclopropoxy)-2-nitrobenzene, yield 92.6%.
0.35 g	With caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 6h;Inert atmosphere;	Into a 25 mL single-necked round-bottom flask 2-fluoronitrobenzene(0.30 g, 2.1 mmol), DMF (4 mL), and <strong>[16545-68-9]cyclopropanol</strong>(0.18 g, 3.2 mmol) were successively added under N2 protection.After that, the mixture was stirred. And Cs2CO3(1.04 g, 3.2mmol) was put into the flask at nitrogen atmosphere. Then theresulting mixture started to be heated to 75 C in a water bath.The reaction was followed by TLC and HPLC. After the reactionwas complete, the resulting mixture was diluted with H2O (30mL) and extracted with AcOEt (3 × 10 mL). Then the combinedorganic phase was washed with saturated aqueous NaCl (3 × 10mL) and dried over Na2SO4 for 0.5 h. After that, the organicphase was concentrated under reduced pressure to give crudeproduct. Further, column chromatography (eluent: petroleumether/ethyl acetate = 10:1) on silica gel was needed to afford thepure product as a yellow oily liquid in 92.6% yield (0.35 g).Data for 1-(Cyclopropyloxy)-2-nitrobenzene as TypicalExample1H NMR (600 MHz, CHCl3-d): = 7.83 (dd, J = 8.2, 1.6 Hz, 1 H),7.55 (m, 1 H), 7.48 (dd, J = 8.4, 1.2 Hz, 1 H), 7.08-7.03 (m, 1 H), 3.90 (m, 1 H), 0.91-0.86 (m, 4 H) ppm. 13C NMR (151 MHz,CHCl3-d): = 152.48, 139.72, 133.92, 125.44, 120.53, 115.56,52.36, 6.43 ppm. MS (EI): m/z = 178.0 [M]

Reference： [1]Patent: CN109265352,2019,A .Location in patent: Paragraph 0030; 0040-0043; 0066-0068; 0069-0071
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 7589 - 7613
[3]Synlett,2019,vol. 30,p. 982 - 986

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