[ CAS No. 556-48-9 ] {[proInfo.proName]}

Name: 556-48-9|Cyclohexane-1,4-diol|98%
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Quality Control of [ 556-48-9 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 556-48-9 ]

CAS No. :	556-48-9	MDL No. :	MFCD00001448
Formula :	C₆H₁₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VKONPUDBRVKQLM-UHFFFAOYSA-N
M.W :	116.16	Pubchem ID :	11162
Synonyms :

Calculated chemistry of [ 556-48-9 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	31.17
TPSA :	40.46 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.38
Log Po/w (XLOGP3) :	0.19
Log Po/w (WLOGP) :	0.28
Log Po/w (MLOGP) :	0.21
Log Po/w (SILICOS-IT) :	0.63
Consensus Log Po/w :	0.54

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.68
Solubility :	24.3 mg/ml ; 0.209 mol/l
Class :	Very soluble
Log S (Ali) :	-0.6
Solubility :	29.3 mg/ml ; 0.252 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.12
Solubility :	152.0 mg/ml ; 1.31 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.27

Safety of [ 556-48-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 556-48-9 ]

* 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 [ 556-48-9 ]
Downstream synthetic route of [ 556-48-9 ]

[ 556-48-9 ] Synthesis Path-Upstream 1~16

1
[ 556-48-9 ]
[ 13482-23-0 ]

Reference： [1] Journal of Medicinal Chemistry, 1989, vol. 32, # 2, p. 351 - 357
[2] Patent: US2014/256706, 2014, A1,
[3] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 6671 - 6679

2
[ 67-56-1 ]
[ 542-28-9 ]
[ 627-93-0 ]
[ 4547-43-7 ]
[ 1119-40-0 ]
[ 14273-92-8 ]
[ 931-17-9 ]
[ 556-48-9 ]
[ 106-65-0 ]

Reference： [1] Patent: EP1189859, 2004, B1, . Location in patent: Page 9

3
[ 67-56-1 ]
[ 124-04-9 ]
[ 1191-25-9 ]
[ 556-48-9 ]
[ 637-88-7 ]
[ 542-28-9 ]
[ 627-93-0 ]
[ 4547-43-7 ]
[ 1119-40-0 ]
[ 14273-92-8 ]
[ 931-17-9 ]
[ 106-65-0 ]

Reference： [1] Patent: WO2004/46072, 2004, A1, . Location in patent: Page/Page column 9-10

4
[ 67-56-1 ]
[ 64-18-6 ]
[ 110-94-1 ]
[ 124-04-9 ]
[ 1191-25-9 ]
[ 13392-69-3 ]
[ 556-48-9 ]
[ 627-93-0 ]
[ 4547-43-7 ]
[ 1119-40-0 ]
[ 14273-92-8 ]
[ 931-17-9 ]
[ 106-65-0 ]

Reference： [1] Patent: WO2006/48170, 2006, A1, . Location in patent: Page/Page column 13

5
[ 67-56-1 ]
[ 64-18-6 ]
[ 110-94-1 ]
[ 124-04-9 ]
[ 1191-25-9 ]
[ 13392-69-3 ]
[ 556-48-9 ]
[ 542-28-9 ]
[ 627-93-0 ]
[ 4547-43-7 ]
[ 1119-40-0 ]
[ 14273-92-8 ]
[ 931-17-9 ]
[ 106-65-0 ]

Reference： [1] Patent: WO2004/26798, 2004, A2, . Location in patent: Page/Page column 10

6
[ 556-48-9 ]
[ 41043-88-3 ]

Reference： [1] Chemistry - A European Journal, 2007, vol. 13, # 17, p. 4859 - 4872
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 8, p. 2496 - 2511
[3] Tetrahedron, 1987, vol. 43, # 12, p. 2681 - 2688
[4] Tetrahedron, 2012, vol. 68, # 10, p. 2363 - 2373
[5] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 6671 - 6679

7
[ 556-48-9 ]
[ 108-24-7 ]
[ 41043-88-3 ]

Reference： [1] Journal of the Chemical Society, 1940, p. 10,14

8
[ 556-48-9 ]
[ 2987-06-6 ]

Reference： [1] Journal of Organic Chemistry, 2006, vol. 71, # 18, p. 6851 - 6858
[2] Tetrahedron, 2000, vol. 56, # 38, p. 7513 - 7524
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 46 - 47
[4] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1973, p. 2165 - 2173
[5] Gazzetta Chimica Italiana, 1965, vol. 95, p. 438 - 447
[6] Chemistry - A European Journal, 2017, vol. 23, # 65, p. 16574 - 16585

9
[ 110-82-7 ]
[ 504-01-8 ]
[ 556-48-9 ]

Reference： [1] Molecules, 2015, vol. 20, # 10, p. 19203 - 19220

10
[ 126716-90-3 ]
[ 504-01-8 ]
[ 556-48-9 ]
[ 108-93-0 ]

Reference： [1] Green Chemistry, 2017, vol. 19, # 1, p. 305 - 310

11
[ 75-07-0 ]
[ 1165952-91-9 ]
[ 931-17-9 ]
[ 504-01-8 ]
[ 556-48-9 ]
[ 40391-19-3 ]
[ 822-66-2 ]

Reference： [1] Journal of Organic Chemistry, 1986, vol. 51, # 4, p. 445 - 449

12
[ 556-48-9 ]
[ 74-88-4 ]
[ 18068-06-9 ]

Yield	Reaction Conditions	Operation in experiment
36%	Stage #1: With potassium hydroxide In water for 1 h; Reflux Stage #2: at 20℃; for 24 h;	An aqueous solution (20 mL) of 1,4-cyclohexanediol (17.5 g, 150 mmol) and KOH (9.3 g, 170 mmol) was heated to reflux for one hour. After cooling to room temperature, water was removed under reduced pressure, then CH₃I (32.0 g, 230 mmol) was added. After 24 hours stirring at room temperature, the reaction mixture was quenched with 100 mL water, and extracted with CHCl₃(100 mL×3). The combined organic fraction was dried, then purified in flash column chromatography (washed out at ethyl acetate: hexane=1:1) to give 7.14 g (36percent) pale yellow liquid as the titled compound (Known compound, ACS Registry No. 18068-06-9).

Reference： [1] Journal of Medicinal Chemistry, 1989, vol. 32, # 2, p. 351 - 357
[2] Patent: US2014/256706, 2014, A1, . Location in patent: Paragraph 0337; 0338
[3] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 6671 - 6679
[4] Patent: US4639521, 1987, A,
[5] Patent: EP207500, 1991, B1,

13
[ 556-48-9 ]
[ 2615-25-0 ]
[ 15827-56-2 ]

Reference： [1] ChemCatChem, 2013, vol. 5, # 10, p. 2905 - 2912

14
[ 556-48-9 ]
[ 3114-70-3 ]
[ 6850-65-3 ]

Reference： [1] Patent: US6369274, 2002, B1, . Location in patent: Page column 3

15
[ 556-48-9 ]
[ 3114-70-3 ]
[ 6850-65-3 ]
[ 108-91-8 ]

Reference： [1] Journal of Catalysis, 1999, vol. 182, # 2, p. 289 - 291

16
[ 556-48-9 ]
[ 22419-35-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 85 - 89
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 85 - 89

[ 556-48-9 ] Synthesis Path-Downstream 1~88

1
[ 556-48-9 ]
[ 822-66-2 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1997,p. 657 - 670
[2]Bioorganic Chemistry,1994,vol. 22,p. 172 - 197
[3]Advanced Synthesis and Catalysis,2017,vol. 359,p. 2196 - 2201
[4]Journal of Chemical Research, Miniprint,1992,p. 2409 - 2446
[5]Organic Letters,2017,vol. 19,p. 2130 - 2133
[6]Bulletin de la Societe Chimique de France,1930,vol. <4> 47,p. 463,465
[7]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1929,vol. 189,p. 702
[8]Tetrahedron Letters,1983,vol. 24,p. 107 - 110
[9]Bulletin de la Societe Chimique de France,1928,vol. <4> 43,p. 908

2
[ 556-48-9 ]
[ 30485-71-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1,3,5-trichloro-2,4,6-triazine; N,N-dimethyl-formamide In dichloromethane at 25℃; for 0.25h;
	With hydrogenchloride at 100℃; im geschlossenen Gefaess;
	With hydrogenchloride

Reference： [1]De Luca, Lidia; Giacomelli, Giampaolo; Porcheddu, Andrea [Organic Letters, 2002, vol. 4, # 4, p. 553 - 555]
[2]Sabetay; Palfray [Bulletin de la Societe Chimique de France, 1928, vol. <4> 43, p. 908] Palfray; Rothstein [Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1929, vol. 189, p. 702]
[3]Greene,F.D. et al. [Journal of Organic Chemistry, 1963, vol. 28, p. 55 - 64]

3
[ 556-48-9 ]
[ 1165952-91-9 ]
[ 822-66-2 ]

Reference： [1]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1925,vol. 180,p. 792
Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1923,vol. 177,p. 1184

4
[ 556-48-9 ]
[ 108-24-7 ]
1,4-diacetoxycyclohexane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	at 90℃; for 2h;
92%	With nickel dichloride at 20℃; for 0.5h; Neat (no solvent);
84%	With N-Bromosuccinimide In dichloromethane at 20℃; for 12h;

31%	With pyridine for 24h; Ambient temperature;
	diacetate of <i>cis</i>-quinitol;
	diacetate of <i>trans</i>-quinitol;

Reference： [1]Cai, Li; Rufty, Chris; Liquois, Megan [Asian Journal of Chemistry, 2014, vol. 26, # 14, p. 4367 - 4369]
[2]Location in patent: experimental part Meshram, Gangadhar; Patil, Vishvanath D. [Synthetic Communications, 2009, vol. 39, # 24, p. 4384 - 4395]
[3]Karimi; Seradj [Synlett, 2001, # 4, p. 519 - 520]
[4]Kikuchi, Yasuaki; Kato, Yasushi; Tanaka, Yasutaka; Toi, Hiroo; Aoyama, Yasuhiro [Journal of the American Chemical Society, 1991, vol. 113, # 4, p. 1349 - 1354]
[5]Baeyer [Justus Liebigs Annalen der Chemie, 1894, vol. 278, p. 108]
[6]Baeyer [Justus Liebigs Annalen der Chemie, 1894, vol. 278, p. 108]

5
[ 556-48-9 ]
[ 108-24-7 ]
[ 41043-88-3 ]

Reference： [1]Journal of the Chemical Society,1940,p. 10,14

6
[ 123-31-9 ]
[ 556-48-9 ]

Yield	Reaction Conditions	Operation in experiment
99.1%	With hydrogen In water at 30℃; for 7h; Autoclave;
99%	With hydrogen In water at 80℃; for 6h;	3.2. Hydrogenation reaction in aqueous phase General procedure: As we have known, a majority of the industrially important arenederivatives are produced from fossil fuel feedstock. However, the rapiddepletion of fossil fuels necessitates a search for sustainable alternativessuch as biomass whose valorization produces oxygenated aromatics[52]. Hence, hydrogenation of aromatic cores of lignin- derived compoundsand other oxygenated aromatics are also indispensable chemicaltransformations. Herein, the Ru/CN-SBA-15 catalyst has beenextended for the hydrogenation of the substrates containing oxygengroup like phenols, aromatic alcohol, ketone, ester and ether (Table 3,entries 7-14). For instance, the phenol and its derivatives were allconverted into the corresponding alicyclic reaction products almoststoichimetrically under very mild conditions (Table 3, entries 7-10). Inparticular, the presence of functional group such as methoxyl or hydroxylgroups did not affect consequence of the hydrogenation reaction,which afforded ideal yield of products (Table 3, entries 8-10). Furthermore,benzyl alcohol was easily hydrogenated to form cyclohexylmethanol under more mild conditions (Table 3, entry 11). Therewith,acetophenone was hydrogenated into 1-cyclohexylethan-1-ol with fullconversion and 95% yield, and a trace of ethylcyclohexane was detectedas a by-product possibly via the tandem consecutive dehydrationand hydrogenation of 1-cyclohexylethan-1-ol (Table 3, entry 12). Notably,the hydrogenation of ethyl benzoate was complete and very selectivewithin 7 h (Table 3, entry 13).
98%	With potassium hydroxide; samarium diiodide In tetrahydrofuran; water for 0.05h; Ambient temperature;

95%	With hydrogen In ethanol at 150℃; Calcination;	1-12; 1-2 Example 12 Weigh 5g Ni(NO3)2·6H2O and dissolve it in 20g water. Then, a mixture of 10 g of γ-Al2O3 and 90 g of inorganic carbon was impregnated. Evaporate the solvent in a water bath at 40°C, dry in an oven at 120°C for 10 hours, and calcinate in oxygen at 500°C for 4 hours to obtain a γ-Al2O3 supported Ni-based catalyst. Before the catalyst is used, perform in-situ reduction activation in the reactor at a flow rate of GHSV=6000h-1. The conditions are: 0.1MPa hydrogen, 10°C/min from room temperature to 550°C, and hold for 3h to obtain activated γ-Al2O3&C The supported Ni-based catalyst is denoted as Ni/γ-Al2O3&C-1.The specific reaction conditions are: 150, 2.5MPa, H2/hydroquinone=30:1 (molar ratio), the composition of the hydroquinone solution is (10g hydroquinone and 90g ethanol), the hydroquinone solution LHSV =6h-1, the catalyst volume is 0.5mL. Liquid phase product offline analysis, DB-1701 capillary column, FID detector to analyze the content of hydroquinone and 1,4-cyclohexanediol.
	With hydrogen; nickel at 130℃; <i>cis</i>-quinitol;
	With sodium hydroxide; hydrogen In water at 70℃; for 2.5h;
	With hydrogen In water at 85℃; for 2h; Autoclave;
	With palladium(II) nitrate dihydrate; hydrogen; titanium(IV) oxide In water at 65℃; for 3h;	14 Implementation Case14 Weigh 0.5 g of titanium dioxide was dissolved in 10 ml of an aqueous solution in a round bottom flask The mixture was stirred and kept at constant temperature. The temperature was set at 60 ° C. 0.054 g of palladium nitrate dihydrate was added with constant stirring and stirring was continuedAfter 12 hours, the mixture was stirred and allowed to stand for 12 hours. The excess water was removed by rotary evaporation, dried overnight, calcined at 400 ° C And finally reduced to 200 ° C for 2 hours in a hydrogen atmosphere to obtain a titanium dioxide-supported catalyst for noble metal palladium. Take the catalyst0.1 g, water 40 ml, reactant hydroquinone 1.5 g added to the reactor, the use of hydrogen replacement reactor gas 4 times, at the temperature 65 ° C, pressure 0.5 MPa, stirring speed 300 rpm, reaction 3 h, cooling to room temperature, the reaction solution was taken out by gas chromatography Analysis: The conversion was 99.01% and the selectivity of 1,4-cyclohexanediol was 98.54%.
	With hydrogen In 1,4-dioxane at 100℃; for 3.33333h; Autoclave;	1.4 Catalytic hydrogenation reaction General procedure: Aniline (0.5 mmol) was mixed with 3 mL dioxane and added into a 10 mL reaction vial equippedwith a magnetic stirring bar. Then 5 mg catalyst was added. The reaction vials were fitted with capsand then placed into a 500 mL autoclave. The autoclave was purged with nitrogen and flushed withhydrogen three times, then pressurized with 2 MPa H2 and heated to 100 °C. Then and the reactionwere kept at this temperature with agitation for 200 min.After completion of the reaction, the reactor was cooled to room temperature by an ice bath. Thenbiphenyl was added to the reaction mixture as internal standard, followed by filtration and analysisof a liquid product by a gas chromatograph (Agilent GC 7890) equipped with an FID using a 30 m ×0.32 mm, 0.25 μm HP-5 capillary column (5% phenyl-, 95% dimethylpolysiloxane). The followingoperating conditions were used: carrier gas: N2, initial flow rate: 0.80 ml/min, split ratio: 40:1,injection temperature of 220 °C, column temperature program: 60 °C (4.5 min), 20 °C/min to 260 °C(4 min), detector temperature of 300 °C. The qualitative analysis of the products was conducted by aShimadzu GCMS-QP2010 SE gas chromatograph (Rtx-5MS 30 m × 0.25 mm, 0.25 μm, carrier gas:He, initial flow rate: 1.61 ml/min, split ratio: 20:1, injection temperature of 260 °C, columntemperature program: 60 °C (3 min), 20 °C /min to 260 °C (8 min)) equipped with a quadrupole massspectrometer (ESI source temperature of 200 °C). Hydrogenation of other arenes was carried outwith similar procedure.
	With hydrogen In ethanol at 150℃;	1-8; 1-7 Example 1 Weigh 4g Ni(NO3)2·6H2O and 1g Co(NO3)2·6H2O and dissolve in 20g water. It was then immersed in a mixture of mechanically ground 90 g γ-Al2O3 and 10 g TiO2. Evaporate the solvent in a water bath at 60°C, dry in an oven at 120°C for 24 hours, and roast in air at 500°C for 4 hours. In the reactor, at a flow rate of GHSV=6000h-1, 0.1MPa hydrogen, kept at 550°C for 3 hours, to obtain activated γ-Al2O3 and The TiO2 supported NiCo-based catalyst is denoted as NiCo/γ-Al2O3-TiO2.At 150, 2.5MPa, fill H2 in 90g ethanol solution with 10g hydroquinone dissolved, the molar ratio of H2/hydroquinone is 30:1, hydroquinone solution LHSV=4h-1, catalyst The volume is 0.5 mL. Liquid phase product offline analysis, DB-1701 capillary column, FID detector to analyze the content of hydroquinone and 1,4-cyclohexanediol.
	With hydrogen In isopropyl alcohol at 160℃;	1; 2; 3; 4; 5; 6; 7; 8; 9; 10 The reaction conditions are: 160°C, 3.0 MPa, H2/hydroquinone=10:1 (molar ratio), hydroquinone solution LHSV=9h-1, and the catalyst volume is 0.2 mL.

Reference： [1]Shi, Juanjuan; Zhao, Mengsi; Wang, Yingyu; Fu, Jie; Lu, Xiuyang; Hou, Zhaoyin [Journal of Materials Chemistry A, 2016, vol. 4, # 16, p. 5842 - 5848]
[2]Qian, Wei; Lin, Lina; Qiao, Yunxiang; Zhao; Xu, Zichen; Gong, Honghui; Li; Chen; Huang, Rong; Hou, Zhenshan [Applied Catalysis A: General, 2019, vol. 585]
[3]Kamochi, Yasuko; Kudo, Tadahiro [Tetrahedron Letters, 1994, vol. 35, # 24, p. 4169 - 4172]
[4]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Dalian Institute of Chemical Physics (in: CAS) - CN113292396, 2021, A Location in patent: Paragraph 0022-0066
[5]Sabatier; Mailhe [Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1908, vol. 146, p. 1195][Annales de Chimie (Cachan, France), 1909, vol. <8> 16, p. 92]
[6]Crawford, Robert J. [Journal of Organic Chemistry, 1983, vol. 48, # 8, p. 1366 - 1368]
[7]Maximov, Anton; Zolotukhina, Anna; Murzin, Vadim; Karakhanov, Edward; Rosenberg, Edward [ChemCatChem, 2015, vol. 7, # 7, p. 1197 - 1210]
[8]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN107089898, 2017, A Location in patent: Paragraph 0029; 0033
[9]Cao, Yanwei; Zheng, Huan; Zhu, Gangli; Wu, Haihong; He, Lin [Chinese Chemical Letters, 2021, vol. 32, # 2, p. 770 - 774]
[10]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Dalian Institute of Chemical Physics (in: CAS) - CN113292397, 2021, A Location in patent: Paragraph 0022-0069
[11]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Dalian Institute of Chemical Physics (in: CAS) - CN113292395, 2021, A Location in patent: Paragraph 0021-0050

7
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[ 556-48-9 ]
[ 6995-79-5 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1894,vol. 278,p. 108

8
[ 556-48-9 ]
[ 13482-22-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium bromate; ammonium cerium (IV) nitrate; In water; acetonitrile; for 2.5h;Reflux;	Cerium (IV) ammonium nitrate (45.4 g, 82.85 mmol) and sodium bromate (125 g, 0.828 mol) were added to a solution of 1 ,4-cyclohexanediol (commercially available from Sigma-Aldrich, Milwaukee, WI, 278 g, 2.393 mol) in ACN (2.7 L) and water (1.15 L). The resulting mixture was heated at reflux for 2.5 hours and then cooled to room temperature. The resulting solution was extracted with chloroform (1 L x 3), and the combined organic extracts were dried, filtered and concentrated to afford 4-hydroxycyclohexanone (245 g, 91%). m/z (ESI) 1 15 (M+H)+.
75%	With Jones reagent; In acetone; at 0 - 20℃; for 0.666667h;Inert atmosphere;	In a three-necked round-bottom flask fitted with a mechanical stir, cyclohexane-1,4-diol (5.8 g, 50 mmol) was dissolved in 200 mL of acetone. The solution was cooled to 0 C, and freshly prepared Jones reagent (1.6 M in acetone) was added over 25 min. The green-blue solution was allowed to warm to room temperature over 15 min. The reaction mixture was filtered over celite and the solvent was removed in vacuo. Flash column chromatography (hexane/ethyl acetate 1:2) gave 4-hydroxy-cyclohexanone 1 (4.28 g, 75%) as a colorless oil.Rf=0.64 (hexane/ethyl acetate 1:3); 1H NMR (300 MHz, CDCl3) delta=1.18-2.01 (m, 4H, 6-H, 2-H), 2.20-2.30 (m, 2H, 3-H), 2.50-2.57 (m, 2H, 5-H), 2.59 (s, 1H, OH), 4.10-4.15 (m, 1H, 1-H); 13C NMR (300 MHz, CDCl3) delta=33.5, 37.1 (2t, C-2,6, C-3,5), 65.9 (d, C-1), 211.6 (s, C-4) in accordance to literature.
	With sodium bromate; ammonium cerium(IV) nitrate; In water; acetonitrile; for 1.5h;Heating / reflux;	A 100 g 1,4-hexanediol was dissolved in 1.4 L of a mixture of acetonitrile and water (7:3 by volume). A mixture of 45.4 g of sodium bromate and 16.5 g of ammonium cerium (IV) nitrate was slowly added. The reaction was maintained under reflux conditions for 90 min. Once acetonitrile was removed by rotary evaporation, the solution was diluted with 800 mL of water and continuously extracted with chloroform for 72 h. The organic solution was dried over magnesium sulfate. Finally chloroform was evaporated from the organic solution to yield 99.5 g of a colorless oil (4-hydroxycyclohexanone). 130 g of benzyl chloride were slowly added to a solution of 60 g of 4-hydroxycyclohexanone in 400 mL of triethylamine. The solution was left to react at 25 C. for 2 h. After removal of the solvent, the product was purified by column chromatography to yield 100 g of a white powder 4-benzylestercyclohexanone. To a solution of 20 g 3-chloroperoxybenzoic acid in 200 mL of chloroform was added a solution of 15 g of 4-benzylestercylohexanone in 100 mL of chloroform. The reaction proceeded at 25 C. for 14 h. The solution was passed through Celite, extracted with brine and water successively. The solution was dried over magnesium sulfate and the solvent evaporated. Finally, the product was re-crystallized from a solution of ethyl acetate:hexane (1:4) to yield 7 g of white powder, benzylester protected 4-hydroxylcaprolactone (p-CLOH). 50 mg of 1,6-hexandiol, 20 g of D,L lactide (DLL) monomer and 4 g of p-CLOH were dried by azeotropic distillation of toluene. The monomers were heated to 140 C. to add stannous octoate (0.5 mol %) under a blanket of argon. The reaction was left to proceed at 160 C. for 14 h. The resulting polymer poly(DLL-pCLOH) was dissolved in acetone, precipitated in methanol and dried under reduced pressure. The benzyl protecting group was removed by dissolving 10 g of poly(DLL-pCLOH) in 100 ml of anhydrous ethyl acetate and adding 0.8 g of tin(IV) chloride under a blanket of argon. The reaction proceeded at 25 C. for 90 min. The resulting polymer poly(DLL-CLOH) was precipitated in methanol and dried under reduced pressure. To 4 g of poly(DLL-CLOH) dissolved in 20 mL of predried dichloromethane, was added 1.5 eq. of dry pyridine and was cooled to -5 C. A solution of ethylene chlorophosphate (0.5 mg) in 5 mL of dry chloroform was added dropwise and reacted for 2 h at -5 C. The resultant solution was allowed to reach 25 C. and react for 4 more h. The resulting solution was diluted with 50 mL dichloromethane, and then extracted with distilled water and a 1 M solution of NaHCO3. The organic phase was dried with sodium sulfate and filtered to yield poly(DLL-CLP). 3 g of poly(DLL-CLP) were dissolved in 30 mL of dry acetonitrile and cooled to -10 C. Approximately 300 mL of trimethylamine was condensed into the pressure vessel, which was then slowly heated to 60 C. The solution was stirred for 45 h at this temperature. The resulting polymer, a copolymer of d,l-lactide and caprolactone bearing phosphorylcholine pendant groups (poly(DLL-CLPC)), was precipitated in methanol and dried under reduced pressure.

Reference： [1]Tetrahedron Letters,1994,vol. 35,p. 7151 - 7154
[2]Patent: WO2013/134079,2013,A1 .Location in patent: Paragraph 0219-0220
[3]European Journal of Organic Chemistry,2013,p. 4057 - 4064
[4]Tetrahedron,2006,vol. 62,p. 556 - 562
[5]Synlett,2005,p. 314 - 318
[6]Tetrahedron,2012,vol. 68,p. 2363 - 2373
[7]Tetrahedron,2017,vol. 73,p. 3801 - 3809
[8]Journal of Medicinal Chemistry,2006,vol. 49,p. 2496 - 2511
[9]Journal of Mass Spectrometry,2008,vol. 43,p. 958 - 964
[10]Justus Liebigs Annalen der Chemie,1978,p. 695 - 704
[11]Synthesis,1986,p. 774 - 776
[12]Journal of Organic Chemistry,1998,vol. 63,p. 3474 - 3477
[13]Synlett,1998,p. 1105 - 1107
[14]Chemistry - A European Journal,2007,vol. 13,p. 4859 - 4872
[15]Patent: US2005/208093,2005,A1 .Location in patent: Page/Page column 8
[16]European Journal of Organic Chemistry,2013,p. 3741 - 3750
[17]Biomacromolecules,2018,vol. 19,p. 1082 - 1089

9
[ 110-87-2 ]
[ 556-48-9 ]
[ 64230-40-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With pyridinium p-toluenesulfonate In tetrahydrofuran for 6h; Ambient temperature;
93%	With lithium trifluoromethanesulfonate In 1,2-dichloro-ethane for 5.5h; Heating;
84%	With pyridinium p-toluenesulfonate In dichloromethane at 10 - 20℃; for 7h; Inert atmosphere;	1 Synthesis examples of the compound (5-2) Under a nitrogen atmosphere, the compound fourneckedflask 1000ml (51)58.1g (500mmol), ptoluenesulfonicacid pyridinium (PPTS) 6.3g (25mmol) and were homogeneously stirred dichloromethaneadded 600 ml. While maintaining the internal temperature below 10 ° C, it was added dropwise 3,4dihydro2Hpyran(DHP)21.0g (250mmol) over 1 hour. It was further stirred for 6 hours at room temperature. The reaction mixture was washed withsaturated sodium hydrogen carbonate aqueous solution, and dried over sodium sulfate. Filtered sodium sulfate, andconcentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to givecompound (52)was obtained 42.1 g (84% yield DHP basis).

65%	With acidic resin (Dowex 50Wx₈, trade name, Dow Chemical Company) In toluene at 20℃; for 17h;	372.a Example 372; Synthesis of 4-(1H-indazol-5-yloxy)cyclohexanol; (a) Synthesis of 4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanol An acidic resin (Dowex 50Wx8, trade name, Dow Chemical Company, 800 mg) and dihydropyran (1.89 ml, 20.7 mol) were added dropwise to a solution of 1,4-cyclohexanediol (4.0 g, 34.4 mol) in toluene (80 ml) at room temperature and vigorously stirred. After 17 hours, the reaction mixture was filtered by the use of Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-(tetrahydro-2H-pyran-2-yloxy)cyclo-hexanol (2.69 g, 65%).
48%	With pyridinium p-toluenesulfonate In tetrahydrofuran; dichloromethane at 20℃; for 24h;
27.6 g	With pyridinium p-toluenesulfonate In dichloromethane; water at 20℃; for 8h;	10 20.0 g (0.17 mol) of the compound represented by the formula (I-39a) and 2.16 g (8.6 mmol) of pyridinium paratoluenesulfonate were added to a reaction vessel equipped with a thermometer and a stirrer, and thereto was added dichloromethane And suspended in 100 mL of water. While ice-cooling, 14.5 g (0.17 mol) of 3,4-dihydro-2H-pyran was added dropwise. After stirring at room temperature for 8 hours, purification was carried out by column chromatography to obtain 27.6 g (0.14 mol) of the compound represented by the formula (I-39b).

Reference： [1]Freeman, Fillmore; Kim, Darrick S. H. L.; Rodriguez, Eloy [Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2317 - 2319]
[2]Karimi, Babak; Maleki, Jafar [Tetrahedron Letters, 2002, vol. 43, # 30, p. 5353 - 5355]
[3]Current Patent Assignee: DIC CORP. - JP5822098, 2015, B1 Location in patent: Paragraph 0126; 0127
[4]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED - EP1403255, 2004, A1 Location in patent: Page 103
[5]Kuroda, Chiaki; Murase, Atsushi; Suzuki, Hideyuki; Endo, Toru; Anzai, Shuzo [Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 7, p. 1639 - 1647]
[6]Current Patent Assignee: DIC CORP. - JP6051566, 2016, B2 Location in patent: Paragraph 0123; 0124

10
[ 556-48-9 ]
[ 279-49-2 ]
[ 1165952-92-0 ]
[ 1165952-91-9 ]
[ 822-66-2 ]

Reference： [1]Tetrahedron,1989,vol. 45,p. 7099 - 7108

11
[ 556-48-9 ]
[ 286-40-8 ]
[ 822-66-2 ]

Reference： [1]Journal of Organic Chemistry,1987,vol. 52,p. 1577 - 1582

12
[ 556-48-9 ]
[ 1165952-92-0 ]
[ 127505-63-9 ]
[ 1165952-91-9 ]
[ 822-66-2 ]

Reference： [1]Tetrahedron,1989,vol. 45,p. 7099 - 7108

13
[ 556-48-9 ]
[ 98-88-4 ]
[ 6308-92-5 ]
[ 19150-32-4 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1982,p. 1485 - 1492
[2]Medicinal Chemistry Research,2004,vol. 13,p. 758 - 769

14
[ 75-07-0 ]
[ 1165952-91-9 ]
[ 931-17-9 ]
[ 504-01-8 ]
[ 556-48-9 ]
[ 40391-19-3 ]
[ 822-66-2 ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 445 - 449

15
[ 556-48-9 ]
[ 18162-48-6 ]
[ 126931-29-1 ]
1,4-Bis-(tert-butyl-dimethyl-silanyloxy)-cyclohexane [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 3388 - 3390

16
[ 556-48-9 ]
[ 98-59-9 ]
[ 92121-36-3 ]

Yield	Reaction Conditions	Operation in experiment
46%	With pyridine In chloroform at 0 - 20℃; for 18h;	(4-Hydroxycyclohexyl) 4-methylbenzenesulfonate (Intermediate DU) To a solution of pyridine (12.3 g, 155 mmol) in CHCl3 (150 mL) was added cyclohexane-1,4-diol (15.0 g, 129 mmol) at rt. Then the mixture was then cooled to 0° C. and 4-methylbenzenesulfonyl chloride (24.6 g, 129 mmol) was added into the mixture. The reaction mixture was then allowed to warm to rt and stirred for 18 hrs. On completion, the reaction mixture was acidified with 1N HCl solution until the pH=5-6, and extracted with EA (3×30 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (16.0 g, 46% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.85-7.76 (m, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.66-4.49 (m, 1H), 3.80-3.70 (m, 1H), 2.47 (s, 3H), 1.97-1.91 (m, 2H), 1.72-1.65 (m, 2H), 1.64-1.50 (m, 4H).
46%	With pyridine In chloroform at 0 - 25℃; for 18h;	22.3 Step 3: (4-Hydroxycyclohexyl) 4-methylbenzenesulfonate (7): To a solution of Py (12.3 g, 155 mmol) in CHCl3 (150 mL) was added cyclohexane- 1,4-diol (15.0 g, 129 mmol) at 25 °C. Then the mixture was cooled to 0 °C and 4- methylbenzenesulfonyl chloride (24.6 g, 129 mmol) was added into the mixture. The reaction mixture was stirred at 25 °C for 18 hrs. On completion, the reaction mixture was acidified with 1N HCl solution until pH = 5-6, extracted with EA (3 X 30 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (16.0 g, 46% yield) as white solid. 1H NMR (400MHz, CDCl3) d 7.85 - 7.76 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.66 - 4.49 (m, 1H), 3.80 - 3.70 (m, 1H), 2.47 (s, 3H), 1.97 - 1.91 (m, 2H), 1.72 - 1.65 (m, 2H), 1.64 - 1.50 (m, 4H)
	In pyridine

	With pyridine In chloroform at 0 - 20℃; for 16h; Inert atmosphere;	19 4-hydroxycyclohexyl 4-methylbenzenesulfonate (21): To a solution of pyridine (4 g, 0.025 mol) in CHCl3 (25 mL) was added Cyclohexanediol (2.5 g, 0.021 mol) at room temperature. This was then cooled to 0 °C, and tosyl chloride (4.1 g, 0.021) added to the mixture. The reaction was stirred for 16 h under argon at room temperature. Upon completion of the reaction from TLC, the reaction mixture was poured into dilute HCl, and the solid precipitate collected by filtration, washed with water and dried (Na2CO3).
	With pyridine In chloroform at 0 - 20℃;
	With pyridine
	With pyridine In chloroform at 0 - 20℃;
12 g	With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	70.70.1 70.1 4-Hydroxycyclohexyl p-toluenesulfonate 70.1 4-Hydroxycyclohexyl p-toluenesulfonate A 250 mL single-necked reaction flask was charged with 1,4-cyclohexanediol (10.0 g), and dichloromethane (50 mL) and triethylamine (26 mL) were added thereto. Under nitrogen protection, the system was cooled to 0°C. Then, p-toluenesulfonyl chloride (16.4 g) was added. After the completion of the addition, the mixture was naturally warmed to room temperature and reacted overnight. The reaction was complete as monitored by TLC. The mixture was subjected to purification by column chromatography to obtain 12 g of 4-hydroxycyclohexyl p-toluenesulfonate.
	With pyridine; dmap In chloroform at 0 - 20℃; for 18.1667h;	1 Synthesis of compound (c) 1,4-Cyclohexanediol (Compound (a))Dissolve 8.00 g in 5 mL of chloroform at room temperatureFurthermore, N, N-dimethyl-4-aminopyridine 0.842 gAnd 15 mL of pyridine were added to the solution and stirred under ice cooling (0 ° C.).Next, a solution prepared by dissolving 6.32 g of toluenesulfonyl chloride (compound (b)) in 10 mL of chloroform was added to this solution.After stirring under ice-cooling (0 ° C.) for 10 minutes, the reaction was carried out at room temperature for 18 hours with stirring. About the reacted liquidThe liquid separation operation was performed in the order of a 5 mass% hydrochloric acid aqueous solution and a saturated sodium hydrogen carbonate aqueous solution. Next, compound (c) was separated by column chromatography (carrier: silica gel, developing solution: hexane / ethyl acetate = 1/1 (volume ratio)). The separated compound (c) was dissolved in 20 mL of chloroform.

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - US2019/192668, 2019, A1 Location in patent: Paragraph 2522; 2523
[2]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/10210, 2020, A1 Location in patent: Paragraph 00946
[3]Davies, Ann P.; Legon, A. C.; Millen, D. J.; Roberts, A. J. [Journal of Molecular Structure, 1984, vol. 112, p. 9 - 18]
[4]Current Patent Assignee: UNIVERSITY OF KANSAS - WO2013/119985, 2013, A1 Location in patent: Paragraph 00327; 00328; 00329
[5]Current Patent Assignee: UNIVERSITY OF KANSAS - WO2015/200514, 2015, A2 Location in patent: Page/Page column 70
[6]Anyika, Mercy; McMullen, Mason; Forsberg, Leah K.; Dobrowsky, Rick T.; Blagg, Brian S. J. [ACS Medicinal Chemistry Letters, 2016, vol. 7, # 1, p. 67 - 71]
[7]Forsberg, Leah K.; Anyika, Mercy; You, Zhenyuan; Emery, Sean; McMullen, Mason; Dobrowsky, Rick T.; Blagg, Brian S.J. [European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1428 - 1435]
[8]Current Patent Assignee: NANJING GEAR PHARMA TECH; SINO BIOPHARMACEUTICAL LIMITED - EP3689860, 2020, A1 Location in patent: Paragraph 0603; 0604
[9]Current Patent Assignee: TOKYO UNIVERSITY OF SCIENCE - JP2021/75500, 2021, A Location in patent: Paragraph 0065-0069

17
[ 556-48-9 ]
[ 74-88-4 ]
[ 18068-06-9 ]

Yield	Reaction Conditions	Operation in experiment
36%		An aqueous solution (20 mL) of 1,4-cyclohexanediol (17.5 g, 150 mmol) and KOH (9.3 g, 170 mmol) was heated to reflux for one hour. After cooling to room temperature, water was removed under reduced pressure, then CH3I (32.0 g, 230 mmol) was added. After 24 hours stirring at room temperature, the reaction mixture was quenched with 100 mL water, and extracted with CHCl3 (100 mL×3). The combined organic fraction was dried, then purified in flash column chromatography (washed out at ethyl acetate: hexane=1:1) to give 7.14 g (36%) pale yellow liquid as the titled compound (Known compound, ACS Registry No. 18068-06-9).
	With potassium hydroxide; In water;	(1) 4-Methoxycyclohexanol To mono-potassium salt of 1,4-cyclohexanediol which had been prepared from 17.5 g of 1,4-cyclohexanediol and 9.3 g of potassium hydroxide, 32 g of methyl iodide was added, and the resultant mixture was heated under reflux for 5 hours. After the reaction was completed, water was added and then the mixture was extracted with chloroform. The extract was subjected to distillation under reduced pressure to obtain 10.34 g of 4-methoxycyclohexanol. b15: 100-103 C. NMR deltaTMSCCl4: 1.2-2.0 (8H, m); 2.68 (1H, s); 3.0-3.2 (1H, m); 3.24 (3H, s); 3.5-3.7 (1H, m).
	With potassium hydroxide; In water;	(1) 4-Methoxycyclohexanol To mono-potassium salt of 1,4-cyclohexanediol which had been prepared from 17.5 g of 1,4-cyclohexanediol and 9.3 g of potassium hydroxide, 32 g of methyl iodide was added, and the resultant mixture was heated under reflux for 5 hours. After the reaction was completed, water was added and then the mixture was extracted with chloroform. The extract was subjected to distillation under reduced pressure to obtain 10.34 g of 4-methoxycyclohexanol. b15: 100-103C.

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 351 - 357
[2]Patent: US2014/256706,2014,A1 .Location in patent: Paragraph 0337; 0338
[3]Journal of Organic Chemistry,2017,vol. 82,p. 6671 - 6679
[4]Patent: US4639521,1987,A
[5]Patent: EP207500,1991,B1

18
[ 556-48-9 ]
[ 100-39-0 ]
[ 2976-80-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h;
51%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 24h;
32%	With sodium hydride In N,N-dimethyl-formamide for 24h;

	(i) Na, xylene, (ii) /BRN= 385801/; Multistep reaction;
	With sodium 1.) dioxane, reflux, 4 h, 2.) dioxane, reflux, 20 h; Yield given. Multistep reaction;
	With sodium In tetrahydrofuran at 40 - 50℃; for 18h;
	Stage #1: 1,4-Cyclohexanediol With sodium hydride In N,N-dimethyl-formamide at 0℃; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 15h;	45.2 Step 2. Preparation of 4-(benzyloxy)cyclohexanol According to the similar procedure of step 1 in Example 37, the desired product was obtained. 1H-NMR (400 MHz, CDCl3) δ 1.31 (2H, m), 1.63 (3H, m), 1.96 (3H, m), 3.38, 3.49 (1H, m), 3.70 (1H, m), 4.52 (2H, m), 7.27-7.34 (5H, m).
	With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 12h;	Step 1: To a solution of cyclohexane-1, 4-diol (100 g, 860 mmol) in DMF (2.5 L) was added NaH (68.9 g, 1.72 mol) at 0°C. Benzyl bromide (161 g, 946 mmol) was then added dropwise and the resulting solution stirred at ambient temperature for 12 h. The reaction mixture was quenched by addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (3x). The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate : petroleum ether (1 : 50 to 1 : 3) to yield 4-(benzyloxy)cyclohexan-l-ol. 1HNMR (400 MHz, CDC13) δ 7.23 - 7.39 (m, 5H), 4.53 (d, J = 5.6 Hz, 2H), 3.63 - 3.79 (m, 1H), 3.34 - 3.52 (m, 1H), 1.96 - 2.10 (m, 2H), 1.85 - 1.94 (m, 1H), 1.63 - 1.77 (m, 2H), 1.54 - 1.62 (m, 1H), 1.24 - 1.48 (m, 3H), 1.24 - 1.48 (m, 1H).

Reference： [1]Garg, Gaurav; Forsberg, Leah K.; Zhao, Huiping; Blagg, Brian S. J. [Chemistry - A European Journal, 2017, vol. 23, # 65, p. 16574 - 16585]
[2]Uyanik, Muhammet; Akakura, Matsujiro; Ishihara, Kazuaki [Journal of the American Chemical Society, 2009, vol. 131, p. 251 - 262]
[3]Baghdasarian, Glen; Woerpel [Journal of Organic Chemistry, 2006, vol. 71, # 18, p. 6851 - 6858]
[4]Russo,G.; Danieli,B. [Gazzetta Chimica Italiana, 1965, vol. 95, p. 438 - 447]
[5]Keck, Gary E.; Dougherty, Shawn M.; Savin, Kenneth A. [Journal of the American Chemical Society, 1995, vol. 117, # 23, p. 6210 - 6217]
[6]Crotti, Paolo; Di Bussolo, Valeria; Favero, Lucilla; Pineschi, Mauro; Marianucci, Francesco; Renzi, Gabriele; Amici, Giuseppina; Roselli, Graziella [Tetrahedron, 2000, vol. 56, # 38, p. 7513 - 7524]
[7]Current Patent Assignee: ASAN FOUNDATION - US2012/53180, 2012, A1 Location in patent: Page/Page column 41
[8]Current Patent Assignee: MERCK & CO INC; SHAW DAVID MATTHEW; MANSOOR UMAR FARUK; CHRISTIAN ALEC H; MENNIE KATRINA MARIE; REUTERSHAN MICHAEL H; MUSACCHIO ANDREW J; CANDITO DAVID A - WO2022/13408, 2022, A2 Location in patent: Page/Page column 75

19
[ 556-48-9 ]
[ 13482-22-9 ]
[ 637-88-7 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1997,vol. 70,p. 2561 - 2566
[2]Bulletin of the Chemical Society of Japan,1997,vol. 70,p. 2561 - 2566
[3]Synlett,2014,vol. 25,p. 2757 - 2760
[4]Journal of Fluorine Chemistry,2003,vol. 119,p. 81 - 82
[5]Tetrahedron Letters,1995,vol. 36,p. 3031 - 3034
[6]Tetrahedron Letters,1995,vol. 36,p. 6923 - 6926
[7]Journal of Organic Chemistry,2001,vol. 66,p. 6620 - 6625
[8]Journal of Organic Chemistry,2000,vol. 65,p. 6502 - 6507
[9]Magnetic Resonance in Chemistry,2017,vol. 55,p. 1073 - 1078

20
[ 556-48-9 ]
[ 3114-70-3 ]
[ 6850-65-3 ]
N-Cyclohexyl-cyclohexane-1,4-diamine [ No CAS ]
[ 108-91-8 ]
4-(4-amino-cyclohexylamino)-cyclohexanol [ No CAS ]
N-(4-amino-cyclohexyl)-1,4-cyclo-hexanediamine [ No CAS ]

Reference： [1]Journal of Catalysis,1999,vol. 182,p. 289 - 291

21
[ 556-48-9 ]
[ 7726-95-6 ]
[ 822-66-2 ]

Reference： [1]Bulletin de la Societe Chimique de France,1930,vol. <4> 47,p. 463,465

22
[ 556-48-9 ]
[ 7664-93-9 ]
[ 827-52-1 ]

Reference： [1]Chemische Berichte,1901,vol. 34,p. 507

23
[ 7647-01-0 ]
[ 556-48-9 ]
[ 16890-91-8 ]
[ 16749-11-4 ]
[ 30485-71-3 ]
[ 822-66-2 ]

Reference： [1]Annales de Chimie (Cachan, France),1930,vol. <10> 14,p. 461,515

24
[ 556-48-9 ]
[ 7664-93-9 ]
[ 1165952-92-0 ]
[ 1165952-91-9 ]
[ 822-66-2 ]

Reference： [1]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1923,vol. 177,p. 1183
Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1928,vol. 187,p. 1103

25
[ 7647-01-0 ]
[ 556-48-9 ]
[ 19398-57-3 ]
[ 30485-71-3 ]
[ 1165952-91-9 ]
[ 822-66-2 ]

Reference： [1]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1929,vol. 189,p. 702

26
[ 556-48-9 ]
[ 92121-36-3 ]
[ 24293-30-9 ]
[ 6674-22-2 ]
[ 98-59-9 ]
[ 822-66-2 ]

Reference： [1]Journal of Pharmacy and Pharmacology,1997,vol. 49,p. 835 - 842

27
[ 556-48-9 ]
[ 999-97-3 ]
[ 55724-30-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	In dichloromethane at 20℃; for 0.0666667h;
97%	With boric acid In acetonitrile at 20℃; for 2h;
95%	With aminosulfonic acid In acetonitrile at 20℃; for 2h;

90%	Stage #1: 1,4-Cyclohexanediol With Iron(III) nitrate nonahydrate; sodium iodide In dichloromethane at 20℃; Stage #2: 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane at 20℃; for 0.0416667h;
85%	With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 0.5h;

Reference： [1]Karimi; Golshani [Journal of Organic Chemistry, 2000, vol. 65, # 21, p. 7228 - 7230]
[2]Location in patent: experimental part Rostami, Amin; Akradi, Jamal; Ahmad-Jangi, Firoz [Journal of the Brazilian Chemical Society, 2010, vol. 21, # 8, p. 1587 - 1592]
[3]Location in patent: experimental part Rostami, Amin; Ahmad-Jangi, Firoz; Zarebin, Mohammad Rezgar; Akradi, Jamal [Synthetic Communications, 2010, vol. 40, # 10, p. 1500 - 1507]
[4]Location in patent: experimental part Khazaei, Ardeshir; Rahmati, Sadegh; Rostami, Amin [Helvetica Chimica Acta, 2009, vol. 92, # 7, p. 1434 - 1438]
[5]Location in patent: experimental part Khazaei, Ardeshir; Rostami, Amin; Mantashlo, Fatemeh [Phosphorus, Sulfur and Silicon and the Related Elements, 2009, vol. 184, # 9, p. 2288 - 2296]

28
[ 20924-05-4 ]
[ 556-48-9 ]
(5-methyl-2,4-dioxo-3,4-dihydro-2<i>H</i>-pyrimidin-1-yl)-acetic acid 4-[(5-methyl-2,4-dioxo-3,4-dihydro-2<i>H</i>-pyrimidin-1-yl)-acetoxy]-cyclohexyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dmap; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 48h;

Reference： [1]Thibault, Raymond J.; Hotchkiss, Peter J.; Gray, Mark; Rotello, Vincent M. [Journal of the American Chemical Society, 2003, vol. 125, # 37, p. 11249 - 11252]

29
[ 556-48-9 ]
[ 18162-48-6 ]
[ 126931-29-1 ]

Yield	Reaction Conditions	Operation in experiment
86.7%	With 1H-imidazole; In tetrahydrofuran; at 20℃; for 16h;	To a solution of cyclohexane-1,4-diol (100 g, 862 mol) in THF (1000 mL) was addedimidazole (58.6 g, 862 mmol) and TBSC1 (130 g, 862 mmol), the reaction was stirred at ambienttemperature for about 16 hours. The solid was filtered, washed with THF (100 mL), the filtrate was concentrated under reduced pressure. The crude product (about 60 g) was purified by column of A1203 to give the product as colorless oil (172 g, 86.7%). MS (ESI) m/e [M+1]231.0.
66%	With 1H-imidazole; In tetrahydrofuran; N,N-dimethyl-formamide; at 0℃;	A solution of tert-butyldimethylsilyl chloride (1.5 g, 9.9 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added, dropwise, at 0 C., to a solution of 1,4-cyclohexanediol (1.0 g, 8.6 mmol) and imidazole (1.5 g, 22.0 mmol) in anhydrous tetrahydrofuran (5 mL). After completion of the addition brine was added and the resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (hexane /EtOAc, 80/20) to afford 1.3 g (66% yield) of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanol as a colorless oil.
42%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;Cooling with ice;	To an ice cold solution of cyclohexane-1,4-diol (3.0 g, 25.86 mmol) in DMF (50 mL) was added imidazole (5.3 g, 77.58 mmol) followed by TBS-Cl (4.7 g, 31.03 mmol). The mixture was stirred at RT for 2 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as colorless oily liquid (2.5 g, 42 %). ES-MS: m/z 231.2 (M+H)+.

	With dmap; triethylamine; In N-methyl-acetamide; water;	Reference Example 21 Production of 4-[(tert-butyldimethylsilyl)oxy]cyclohexanol: To a solution of 1,4-cyclohexandiol (cis: trans=ca. 1:1, 25.0 g) and t-butylchlorodimethylsilane (32.4 g) in dimethylformamide (150 ml) was added slowly and dropwise a solution of triethylamine (21.8 g) and 4-(dimethylamino)pyridine (1.05 g) in dimethylformamide (50 ml) at 0 C. After stirring for one hour, to the reaction mixture were added water and ether. The ether layer was separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography (support; silica gel, 300 g, developing agent; ethyl acetate:hexane=1:5) to obtain the object compound (17.8 g) as a mixture of cis and trans isomers (ca. 1:1). IR (Neat): 3350, 2955, 2940, 2895, 2865, 1375, 1255 cm-1 1 H-NMR (CDCl3) delta: -0.03 (6H,s), 0.90(9H,s), 1.13-1.90(8H,m), 1.30(1H,s), 3,40-3.80(2H,m) cm-1.
	With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃;	[00433] Step A: Cyclohexane-1,4-diol (1000 g, 8609 mmol) was dissolved in DMF (5000 mL) and cooled to 0 C and treated with 1H-imidazole (146.5 g, 2152 mmol) , followed by tert-butylchlorodimethylsilane (324.4 g, 2152 mmol) in portions, keeping the temperature below 5 C. The reaction mixture was warmed to room temperature overnight. The reaction mixture was partitioned between 9 L 80% brine and 4 L MTBE, washed with brine and concentrated to an oil and dried under high vacuum in 40 C water bath to afford crude 4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-ol (473 g, 2053 mmol, 95.38 % yield) as an oil.

Reference： [1]Patent: WO2016/161960,2016,A1 .Location in patent: Paragraph 0482
[2]Patent: US2012/15962,2012,A1 .Location in patent: Page/Page column 59
[3]Organic Letters,2003,vol. 5,p. 2319 - 2321
[4]Patent: WO2016/203112,2016,A1 .Location in patent: Page/Page column 62
[5]Patent: US4946846,1990,A
[6]Organic and Biomolecular Chemistry,2011,vol. 9,p. 783 - 792
[7]Organic Letters,2011,vol. 13,p. 406 - 409
[8]Patent: WO2019/113190,2019,A1 .Location in patent: Paragraph 00433

30
[ 556-48-9 ]
[ 105-58-8 ]
1,4-bis(ethoxycarbonyloxy)cyclohexane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With MgLa mixed oxides at 129.85℃; for 0.75h;
97%	at 129.85℃; for 0.5h;
97%	With MgLa mixed oxide at 125℃; for 0.75h;

94%

With immobilized 1,5,7-triazabicyclo[4.4.0]dec-5-ene on magnetic γ-Fe2O3 nanoparticles at 125℃; for 10h;

Reference： [1]Veldurthy, Bhaskar; Clacens, Jean-Marc; Figueras, Francois [Journal of Catalysis, 2005, vol. 229, # 1, p. 237 - 242]
[2]Veldurthy, Bhaskar; Clacens, Jean-Marc; Figueras, Francois [European Journal of Organic Chemistry, 2005, # 10, p. 1972 - 1976]
[3]Veldurthy, Bhaskar; Figueras, Francois [Chemical Communications, 2004, # 6, p. 734 - 735]
[4]Wu, Liqiang; Tian, Shuanbao [European Journal of Inorganic Chemistry, 2014, vol. 2014, # 12, p. 2080 - 2087]

31
[ 556-48-9 ]
[ 6995-79-5 ]

Reference： [1]Organic Letters,2005,vol. 7,p. 5035 - 5038
[2]Journal of the American Chemical Society,1991,vol. 113,p. 1349 - 1354

32
[ 556-48-9 ]
[ 58479-61-1 ]
[ 952589-06-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With 1H-imidazole In dichloromethane; N,N-dimethyl-formamide at 20℃; for 16h;	D 4-(f-Butyl-diphenyl-silanyloxy)-cis/trans-cyclohexanol; To a solution of 1 ,4-cyclohexanediole (20 g, 0.172 mol) and imidazole (11.72 g, 0.172 mol) in a mixture of DCM/DMF 2:1 (600 ml.) was added a solution of f-butyl-chloro- diphenylsilane (47.33 g, 0.172 mol) in DCM (150 ml.) and the resulting mixture was stirred for 16 hrs at room temperature. The mixture was washed with aq. sat. NH4CI (2x100 ml_), aq. sat. NaHCO3 (2x100 ml.) and water (100 ml_). The organic phase was dried (MgSO4), filtered and evaporated in vacuo affording 50.8 g (83 %) of 4-(f-butyl-diphenyl-silanyloxy)-cis/trans- cyclohexanol as an oil. 1 H-NMR (400 MHz, CDCI3) 1.01 (s, 1 H), 1.03 - 1.10 (m, 9H), 1.10 - 1.23 (m, 1 H), 1.28 - 1.49 (m, 2H), 1.56 - 1.67 (m, 1 H), 1.67 - 1.83 (m, 3H), 1.83 - 1.94 (m, 1 H), 3.59 - 3.77 (m, 1 H), 3.81 - 3.89 (m, 1 H), 4.12 (q, 1 H), 7.30 - 7.47 (m, 6H), 7.59 - 7.74 (m, 4H), m/z: 355 (M+1 )+;
66%	With 1H-imidazole In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 24h;
54%	With 1H-imidazole In 1,4-dioxane; water at 15 - 20℃; for 15h;	74 Synthesis of Compound 74.1. Synthesis of 2-(1-((R)-2-(2-ethylphenyl)-2-(((1s,4S)-4-hydroxycyclohexyl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid (I-245) Synthesis of Compound 74.1. Into a 1000-mL 3-necked round-bottom flask was placed cyclohexane-1,4-diol (20 g, 172.18 mmol, 1.00 equiv), 1,4-dioxane (500 mL) and 1H-imidazole (17.58 g, 258.24 mmol, 1.50 equiv). This was followed by the addition of a solution of tert-butyl(chloro)diphenylsilane (49.69 g, 180.78 mmol, 1.05 equiv) in dioxane (100 mL) dropwise with stirring at 15° C. The resulting solution was stirred for 15 h at 15-20° C. The solids were filtered out. The filtrate was diluted with 200 mL of water. The resulting solution was extracted with 3*200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:60-1:50-1:30-1:20). Purification afforded 32.98 g (54%) of 4-[(tert-butyldiphenylsilyl)oxy]cyclohexan-1-ol (74.1) as a white semi-solid. Synthesis of Compound 74.2. Compound 74.2 was prepared in a manner analogous to compounds 57.4 and 57.5, substituting 74.1 for isopropanol in the epoxide-opening step. Purification:

54%

With 1H-imidazole In 1,4-dioxane at 15 - 20℃; for 15h;

109 Synthesis of Compound 109.2. Example 109 2-[1-[(2R)-2-[(4-hydroxycyclohexyl)oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxo-1H,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid (I-277) Synthesis of Compound 109.2. Into a 1000-mL 3-necked round-bottom flask was placed cyclohexane-1,4-diol (20 g, 172.18 mmol, 1.00 equiv), 1,4-dioxane (500 mL) and 1H-imidazole (17.58 g, 258.24 mmol, 1.50 equiv). This was followed by the addition of a solution of tert-butyl(chloro)diphenylsilane (49.69 g, 180.78 mmol, 1.05 equiv) in dioxane (100 mL) dropwise with stirring at 15° C. The resulting solution was stirred for 15 h at 15-20° C. The solids were filtered out. The filtrate was diluted with 200 mL of water. The resulting solution was extracted with 3*200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:60-1:50-1:30-1:20). Purification afforded 32.98 g (54%) of 109.2 as a white semi-solid. Synthesis of Compound 109.4. Compound 109.4 was prepared from 109.2 and 57.2 using the procedure for the synthesis of 57.5. Purification: Chiral preparative HPLC under the following conditions (Gilson): Column: Venusil Chiral OD-H, 21.1*25 cm, 5 μm; mobile phase: hexanes and ethanol (hold at 5% ethanol for 15 min); detector: UV 220/254 nm. Synthesis of Compound 109.7. Compound 109.7 was prepared from 70.1 and 109.4 in a manner analogous to Example 57. Isolated a white solid in 14% yield from 70.1.

Reference： [1]Current Patent Assignee: VTV THERAPEUTICS INC. - WO2007/115935, 2007, A1 Location in patent: Page/Page column 65
[2]Uyanik, Muhammet; Akakura, Matsujiro; Ishihara, Kazuaki [Journal of the American Chemical Society, 2009, vol. 131, p. 251 - 262]
[3]Current Patent Assignee: GILEAD SCIENCES INC - US2013/123231, 2013, A1 Location in patent: Paragraph 0781; 0782; 0783
[4]Current Patent Assignee: GILEAD SCIENCES INC - US2013/123231, 2013, A1 Location in patent: Paragraph 0962; 0963; 0964

33
[ 556-48-9 ]
[ 98-88-4 ]
[ 6308-92-5 ]

Yield	Reaction Conditions	Operation in experiment
30%	With pyridine; dmap; In dichloromethane; at 25℃; for 4.0h;	Example 9Synthesis of [F-18]-l-(4-fluorocyclohexyl)-l-methyl-4-phenylpiperazinium iodideA solution of 1,4-cyclohexadiol (cis/trans mixture, 10 g, 86 mmol), benzoyl chloride (12 g, 86 mmol), and DMAP (50 mg) in methylene chloride/pyridine (80/20) was stirred at 250C for 4 hr. The reaction mixture washed with 10% HCl until the aqueous layer was acidic and methylene chloride layer was washed with sat'd NaHCOs, brine, and dried (Na2SO4). After solvent removal, chromatography (silica gel, methylene chloride/methanol, 95:5) of the crude material gave 6 g (30%) of the benzoyl alcohol.4-Benzoylcyclohexanol (5 g, 23 mmol) was oxidized using PCC (7.4 g, 34.5) mmol) in methylene chloride (50 mL) for 2 hours at 250C. The black reaction mixture was filtered through a short bed of silica gel and solvent was removed. Chromatography (silica gel, hexane/ethyl acetate, 85:15) afforded 3 g (60%) of the ketone; Mp 58-6O0C.Reductive amination to give l-(4-benzoyoxycyclohexyl)-4-phenylpiperazine was done using a published procedure [J. Org. Chem. 1996, 61, 3849-3862]. 1-Phenylpiperazine(1 g, 6.2 mmol) and 4-benzoyoxycyclohexanone (1.4 g, 6.2 mmol) were mixed in 1,2- dichoroethane (35 mL) and then treated with sodium triacetoxyborohydride (1.2 g) and glacial acetic acid (0.25 g). The mixture was stirred at 250C under nitrogen for 16 hours. <n="99"/>The reaction mixture was quenched by adding 1 N NaOH (20 mL) and the product was extracted with methylene chloride. The extract was washed with brine, dried (MgSO4), and solvent was evaporated to give the crude free base. Chromatography (silica gel, methylene chloride, 95:5) afforded 1.8 g (80%) of l-(4-benzoyoxycyclohexyl)-4-phenylpiperazine. Deprotection of l-(4-benzoyoxycyclohexyl)-4-phenylpiperazine (1 g, 2.7 mmol) was done in methanol (25 mL) using IM lithium hydroxide (5 mL) at 8O0C for 1 hr, which gave 0.6 g (85%) of l-(4-hydroxycyclohexyl)-4-phenylpiperazine. l-(4-Hydroxycyclohexyl)-4-phenylpiperazine (0.5 g, 1.9 mmol) was converted to the mesylate using methane sulfonyl chloride (0.23 g, 2 mmol) in 10 mL of methylene chloride/pyridine (90/10) at 25 0C. The reaction mixture was stirred for 2 hours and volatiles were removed under vacuum. The crude product was dissolved in methylene chloride (20 mL) and washed with sat'd NaHCO3 twice and dried (MgSO4). After solvent removal, the crude product was chromato graphed on silica gel using methylene chloride/methanol (90:10), which gave 0.4 g (80%) of the piperazine mesylate. 1H NMR (CDCl3), deltal.4-2.4 (9H, m, ring-CH), 2.7 (4H, m, piperazine-CH2), 3.05 (3H, s, CH3), 3.2 (4H, m, piperazine-CH2), 4.6 (IH, m, 0-CH), 6.83-6.9 (2H, m, phenyl-CH), 7.2-7.3 (3H, m, phenyl-CH).A Wheaton 5-mL reaction vial containing fluorine-18 (20 mCi) in 0.5 mL of 18O- enriched water, Kryptofx 2.2.2 (10 mg), and potassium carbonate (2 mg) was heated at 1180C and solvent was evaporated with the aid of a nitrogen gas flow. The K18F/Kryptofx complex was dried three times by the addition of 1 mL of acetonitrile followed by evaporation of the solvent using a nitrogen flow. A solution of 5 mg of l-(4- methanesulfonyoxycyclohexyl)-4-phenylpiperazine in 1 ml of acetonitrile was added to the vial and the fluorination reaction was performed at 12O0C for 10 min. Solvent was removed using a nitrogen flow and replaced with 1 mL of a hexane/ethyl acetate/methanol (50:45:5) solution. After mixing, the solution was loaded onto a silica gel SepPak (Waters, Milford, MA) and the activity was eluted with 2 mL of the same solution. The labeled piperazine derivative was purified by HPLC (semi-prep silica gel column, hexane/ethyl acetate/methanol, 50:45:5). The solvent was removed and iodomethane (0.1 mL) in acetonitrile (1 mL) was added to a vial containing the activity. The reaction vial was heat at 12O0C for 20 minutes and solvent was evaporated to afford [F-18]-l-(4-fluorophenyl)-l- methylpiperazinium iodide (7 mCi).
30%	With pyridine; In dichloromethane; at 25℃; for 4.0h;	A solution of 1,4-cyclohexadiol (cis/trans mixture, 10 g, 86 mmol), benzoyl chloride (12 g, 86 mmol), and DMAP (50 mg) in methylene chloride/pyridine (80/20) was stirred at 25C for 4 hr. The reaction mixture washed with 10% HC1 until the aqueous layer was acidic and methylene chloride layer was washed with sat'd NaHCO3, brine, and dried (Na2SO4). After solvent removal, chromatography (silica gel, methylene chloride/methanol, 95: 5) of the crude material gave 6 g (30%) of the benzoyl alcohol

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 85 - 89
[2]Patent: WO2008/22319,2008,A2 .Location in patent: Page/Page column 97-98
[3]Patent: WO2005/82425,2005,A1 .Location in patent: Page/Page column 75
[4]Angewandte Chemie - International Edition,2013,vol. 52,p. 1266 - 1269
Angew. Chem.,2012,vol. 125,p. 1304 - 1307,4

34
[ 556-48-9 ]
[ 18162-48-6 ]
[ 55145-45-4 ]

Yield	Reaction Conditions	Operation in experiment
28%	Stage #1: 1,4-Cyclohexanediol; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Stage #2: With pyridinium chlorochromate In dichloromethane for 1.5h; Further stages.;
	Stage #1: 1,4-Cyclohexanediol; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; Stage #2: With pyridinium chlorochromate In dichloromethane at 0℃; for 3h;	1.3 Step3: 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanone; [00151] To a solution of 1,4-cyclohexanediol (20.0 g, 0.172 mol; Aldrich) and lH-Imidazole (33 g, 0.48 mol; Aldrich) in N,N-dimethylformamide (250 mL, 3.2 mol; Acros) was added a solution of tert-butyldimethylsilyl chloride (20.0 g, 0.133 mol; Aldrich) in N,N- dimethylformamide (100 mL, 1 mol; Acros) via a dropping funnel at 0 °C. The mixture was was allowed to warm to room temperature and stirred overnight. TLC (ethyl acetate/hexane 1 :4) showed almost complete reaction and the mixture was partitioned between water and ether, the organic phase dried over MgSO4 and concentrated in vacuo. [00152] The crude product from above was dissolved in methylene chloride (500 mL, 8 mol; Acros) and mixed with Celite (10Og). Pyridinium chlorochromate (41 g, 0.19 mol; Aldrich) was added in 5 portions at 0 °C. The cooling bath was removed and the mixture stirred for 3 hours. The mixture was filtered thru a short silica gel column and the column washed with methylene chloride. The filtrates were concentrated and further purified on CombiFlash silica gel column with 0-50% ethyl acetate in hexane to give the desired product as a colorless oil.

Reference： [1]Malapelle, Adeline; Coslovi, Anna; Doisneau, Gilles; Beau, Jean-Marie [European Journal of Organic Chemistry, 2007, # 19, p. 3145 - 3157]
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2008/94574, 2008, A2 Location in patent: Page/Page column 36

35
[ 556-48-9 ]
[ 41043-88-3 ]

Reference： [1]Chemistry - A European Journal,2007,vol. 13,p. 4859 - 4872
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 2496 - 2511
[3]Tetrahedron,1987,vol. 43,p. 2681 - 2688
[4]Tetrahedron,2012,vol. 68,p. 2363 - 2373
[5]Journal of Organic Chemistry,2017,vol. 82,p. 6671 - 6679

36
[ 556-48-9 ]
[ 2987-06-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 32 percent / NaH / dimethylformamide / 24 h 2: 99 percent / oxalyl chloride; DMSO; Et₃N / CH₂Cl₂ / -40 - 0 °C
	Multi-step reaction with 2 steps 1: Na / tetrahydrofuran / 18 h / 40 - 50 °C 2: 0.045 g / CrO₃; H₂SO₄ / acetone / 0.08 h / 20 °C
	Multi-step reaction with 2 steps 1: NaH 2: PCC

	Multi-step reaction with 2 steps 1: Na / toluene / Heating 2: CrO₃, H₂SO₄ / acetone
	Multi-step reaction with 2 steps 1: (i) Na, xylene, (ii) /BRN= 385801/ 2: CrO₃, AcOH
	Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 12 h / 20 °C 2: pyridinium chlorochromate / dichloromethane / 12 h / 20 °C / Molecular sieve

Reference： [1]Baghdasarian, Glen; Woerpel [Journal of Organic Chemistry, 2006, vol. 71, # 18, p. 6851 - 6858]
[2]Crotti, Paolo; Di Bussolo, Valeria; Favero, Lucilla; Pineschi, Mauro; Marianucci, Francesco; Renzi, Gabriele; Amici, Giuseppina; Roselli, Graziella [Tetrahedron, 2000, vol. 56, # 38, p. 7513 - 7524]
[3]Shoup, T. M.; Goodman, M. M. [Journal of labelled compounds and radiopharmaceuticals, 1997, vol. 40, p. 46 - 47]
[4]Bloss,A.S. et al. [Journal of the Chemical Society. Perkin transactions II, 1973, p. 2165 - 2173]
[5]Russo,G.; Danieli,B. [Gazzetta Chimica Italiana, 1965, vol. 95, p. 438 - 447]
[6]Garg, Gaurav; Forsberg, Leah K.; Zhao, Huiping; Blagg, Brian S. J. [Chemistry - A European Journal, 2017, vol. 23, # 65, p. 16574 - 16585]

37
[ 556-48-9 ]
[ 2987-06-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1.) Na / 1.) dioxane, reflux, 4 h, 2.) dioxane, reflux, 20 h 2: 91 percent / PCC / CH₂Cl₂ / 3 h / Ambient temperature

Reference： [1]Keck, Gary E.; Dougherty, Shawn M.; Savin, Kenneth A. [Journal of the American Chemical Society, 1995, vol. 117, # 23, p. 6210 - 6217]

38
[ 556-48-9 ]
[ 13482-23-0 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 351 - 357
[2]Patent: US2014/256706,2014,A1
[3]Journal of Organic Chemistry,2017,vol. 82,p. 6671 - 6679

39
[ 556-48-9 ]
[ 3114-70-3 ]
[ 6850-65-3 ]

Reference： [1]Patent: US6369274,2002,B1 .Location in patent: Page column 3

40
[ 556-48-9 ]
[ 58479-61-1 ]
[ 130745-65-2 ]
[ 130745-64-1 ]

Yield	Reaction Conditions	Operation in experiment
1: 16% 2: 16%	With 1H-imidazole In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 0℃; for 1h;	III EXAMPLE III cis-4-(tert-butyl-diphenylsilyloxy)-cyclohexanol and trans-4-(tert-butyl-diphenylsilyloxy)-cyclohexanol A solution of 29.4 g tert-butyldiphenylsilyl chloride in 20 ml of dimethylformamide is added dropwise to an ice-cooled solution of 10.0 g 1,4-cyclohexanediol (cis/trans mixture approx. 1:1) and 14.6 g imidazole in 15 ml dry dimethylformamide and 20 ml dry tetrahydrofuran. The reaction solution is stirred for 1 h in the ice bath and then combined with 100 ml aqueous sodium chloride solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, and the solvent is eliminated totally. The residue is purified by chromatography and resolved into the two isomeric products (ethyl acetate/cyclohexane 1:1). cis-4-(tert-butyl-diphenylsilyloxy)-cyclohexanol: Yield: 4.9 g (16% of theory) Mass spectrum (ESI+): m/z=355 [M+H]+ trans-4-(tert-butyl-diphenylsilyloxy)-cyclohexanol: Yield: 4.8 g (16% of theory) Mass spectrum (ESI+): m/z=355 [M+H]+
1: 16% 2: 16%	With 1H-imidazole In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 0℃; for 1h;	III A solution of 29.4 g tert-butyidiphenylsilyl chloride in 20 ml of dimethylformamide is added dropwise to an ice-cooled solution of 10.0 g 1,4-cyclohexanediol (cis/trans mixture approx. 1:1) and 14.6 g imidazole in 15 ml dry dimethylformamide and 20 ml dry tetrahydrofuran. The reaction solution is stirred for 1 h in the ice bath and then combined with 100 ml aqueous sodium chloride solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, and the solvent is eliminated totally. The residue is purified by chromatography and resolved into the two isomeric products (ethyl acetate/cyclohexane 1:1). cis-4-(tert-butyl-diphenylsilyloxy)-cyclohexanol: Yield: 4.9 g (16% of theory) Mass spectrum (ESI+): m/z=355 [M+H]+ trans-4-(tert-butyl-diphenylsilyloxy)-cyclohexanol: Yield: 4.8 g (16% of theory) Mass spectrum (ESI+): m/z=355 [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/25349, 2006, A1 Location in patent: Page/Page column 17
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/35841, 2006, A1 Location in patent: Page/Page column 19

41
[ 67-56-1 ]
[ 64-18-6 ]
[ 110-94-1 ]
[ 124-04-9 ]
[ 1191-25-9 ]
[ 13392-69-3 ]
[ 556-48-9 ]
[ 542-28-9 ]
[ 627-93-0 ]
[ 4547-43-7 ]
[ 1119-40-0 ]
[ 14273-92-8 ]
[ 931-17-9 ]
[ 106-65-0 ]

Reference： [1]Patent: WO2004/26798,2004,A2 .Location in patent: Page/Page column 10

42
[ 898829-73-7 ]
[ 556-48-9 ]
(1-Benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid 4-hydroxy-cyclohexyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	Stage #1: phosgene; N-(1-benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-amine, hydrochloride salt With sodium hydrogencarbonate In dichloromethane; toluene at 20℃; for 3h; Stage #2: 1,4-Cyclohexanediol In toluene at 60℃; for 60h;	52.B 52B. 52B. (1-Benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid 4-hydroxy-cyclohexyl ester To a stirring suspension of N-1-benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-amine, hydrochloride salt (277 mg, 0.92 mmol), prepared as described in Example 52A, and NaHCO3 (773 mg, 9.2 mmol) in CH2Cl2 (10 mL) at RT was added phosgene (2.4 mL of 20% solution in toluene). After addition, the mixture was stirred at RT for 3 h and filtered. The filtrate was concentrated, the resultant residue dried in vacuo, then dissolved in toluene (5 mL) and treated with 1,4-cyclohexynediol (210 mg, 1.8 mmol). The mixture was stirred at 60° C. for 60 h, cooled to RT, and concentrated. The resultant residue was chromatographed (silica gel) eluding with EtOAc (0-25%) in hexanes to provide the title compound as a white solid (138 mg, 37%). HPLC (method B): 99% pure, retention time=6.76 min, MS (ES): m/z 406 [M+H]+.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2006/160850, 2006, A1 Location in patent: Page/Page column 22-23

43
[ 67-56-1 ]
[ 64-18-6 ]
[ 110-94-1 ]
[ 124-04-9 ]
[ 1191-25-9 ]
[ 13392-69-3 ]
[ 556-48-9 ]
[ 627-93-0 ]
[ 4547-43-7 ]
[ 1119-40-0 ]
[ 14273-92-8 ]
[ 931-17-9 ]
[ 106-65-0 ]

Reference： [1]Patent: WO2006/48170,2006,A1 .Location in patent: Page/Page column 13

44
[ 556-48-9 ]
[ 40161-54-4 ]
4-[2-bromo-5-(trifluoromethyl)phenoxy]cylohexanol [ No CAS ]
4-[2-bromo-5-(trifluoromethyl)phenoxy]cylohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 80℃; for 2h;	INTERMEDIATE 7 <n="47"/>MC181 Y4-[2-Bromo-5-(trifluoromethyl)phenoxy]cvclohexanolTo a solution of <strong>[40161-54-4]4-bromo-3-fluorobenzotrifluoride</strong> (2 g, 8.23 mmol) and a mixture of cis and trans cyclohexane-l,4-diol (3.82 g, 32.9 mmol) in DMF (41.2 ml) was added NaH 5 (0.658 g, 16.46 mmol) at 0 C. The reaction mixture was warmed to room temperature then heated at 80 0C for 2 h. The mixture was poured onto IN HCl (100 mL) and extracted with EtOAc (3x25 mL). The combined organic fractions were washed with water (50 mL) then dried over Na2SO4. Purification by Combiflash chromatography (SiO2-40 g, gradient elution of 10- 50% EtOAc/hexanes over 25 min) afforded the title product as a 7:3 mixture of isomers. 10 Major isomer: 1H NMR (500 MHz, acetone-d6): delta 7.82 (dd, IH), 7.43 (d, IH), 7.23 (d, IH), 4.76-4.70 (m, IH), 3.84-3.76 (m, IH), 3.67 (d, IH), 2.18-2.12 (m, IH), 2.06-1.95 (m, IH), 1.82-1.71 (m, 2H), 1.69-1.60 (m, 2H), 1.55-1.47 (m, 2H). MS: m/z 339, 341 (MH+).

Reference： [1]Patent: WO2008/128335,2008,A1 .Location in patent: Page/Page column 45-46

45
[ 556-48-9 ]
mononitrite ester of cyclohexanediol [ No CAS ]
[ 187347-32-6 ]

Yield	Reaction Conditions	Operation in experiment
1: 59% 2: 37%	With nitrogen(II) oxide; Nitrogen dioxide In acetonitrile at -5 - 0℃; for 1h;	6 A balloon with 5 L of nitrogen monoxide (NO) was attached to a 200 mL four-neck reactor vessel, and the atmosphere in the system was replaced with NO. Then the reactor vessel was cooled to -5° C., and 10 g (217 mmol) of liquid NO2 was added thereto by a syringe. The mixture was stirred at -5° C. for 30 minutes to produce 16.4 g (216 mmol) of N2O3 (blue liquid). A mixture of 15.7 g (135 mmol) of 1,4-cyclohexanediol and acetonitrile (100 mL) was added dropwise to the resulting liquid N2O3 over 30 minutes. Since the reaction was an exothermic reaction, the temperature of the inside of the reactor vessel was controlled at -5° C. to 0° C. After the dropwise addition, the reaction product was analyzed by a gas chromatography, which showed that dinitrite ester of cyclohexanediol and mononitrite ester of cyclohexanediol were produced in yields of 59% (13.9 g, 80 mmol) and 37% (7.26 g, 50 mmol), respectively, based on cyclohexanediol. The yield of nitrites was 97% based on N2O3.

Reference： [1]Current Patent Assignee: DAICEL CORPORATION - US2009/43120, 2009, A1 Location in patent: Page/Page column 4-5

46
[ 556-48-9 ]
[ 874-60-2 ]
[ 1036648-32-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	With pyridine In chloroform at 0℃; for 5h;
67%	With pyridine In chloroform at 0℃; for 5h; Inert atmosphere;
	With triethylamine In tetrahydrofuran at 0 - 70℃; Inert atmosphere;	46 (4-Hydroxycvclohexyl) 4-methylbenzoate To a solution of 1 ,4-cyclohexanediol (1 .00 g, 8.61 mmol) in THF (40 mL), cooled at 0 °C under nitrogen atmosphere, was added triethylamine (1 .2 mL, 8.61 mmol) and p-toluoyl chloride (1 .1 mL, 8.61 mmol). The reaction mixture was heated to 70 °C and stirred overnight. Once cooled, the mixture was quenched with a saturated solution of NaHC03 (15 mL) and extracted with DCM (3 χ 20 mL). The combined organic extracts were filtered over hydrophobic fit and concentrated under reduced pressure. Further purification by flash column chromatography on silica gel eluting 0-40% ethyl acetate in heptane afforded (4-hydroxycyclohexyl) 4-methylbenzoate (0.49 g, 2.09 mmol, 24% yield as a mixture of diasteroisomers) as a white solid. NMR (400 MHz, CDCIs, δ) (3:2 as a mixture of diasteroisomers): 8.00-7.90 (m, 2H), 7.31 -7.22 (m, 2H), 5.20-5.1 1 (m, 0.4H), 5.07-4.98 (m, 0.6H), 3.90-3.77 (m, 1 H), 2.46-2.41 (m, 3H), 2.20-1 .43 (m, 9H)

Reference： [1]Lam, Kevin; Marko, Istvan E. [Chemical Communications, 2009, # 1, p. 95 - 97] Lam, Kevin; Marko, Istvan E. [Organic Letters, 2009, vol. 11, # 13, p. 2752 - 2755]
[2]Lam, Kevin; Marko, Istvan E. [Organic Letters, 2008, vol. 10, # 13, p. 2773 - 2776] Lam, Kevin; Markó, István E. [Tetrahedron, 2009, vol. 65, # 52, p. 10930 - 10940]
[3]Current Patent Assignee: ELI LILLY & CO - WO2017/46604, 2017, A1 Location in patent: Paragraph 00378; 00379

47
[ 556-48-9 ]
[ 3114-70-3 ]

Yield	Reaction Conditions	Operation in experiment
	With (carbonyl)chloro(hydrido)tris(triphenylphosphine)ruthenium(II); ammonia; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-Amyl alcohol; at 140℃; for 20h;Inert atmosphere; Cooling;	Example 6Direct Single-Stage Amination of Alcohols andHydroxy Acids by Means of Ammonia Over aHomogeneous Ruthenium Catalyst and Xantphos ata high V7J Vgas (according to the invention)Under an argon atmosphere, m g of starting material, mRU g of [carbonylchlorohydridotris(triphenylphosphane)ruthenium(II)] and mp g of 9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene as catalyst and V07 ml of 2-methyl-2-butanol as solvent were introduced into a 50 mlsteel tube. The vessel was closed, pressurized three times with 20 bar of argon and depressurized each time. The vessel was then cooled by means of dry ice and m g of ammonia were condensed in. The reactor is heated to T C. and maintained at this temperature for 20 hours. Afier cooling to room temperature, the reactor was depressurized and opened, the solvent was removed on a rotary evaporator and the residue was dissolved in methanol and then analysed by gas chromatography. Reaction parameters and conversions and selectivities to the desired reaction product are shown in Tab. 5. The results show that many different hydroxy-thnctionalized substrates can be aminated by the method described.

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 7599 - 7603
[2]Patent: US2013/331580,2013,A1 .Location in patent: Paragraph 0063

48
[ 556-48-9 ]
[ 62-53-3 ]
[ 52034-23-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	With Pt-Sn/γ-Al2O3 In o-xylene at 145℃; for 24h; Inert atmosphere;	A general procedure for the direct synthesis of diamines 3 from the N-alkylation of amines 2 with diols 1: General procedure: Under nitrogen atmosphere, to a 15-mL Pyrex glass screw-cap tube were added diol 1 (1.0 mmol), amine 2 (2.0 mmol), Pt-Sn/γ-Al2O3 catalyst (200 mg, 0.5 mol % Pt), and o-xylene (5 mL). The resultant mixture was stirred in the sealed tube at 145 °C for 24 h. After cooled to ambient temperature, the catalyst was removed by centrifugation and washed with CH2Cl2 (3 × 5 mL). The combined supernatant was condensed under reduced pressure and subjected to purification by silica gel column chromatography (eluent: petroleum ether (60-90 °C)/EtOAc = 20:1, v/v), affording diamine 3. The known compounds were identified by comparison of their NMR features with the reported data or of their GC traces with those of the authentic samples. The spectroscopic features of these known compounds are in good agreement with those reported in the literatures. All the new products were characterized by NMR and HRMS techniques.

Reference： [1]Wang, Liandi; He, Wei; Wu, Kaikai; He, Songbo; Sun, Chenglin; Yu, Zhengkun [Tetrahedron Letters, 2011, vol. 52, # 52, p. 7103 - 7107]

49
[ 556-48-9 ]
[ 22419-35-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 85 - 89
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 85 - 89

50
[ 556-48-9 ]
[ 111196-81-7 ]
[ 1361391-19-6 ]

Yield	Reaction Conditions	Operation in experiment
66%		Step 1. Preparation of 4-(5-ethylpyrimidin-2-yloxy)cyclohexanol To a stirred solution of cyclohexane-1,4-diol (2.03 g, 17.5 mmol) in DMF (17 mL) was added NaH (95% wt, 177 mg, 7.01 mmol) at 0 C. The mixture was stirred for 30 min at room temperature and <strong>[111196-81-7]2-chloro-5-ethylpyrimidine</strong> (500 mg, 3.51 mmol) was added to the mixture. After being stirred for 16 hours at 70 C., the reaction mixture was diluted with EtOAc and water. The organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give the desired product (520 mg, 66%) as a colorless oil. 1H NMR (400 Hz, CDCl3) delta 1.24 (3H, t, J=7.6 Hz), 1.57-1.84 (5H, m), 2.03-2.20 (3H, m), 2.57 (2H, q, J=7.6 Hz), 3.78-3.82 (1H, m), 4.94-5.01 and 5.06-5.10 (1H, each m), 8.33 (2H, s). LC-MS m/z=222.8 [M+H]+.

Reference： [1]Patent: US2012/53180,2012,A1 .Location in patent: Page/Page column 28

51
[ 556-48-9 ]
[ 106-96-7 ]
[ 1447817-83-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 1,4-Cyclohexanediol With sodium hydride In N,N-dimethyl-formamide; paraffin oil for 5h; Cooling with ice; Inert atmosphere; Stage #2: propargyl bromide In N,N-dimethyl-formamide; toluene; paraffin oil at 20℃; Inert atmosphere;
	With sodium hydride In N,N-dimethyl-formamide at 0℃; for 24h; Schlenk technique; Inert atmosphere;	4-(propargyloxy)cyclohexanone (2-C₂H). A Schlenk flask was flushed with nitrogen and charged with 6.94 g of a mixture oftrans- and cis-cyclohexane-1,4-diol (58.6 mmol), 1.77g of NaH (70.1mmol) and 60 mL of DMF. The mixture was cooled to 0 oC and 7.81 mLof popargyl bromide (70.1mmol) was added dropwise. After 24 h the mixture was diluted with 50 mL of 1MHCl and 50 mL of brine. Theproduct was extracted with diethyl ether (100 + 3 ×50 mL). The extracts were dried over MgSO4. The organic phasewas filtered and the solvent was removed under reduced pressure.
	With sodium hydride

Reference： [1]Yang, Zhigang; Lee, Jae Hong; Jeon, Hyun Mi; Han, Ji Hye; Park, Nayoung; He, Yanxia; Lee, Hyunseung; Hong, Kwan Soo; Kang, Chulhun; Kim, Jong Seung [Journal of the American Chemical Society, 2013, vol. 135, # 31, p. 11657 - 11662]
[2]Pigulski, Bartłomiej; Gulia, Nurbey; Szafert, Sławomir [Tetrahedron Letters, 2013, vol. 54, # 45, p. 6032 - 6034]
[3]Zhang, Yutao; Yan, Chenxu; Zheng, Qiaoqiao; Jia, Qian; Wang, Zhongliang; Shi, Ping; Guo, Zhiqian [Angewandte Chemie - International Edition, 2021, vol. 60, # 17, p. 9553 - 9561][Angew. Chem., 2021, vol. 133, # 17, p. 9639 - 9647,9]

52
[ 928337-00-2 ]
[ 556-48-9 ]
4-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)oxy)-trans-cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 120℃; for 4h; Microbiological reaction;	1.4 4. 4-(( 3-(3-(Trifluoromethoxy)Dhen vDimidazof 1 , 2-blo yridazin-6-yl) oxy) - trans-cvclohexanol 4. 4-(( 3-(3-(Trifluoromethoxy)Dhen vDimidazof 1 , 2-blo yridazin-6-yl) oxy) - trans-cvclohexanol (EX. 8-4). Toluene [00281 ] A solution of 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1 ,2- b]pyridazine (0.3 g, 0.96 mmol) and cyclohexanediol (0.1 1 g, 0.96 mmol) in toluene 5 mL was added potassium tertiary butoxide (0.165 g, 1 .72 mmol) , rac- BINAP (36 mg, 0.057 mmol) and Pd2(dba)3 (26 mg, 0.029 mmol) and the mixture was heated at 120°C for 4 h under microwave irridation. The resulting dark brown solution was cooled down and was concentrated under reduced pressure. The solid was further purified by using combiflash chromatography (12 g column), eluent: 0-10% methanol/DCM and obtained product 4-((3-(3- (trifluoromethoxy)phenyl)imidazo[1 ,2-b]pyridazin-6-yl)oxy)cyclohexanol (50 mg, 0.127 mmol, 13% yield). [00282] 1 H-NMR (CD3OD/400 MHz): δ 8.12 (s, 1 H), 7.93 (s, 1 H), 7.89 (m, 1 H), 7.87 (s, 1 H), 7.87 (m, 1 H), 7.54 (t, J = 8.0 Hz, 1 H), 7.25 (d, J = 9.2 Hz, 1 H), 6.85 (d, J = 9.6 Hz, 1 H), 4.98 (m, 1 H), 3.69 (m, 1 H), 2.22 (m, 2H), 2.02 (m, 2H), 1 .62 (m, 2H), 1 .45 (m, 2H). MS (ES+, m/z): (M+H)+: 394.5.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED - WO2013/13188, 2013, A1 Location in patent: Paragraph 00281; 00282

53
[ 556-48-9 ]
[ 2615-25-0 ]
[ 15827-56-2 ]

Reference： [1]ChemCatChem,2013,vol. 5,p. 2905 - 2912

54
[ 556-48-9 ]
[ 98-88-4 ]
[ 2976-80-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	With pyridine In chloroform at 25℃; for 12h; Inert atmosphere;	200.e e) 4-Benzyloxy-cvclohexanol To a solution of cyclohexane-l,4-diol (10 g, 86.08 mmol) in CHCI3 (100 mL) were added slowly pyridine (10.53 mL, 129.13 mmol) and benzoyl chloride (13.11 mL, 111.91 mmol) at 25°C under argon atmosphere. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with 80 mL CH2CI2 and washed with 200 mL H2O. The organic layer was dried over Na2S04 and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of n-hexane : EtOAc (80 : 20 to 70 : 30). Colorless liquid (58%).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/189841, 2013, A1 Location in patent: Page/Page column 224; 225

55
[ 556-48-9 ]
[ 17178-10-8 ]
[ 107025-44-5 ]

Reference： [1]Journal of Materials Chemistry B,2013,vol. 1,p. 6532 - 6537

56
[ 556-48-9 ]
[ 18162-48-6 ]
[ 103202-63-7 ]
[ 103202-62-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: 1,4-Cyclohexanediol With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: tert-butyldimethylsilyl chloride In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere;	4-O-Tert-butyldimethylsilylcyclohexanol (4) To a solution of cis/trans mixture of 1, 4-cyclohexanediol 15 (200 mg, 1.72 mmol) in N,N-dimethylformamide (5 mL) was added 2.5 equiv. of imidazole (293 mg) and the mixture was stirred at r.t. for 30 min. To the solution was added tert-butyldimethylsilylchloride (1.25 equiv., 293 mg) and the mixture was further stirred f or 3 days in an atmosphere of N2. At the end of the third day, the mixture was diluted with excess CH2Cl2 (30 mL), washed with water (525 mL) and saturated NaCl (aq) solution (125 mL). The organic layer was dried over anhydrous Na2SO4 and then evaporated in vacuo to give 276 mg of the crude product. Purification was done by flash column chromatography using 50% EtOAc in hexanes as the eluent which gave 196 mg (50%) of the product 4. Rf (50% EtOAc/hexanes): 0.87. 1H NMR (500 MHz, CDCl3)d 3.79-3.83 (m, 1H, H-1), 3.65-3.70(m, 1H, H-4), 1.6-1.77 (m, 6H, H-2a,2e,3e,5e,6a,6e), 1.46-1.5(m, 1H, H-3a), 1.28-1.32 (m, 1H, H-5a), 0.89 (s, 9H, t-butyl), 0.04(s, 6H, CH3); 13C NMR (125 MHz, CDCl3) d 78.1 (C-4), 69.7 (C-1),32.1 (C-2, 6), 1.3 (C-3, 5), 30.9 (-CCH3, t-butyl), 25.9 (-CCH3, t-butyl), -2.0 (CH3)
1: 0.151 g 2: 0.189 g	With triethylamine In hexane; acetonitrile at 20℃; for 24h; Inert atmosphere; Overall yield = 30 %;	Typical procedure for the monosilylation of symmetric diols General procedure: In a flame-dried100 mL round-bottom flask equipped with a teflon magnetic stir bar,diol(5.0 mmol) was added to acetonitrile (12.5 mL) and hexanes (37.5 mL).Triethylamine (Et3N, 0.84 mL, 6.00 mmol, 1.2 equiv) and tertbutyldimethylsilylchloride (TBSCl, 0.53 g, 5.0 mmol, 1.0 equiv) were addedto the solution and the resulting biphasic mixture was stirred vigorously atroom temperature for 24 h under a N2 atmosphere. The reaction was quenchedwith saturated aqueous ammonium chloride (NH4Cl, 50 mL), and extractedwith ethyl acetate (EtOAc, 3 50 mL). The combined organic phase waswashed with brine (3 50 mL) and dried over anhydrous sodium sulfate(Na2SO4). The crude product was purified by silica gel column chromatography(10-15% EtOAc/hexanes).
1: 2.55 g 2: 1.53 g	With triethylamine In N,N-dimethyl-formamide at 0 - 35℃; for 1h;	31.A-1 A-1) cis-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexanol and trans-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexanol A) 1-(trans-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine A-1) cis-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexanol and trans-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexanol [0493] To a solution of cyclohexane-1,4-diol (cis/trans mixture, 5.00 g) in DMF (40 mL) were added triethylamine (6.60 mL) and tert-butyl(chloro)dimethylsilane (7.79 g) at 0°C, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title cis form (2.55 g) and trans form 1.53 g). cis-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexanol 1H NMR (300 MHz, DMSO-d6) δ 0.03 (6H, d, J = 6.0 Hz), 0.83-0.90 (9H, m), 1.35-1.63 (8H, m), 3.47 (1H, tq, J = 7.4, 3.4 Hz), 3.75 (1H, tt, J = 5.8, 2.9 Hz), 4.37 (1H, d, J = 3.8 Hz). trans-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexanol 1H NMR (300 MHz, DMSO-d6) δ 0.00-0.04 (6H, m), 0.80-0.89 (9H, m), 1.09-1.32 (4H, m), 1.74 (4H, d, J = 8.7 Hz), 3.35-3.49 (1H, m), 3.53-3.66 (1H, m), 4.45 (1H, d, J = 4.2 Hz).

Reference： [1]Basava, Vikram; Romlein, Heather; Bitsaktsis, Constantine; Marzabadi, Cecilia H. [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 697 - 705]
[2]Wilke, Burkhardt I.; Dornan, Mark H.; Yeung, Jon; Boddy, Christopher N.; Pinto, Atahualpa [Tetrahedron Letters, 2014, vol. 55, # 16, p. 2600 - 2602]
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2857400, 2015, A1 Location in patent: Paragraph 0493

57
[ 1037479-62-1 ]
[ 556-48-9 ]
4-[6-chloro-1-(tetrahydropyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 1,4-Cyclohexanediol With sodium hydride In tetrahydrofuran; mineral oil for 0.5h; Inert atmosphere; Cooling with ice; Stage #2: 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazolo [3 ,4-d]pyrimidine In tetrahydrofuran; mineral oil at 20℃;	3.ii (ii) 4-[6-Chloro-1 -(tetrahydro-pyran-2-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yloxy]- cyclohexanol 1 ,4-Cyclohexanediol (1 .91 g, cis-trans mixture) was dissolved in 25 ml dry THF in a reaction vessel containing a magnetic stirring bar under a argon atmosphere, and the mixture cooled on an ice bath. Then sodium hydride (132 mg, 60% suspension in mineral oil) was added and the mixture stirred on an ice bath for approximately 30 min before addition of 4,6-dichloro-1 -(tetrahydro-pyran-2-yl)-1 H-pyrazolo[3,4- d]pyrimidine (948 mg) dissolved in 10 ml THF. The ice bath was removed and the mixture stirred at RT until complete conversion of the starting material as monitored by HPLC/MS. Then the reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3 x 100 ml) and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a mixture of EtOAc and Hep as the eluent to afford 4-[6-chloro-1 -(tetrahydro-pyran-2-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yloxy]- cyclohexanol as a colorless oil after evaporation. Yield: 755 mg (65%). MS (ES+): m/e = 353.0 (M+H), chloro pattern

Reference： [1]Current Patent Assignee: SANOFI - WO2014/140065, 2014, A1 Location in patent: Page/Page column 90; 91

58
[ 110-82-7 ]
[ 504-01-8 ]
[ 556-48-9 ]

Yield	Reaction Conditions	Operation in experiment
	With [Cu3(mu3-5-(4-pyridyl)tetrazolate)4(mu2-N3)2(DMF)2]n·(DMF)2n; dihydrogen peroxide; In neat (no solvent); at 20℃; under 760.051 Torr; for 24h;Green chemistry;	General procedure: The peroxidative oxidation reactions were typically carried out as follows: 0.1-20 mumol of the catalystwas added to 5.00 mmol of the cycloalkane, whereafter 10.00 mmol of 30% H2O2 (1.02 mL) or of 70%TBHP (688 muL) were added and the reaction solution was stirred for 10 h at r.t. and normal pressure.In the experiments with radical traps, CBrCl3 (5.00 mmol) or NHPh2 (5.00 mmol) was added to thereaction mixture.

Reference： [1]Molecules,2015,vol. 20,p. 19203 - 19220

59
[ 556-48-9 ]
(2S,4R)-1-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1,3-oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid [ No CAS ]
(2S,4R)-4-hydroxycyclohexyl 1-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1,3-oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 10h; Inert atmosphere;	147.1 Step 1) : (2S, 4R) -4-hydroxycyclohexyl 1- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -2-(3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carbonyl) -4- ( (methoxycarbonyl) amino) pyrrolidine-2-carboxylate A mixture of (2S, 4R) -1- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carbonyl) -4- ( (methoxycarbonyl) amino) pyrrolidine-2-carboxylic acid (280 mg, 0.43 mmol) , cyclohexane-1, 4-diol (254 mg, 2.19 mmol) , EDCI (340 mg, 1.77 mmol) and HOAT (90 mg, 0.66 mmol) in DCM (10 mL) was stirred at 0 , and DIPEA (0.3 mL, 2.0 mmol) was added dropwise. After the addition, the mixture was stirred at rt for 10 h and washed with water (10 mL × 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 2/3 to give the title compound as a white solid (41 mg, 12) .1H NMR (400 MHz, CDCl3) : δ ppm 7.52-7.62 (m, 2H) , 7.24-7.28 (m, 1H) , 6.72 (t, JF-H 75.1 Hz, 1H) , 5.25-5.38 (m, 2H) , 4.68-4.86 (m, 2H) , 4.37-4.49 (m, 1H) , 3.98-4.02 (m, 2H) , 3.70-3.81 (m, 5H) , 2.22-2.49 (m, 2H) , 1.87-2.04 (m, 4H) , 1.66-1.85 (m, 4H) , 1.50-1.56 (m, 3H) , 1.44 (s, 9H) , 1.33-1.39 (m, 1H) , 0.69-0.73 (m, 2H) , 0.42-0.46 (m, 2H) and MS-ESI: m/z 737.30 [M+H] +.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2016/34134, 2016, A1 Location in patent: Paragraph 00736

60
[ 1717-59-5 ]
[ 556-48-9 ]
4-(difluoromethoxy)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium sulfate; In acetonitrile; at 40 - 45℃; for 1h;	Preparation of 4-(d ifluoromethoxy)cyclohexanol To the mixture of cyclohexane-1,4-diol (11.6 g, 0.1 mol) and Na2SO4 (7.1 g, 0.05 mol) inCHCN(12O mL), FSO2CF2COOH(21.36 g, 0.12 mol) in CH3CN(30 mL) was added dropwise over aperiod of 1 hour to maintain the temperature at 40 to 45C. After addition, the liquid was poured into 200mL of water, extracted with DCM (100 mL*3). The combined extracts was dried over Na2SO4, evaporated, and finally purified by flash column chromatography on silica to give 6.2 g of the titled compound in 37% yield. Note: 4-(difluoromethoxy)cyclohexanol is quite unstable. It is best to use thiscompound to the next step reaction immediately after simple purification.H1 NMR (400 MHz, CDCI3): oe 6.21 (t, 0.5H), 6.19 (t, 0.5H), 4.23 (m, 1H), 3.73 (m, 1H), 1.95 (m, 2H), 1.70 (m, 2H), 1.60 (m, 2H), 1.40 (m, 2H).F19 NMR (376.5 MHz, CDCI3): oe -80.9 (s), -80.8 (s).
	With sodium sulfate; In acetonitrile; at 40 - 45℃;	A solution of FSO2CF2COOH (18.3 g, 103 mmol) in CH3CN (30 mL) was added dropwise overa period of 1 hour to a mixture of M-1-22_1 (10 g, 86 mmol) and Na2504 (6.1 g, 43 mmol) inCH3CN (120 mL) at 40 to 45C. After addition, the solution was poured into water (200 mL).The aqueous phase was extracted with DCM (3 x 100 mL). The combined organic phase waswashed with saturated brine (2 x 200 mL), dried over anhydrous Na2504, filtered, concentrated and purified by flash column (0-400% of EtOAc in PE) to give M-1-22_2 (6 g, crude) as an oil. ?H NMR (400 MHz, CDC13) oe 6.42-6.02 (m, 1H), 4.30-4.10 (m, 1H), 3.80-3.60 (m, 1H), 2.20- 1.30 (m, 8H).

Reference： [1]Patent: WO2016/71239,2016,A1 .Location in patent: Page/Page column 38
[2]Patent: WO2018/75699,2018,A1 .Location in patent: Paragraph 00524

61
(S)-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetic acid [ No CAS ]
[ 556-48-9 ]
C₂₅H₂₇ClN₄O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With toluene-4-sulfonic acid In chloroform at 55 - 60℃; for 30h; Inert atmosphere;	1.2 Synthesis of Compound l-Exampie 1 [ 0268] Step 2: i oluenesulfonic acid (0.3 g, 0.1 equiv.) was added to a solution of L4- cyxlohexauedio (14 g, 10 equfv.; CAS No. 556-48-9, mixture of cis and trans) and S4 (5 g, 1 equiv.) in chloroform (200 ml) under an atmosphere of nitrogen and at a temperature of 55 °C to 60 °C over 6 hours. The reaction was monitored by HPI,C. After 24 hours. HPLC indicated 94% conversion. The reaction mixture was cooled to room temperature and aqueous saturated sodium bicarbonate solution was added to quench the reaction. The organic and aqueous layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution (10 niL/g) and water (10 mL/g), dried with IvgSCX;, filtered and concentrated under reduced pressure to provide a light brown semi-solid. The residue was purified by flash column chromatography (gradient 0% to 5 % meihanol-ethyl acetate) to afford Corapeaml 1 as off-white solid, The off-white solid was dissolved in methyl tert-butyl ether (MBTB) and Compoiind I was iriturated from the solution by adding heptane (--- 50 Ml MBTE heptanes). The solid was filtered and dried under vacuum at 35 °C overnight. The desired product, Compound 1, was isolated as a solid (3.6 g, 59 %). [0269\| }H NMR (300 MHz, CIX, 25 °C) is shown in FIG. 9. HRMS(ESi) calc for C2s7CiN4'Compou ~Ex

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2016/69578, 2016, A1 Location in patent: Paragraph 00268; 00269

62
[ 556-48-9 ]
[ 10543-12-1 ]
C₂₆H₂₈O₁₀ [ No CAS ]

Reference： [1]Patent: JP5962949,2016,B2 .Location in patent: Paragraph 0145; 0146

63
[ 556-48-9 ]
[ 79-03-8 ]
1,4-bis(propanoyloxy)cyclohexane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.7%	With triethylamine In dichloromethane at 10 - 20℃; for 6h;	12 Preparation of 1,4-bis(propanoyloxy)cyclohexane 5 g (43 mmol) of 1,4-cyclohexanediol and 80 ml of dichloromethane were added to a 1-necked round bottom flask (250 ml), and the mixture was cooled to 10 ° C using ice bath. 10 g (99 mmol) of triethylamine A mixture of 10.55 g (99 mmol) of propanoyl chloride and 100 ml of dichloromethane was slowly added dropwise. After completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered and washed three times with 5% brine. The organic layer was dehydrated using anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 9.3 g (yield: 94.7%) of 1,4-bis (propanoyloxy) cyclohexane.

Reference： [1]Current Patent Assignee: A C T (unclear) - KR101511279, 2015, B1 Location in patent: Paragraph 0073; 0074

64
[ 556-48-9 ]
[ 598-21-0 ]
C₁₀H₁₄Br₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-methylcyclohexylamine In 1,4-dioxane at 40℃; for 40h;	1 Synthesis of a salt of the formula (I-56) A compound of 58.1 part eq. (I-56-a), N-methylpiperidine 208.3 part and a benzodioxane 870,0.5hr, stirring at 40 ° C 30 minutes. Thereafter, a compound represented by 403.7 eq. (I-56- b) added, at 40 ° C 40 hours. The obtained reaction mixture, methanol 64 are added with stirring, to recover the supernatant liquid. The recovered supernant after concentration, the obtained conc., methyl isobutyl ketone 1500 portion 750 and ion-exchanged water is added, with stirring at 23 ° C 30 minutes. Thereafter, is placed, the organic layer is obtained. The organic layer, 750 ion exchanged water is added, with stirring at 23 ° C 30 minutes. Thereafter, is placed, the .. organic layer is obtained Furthermore, the above operation is repeated 10 times The recovered organic layer after concentration, obtained a concentrate, fractionating column (column fractionating conditions fixed phase: melk made by silica gel 60-200 mesh expansion solvent: toluene) by , a compound represented by 15.7 eq. (I-56-c) was obtained.A compound represented by 3.58 eq. (I-56-c) aminoacetonitrile 26.7 part and part, 0.5hr, stirring at 23 ° C 30 minutes. Thereafter, a compound represented by 1.76 eq. (I-56-d) added, 12 hours at 23 ° C. A reaction mixture obtained by filtration, represented by salt 4.00 eq. (I-56-e) obtd. part.The method described in the patent Number 2008-209917 obtained by salt 1.00 part represented by eq. (I-56-f), represented by salt 1.47 part eq. (I-56-e), chloroform, 10 parts and ion-exchangedwater 0.5hr 5 part, 15 hours at 23 ° C. 2 layer separating the reaction liquid is obtained, since, by taking the chloroform layer, further, the chloroform layer 5 is added in an ion exchange water, washing. This operation is repeated5 Times. Chloroform Is Concentrated, The Residue Obtained, Tert-Butyl Methyl Ether 10 23 ° C Is Added With Stirring At 30 Minutes, By Filtration, Represented By A Obtd. Eq. (I-56) Salt 1.62.
	Stage #1: 1,4-Cyclohexanediol With N-methylcyclohexylamine In 1,4-dioxane at 40℃; for 0.5h; Stage #2: 2-Bromoacetyl bromide In 1,4-dioxane at 40℃; for 40h;	1 58.1 parts of the compound represented by the formula (I-187-a), 208.3 parts of N-methylpiperidine and 870 parts of dioxane were charged in a reactor and stirred at 40 ° C. for 30 minutes. Thereafter, 403.7 parts of the compound represented by the formula (I-187-b) was added, and the mixture was stirred at 40 ° C. for 40 hours. To the resulting reaction mixture, 64 parts of methanol was added and stirred, and then the supernatant was recovered. After concentrating the recovered supernatant, 1500 parts of methyl isobutyl ketone and 750 parts of ion exchanged water were added to the obtained concentrate, and the mixture was stirred at 23 ° C. for 30 minutes. Thereafter, the mixture was allowed to stand and liquid separation to obtain an organic layer. 750 parts of ion-exchanged water was added to the obtained organic layer, and the mixture was stirred at 23 ° C. for 30 minutes. Thereafter, the mixture was allowed to stand and liquid separation to obtain an organic layer. This washing operation was repeated ten more times. After concentrating the recovered organic layer, the resulting concentrate was subjected to column fractionation (column fractionation conditions: stationary phase: silica gel 60-200 mesh developing solvent: toluene, manufactured by Merck) to give a compound of formula (I-187 -c) was obtained

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - JP5921980, 2016, B2 Location in patent: Paragraph 0288-0290
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - JP6177597, 2017, B2 Location in patent: Paragraph 0342-0343

65
[ 556-48-9 ]
2'-(2-fluoropyridin-4-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine] [ No CAS ]
4-((4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyridin-2-yl)oxy)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: 1,4-Cyclohexanediol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 2'-(2-fluoropyridin-4-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine] In N,N-dimethyl-formamide at 120℃; for 0.75h; Microwave irradiation;	54 Example 54: 4-((4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,l- c] [l,4]oxazin]-2'-yl)pyridin-2-yl)oxy)cyclohexanol A microwave vial was charged with cyclohexane-l,4-diol (0.186 g, 1.603 mmol) and DMF (3 mL), next NaH (0.075 g, 1.870 mmol) was added and reaction stirred at rt for about 10 min then 2'-(2-fluoropyridin- 4-yl)-6^8'-dihydro-2H-spiro[benzomran-3,9'-pyrido[3^2':4,5]imidazo[24-c][l,4]oxazine] (0.2 g, 0.534 mmol, Preparation 87) was added and vial was irradiated for about 45 min at about 120 °C. Reaction quenched with slow addition of water and extracted with DCM (30mL), organic washed with water and brine and dried over MgSO/i, then filtered and evaporated under reduced pressure to give a residue. The residue was purified on silica gel chromatography (0-15% MeOH/DCM over 25 min) to give the title compound (0.095g, 35%). LC/MS (Table 1, Method i) Rt = 0.78 min; MS m/z: All (M+ H)+. (TNF IC50 = A).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/168641, 2016, A1 Location in patent: Page/Page column 301

66
[ 1965-09-9 ]
[ 556-48-9 ]
[ 108-93-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 81 %Chromat. 2: 59 %Chromat.	With hydrogen; lanthanum(lll) triflate In isopropyl alcohol at 150℃; for 8h; Autoclave;
1: 67 %Spectr. 2: 62 %Spectr.	With 20% nickel supported on carbon nanotube In isopropyl alcohol at 210℃; for 4h; Autoclave;

Reference： [1]Cui, Xinjiang; Yuan, Hangkong; Junge, Kathrin; Topf, Christoph; Beller, Matthias; Shi, Feng [Green Chemistry, 2017, vol. 19, # 1, p. 305 - 310]
[2]Chen, Changzhou; Liu, Peng; Xia, Haihong; Zhou, Minghao; Jiang, Jianchun [Journal of the Chinese Chemical Society, 2021, vol. 68, # 4, p. 582 - 591]

67
[ 126716-90-3 ]
[ 504-01-8 ]
[ 556-48-9 ]
[ 108-93-0 ]

Reference： [1]Green Chemistry,2017,vol. 19,p. 305 - 310

68
[ 556-48-9 ]
[ 874-60-2 ]
cyclohexane-1,4-diyl bis(4-methylbenzoate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With pyridine In dichloromethane at 45℃; for 4h; Inert atmosphere; Schlenk technique;	1 5.3. Synthesis of di-esters 8-14. 1.74 g of 1,4-cyclohexanediol (15 mmol) was dissolved in 100 mL of dried dichloromethane at room temperature in a 250 mL one-necked round-bottom flask. 4.8 mL pyridine (60 mmol) and the corresponding acid chloride (2.2 equiv) were added and dissolved. The reaction mixture was stirred and heated up to 45 °C. The reaction was performed under stirring and reflux for 4 h at 45 °C. Afterwards, the solution was cooled down to room temperature and extracted three times with a HCl/water solution (2.3 mL HCl (1 N), 100 mL deionized water). The mixture was dried by adding sodium sulfate and filtering afterwards. The solvent was removed under vacuum and the esters purified by column chromatography (methyl-tert-butyl ether/hexane 2:5); both the cis- and the trans-diesters as mixtures were obtained (cf. Fig. 3). Only the esters 8-9 could be isolated as crystalline solids 5.3.1. Cyclohexane-1,4-diyl bis(4-methylbenzoate) (8) 1H NMR (300 MHz, CD2Cl2, ppm) δ = 7.98 (d, 4H, 11-H, 15-H, 21-H, 25-H), 7.26 (d, 4H, 12-H, 14-H, 22-H, 24-H), 5.11 (sept, 2H, 1-H, 4-H), 2.4 (s, 6H, 16-H, 26-H), 2.16-1.6 (m, 8H, 2-H, 3-H, 4-H, 6-H); 13C NMR (75 MHz, CD2Cl2, ppm) δ = 166.4 (C-8, C-18), 144.2 (C-13, C-23), 131.1 (C-10, C-20), 130.1 (C-11, C-15, C-21, C-25), 129.6 (C-12, C-14, C22, C-24), 71.6 (C-1, C-4), 28,3 (C-2,C-3, C-5, C-6), 21,9 (C-16, C-26). IR (solid): ν = 2954, 2926, 2855, 1719, 1360, 1270, 1102, 754 cm-1. MS (ESI): m/z calculated for C22H24O4: [M+H]+: 352.1675; found: 352.1654.

Reference： [1]Kleinpeter, Erich; Werner, Peter; Linker, Torsten [Tetrahedron, 2017, vol. 73, # 27-28, p. 3801 - 3809]

69
[ 556-48-9 ]
[ 122-01-0 ]
cyclohexane-1,4-diyl bis(4-chlorobenzoate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With pyridine In dichloromethane at 45℃; for 4h; Inert atmosphere; Schlenk technique;	2 5.3. Synthesis of di-esters 8-14. General procedure: 1.74 g of 1,4-cyclohexanediol (15 mmol) was dissolved in 100 mL of dried dichloromethane at room temperature in a 250 mL one-necked round-bottom flask. 4.8 mL pyridine (60 mmol) and the corresponding acid chloride (2.2 equiv) were added and dissolved. The reaction mixture was stirred and heated up to 45 °C. The reaction was performed under stirring and reflux for 4 h at 45 °C. Afterwards, the solution was cooled down to room temperature and extracted three times with a HCl/water solution (2.3 mL HCl (1 N), 100 mL deionized water). The mixture was dried by adding sodium sulfate and filtering afterwards. The solvent was removed under vacuum and the esters purified by column chromatography (methyl-tert-butyl ether/hexane 2:5); both the cis- and the trans-diesters as mixtures were obtained (cf. Fig. 3). Only the esters 8-9 could be isolated as crystalline solids.

Reference： [1]Kleinpeter, Erich; Werner, Peter; Linker, Torsten [Tetrahedron, 2017, vol. 73, # 27-28, p. 3801 - 3809]

70
[ 106-51-4 ]
[ 556-48-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen In water at 120℃; for 2h;	10 Implement Case 10 Weigh 0.5g of titanium dioxide dissolved in 10ml of aqueous solution in a round-bottomed flask, with constant stirring 0.076g of palladium nitrate dihydrate solid was added, stirring was continued for 12 hours, turn off the stirring, still 12 hours after the rotary evaporator to remove excess water , Dried overnight, calcined at 450 ° C for 6 hours, and finally reduced at 200 ° C for 4 hours in a hydrogen atmosphere to obtain a titanium dioxide supported noble metal palladium catalyst.Take catalyst 0.1g, water 25ml, p-benzoquinone 0.5g was added to the reactor, the hydrogen replacement reaction kettle air 5 times, at a temperature of 120 , pressure 1.0MPa, stirring speed 900rpm, the reaction 2h, cooled to room temperature, The reaction solution was analyzed by gas chromatography: the conversion rate was 98.85% and the selectivity was 100%.

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN105949033, 2016, A Location in patent: Paragraph 0015-0024

71
[ 556-48-9 ]
C₁₇H₂₆O₆ [ No CAS ]
C₄₀H₆₀O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.7 g	With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 10h; Inert atmosphere; Cooling with ice;	4 (Example 4) Preparation of a compound represented by the formula (I-4) In a nitrogen atmosphere, 3.0 g of the compound represented by the formula (I-4-1), 0.5 g of the compound represented by the formula (I-4-2), 0.5 g of N, N-dimethylaminopyridine And 40 mL of dichloromethane were added. While ice-cooling, 1.4 g of diisopropylcarbodiimide was added dropwise and the mixture was stirred at room temperature for 10 hours. The precipitate was removed by filtration, and the filtrate was washed successively with 1% hydrochloric acid, water and brine. After recrystallization (dichloromethane / methanol), purification was carried out by column chromatography (silica gel, dichloromethane) and recrystallization (dichloromethane / methanol) to obtain 1.7 g of a compound represented by the formula (I-4) .
1.7 g	With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 10h; Inert atmosphere; Cooling with ice;	4 Example 4 Production of a compound represented by the formula (I-4) Under a nitrogen atmosphere, 3.0 g of the compound represented by the formula (I-4-1), 0.5 g of the compound represented by the formula (I-4-2), N, N-dimethylaminopyridine 0. 1g, 40 mL of dichloromethane was added. 1.4 g of diisopropylcarbodiimide was added dropwise while cooling with ice, and the mixture was stirred at room temperature for 10 hours. After removing the precipitate by filtration, the filtrate was washed successively with 1% hydrochloric acid, water and brine. After recrystallization (dichloromethane / methanol), purification was performed by column chromatography (silica gel, dichloromethane) and recrystallization (dichloromethane / methanol) to obtain 1.7 g of the compound represented by the formula (I-4).

Reference： [1]Current Patent Assignee: DIC CORP. - JP2017/218391, 2017, A Location in patent: Paragraph 0140; 0141
[2]Current Patent Assignee: DIC CORP. - JP2021/20913, 2021, A Location in patent: Paragraph 0140-0141

72
[ 556-48-9 ]
[ 58512-50-8 ]

Yield	Reaction Conditions	Operation in experiment
37%	With triethylamine; acetyl chloride In dichloromethane at 0℃; for 1h;	189.1 Step 1 To a 1000 mL round bottom flask vas added cydohexane-1,4-diol220a (10 g, 86.09mmol, 1.00 equiv.), dichlorometha.ne (200 mL), and TEA (17.4 g, 171.95 mmol, 2.00 equiv.).Acetyl chloride (6 7 g, 85.35 mmoL LOO equiv.) vvas added dropwise at 0°C with stirring.10 The resulting mixture was stirred at 0 °C for 1h, and then diluted with 100 mL of DCM. Themixture was washed with I-hO (500 mL x 2) and brine (500 mL x 2), dried over anhydroussodium sulfate :md concentrated under vacuum. The residue was purified by silica gel columnchromatography eluting vith ethyl acetate/petroleum ether (0-.50%) to give 4-hydroxycydohexyl acetate 220b (5g, 37%) as a colorless oil.

Reference： [1]Current Patent Assignee: ARDELYX, INC. - WO2018/39386, 2018, A1 Location in patent: Page/Page column 362; 363

73
[ 556-48-9 ]
[ 124-63-0 ]
4-(methanesulfonyloxy)cyclohexyl acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine at 0 - 20℃; for 2h;	189.2 .S'te]l 2. To a 500 mL round bottom Hask was added a solution of 4-hydroxycyclohexyl acetate220b (7 g, 44.2.5 mmoL LOO equiv.) in dichloromethane (140 mL) and TEA (4.9 g, 48.42mmol, 1.10 equiv.), the mixture vas cooled at 0°C. Methanesulfonyl chloride (5.5 g, 48.01mmol, 1.10 equiv.) was added dropwise with stirring. Cooling bath was removed, and the reaction mixture wa.-.: stirred at room temperature for 2 h. The reaction was quenched by theaddition of20 mL of water/ice. The mixture was diluted with 100 mL ofDCM, washed withbrine (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue v.·as purified by silica gel column chromatography eluting with ethyl5 acetate/petroleum ether (0-50%) to provide 4-(methanesulfonyloxy)cyclohexyl acetate 220c(7g, 66%) as a colorless oil.

Reference： [1]Current Patent Assignee: ARDELYX, INC. - WO2018/39386, 2018, A1 Location in patent: Page/Page column 362; 363; 364

74
[ 93-40-3 ]
[ 556-48-9 ]
cyclohexane 1,4-diyl bis(2-(3,4-dimethoxyphenyl)acetate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 24h;	General method for the synthesis of monoesters/diesters A General procedure: To a stirred solution of 3,4-dimethoxyphenylacetic acid (0.19 g, 1.00 mmol) and thecorresponding alcohol (1.00 mmol)/diol (0.50 mmol) in CH2Cl2 (10 mL), 10% DMAP (0.01g, 0.10 mmol) was added and the mixture was cooled to 0°C. Then EDC (0.19 g, 1.00 mmol)was added and the reaction mixture was stirred at 0°C for 30 min and at room temperature for24 hours. Then CH2Cl2 (10 mL) and H2O (10 mL) were added and the organic phase wassuccessively washed with HCl 0.6 N (10 mL), H2O (10 mL), NaHCO3 5% (10 mL), H2O (10mL) and brine (10 mL), dried over Na2SO4 and the volatiles were removed in vacuo. Theresidue was purified with column chromatography using CH2Cl2/MeOH: 9.5/0.5 as eluent

Reference： [1]Pagoni, Aikaterini; Vassiliou, Stamatia [Natural Product Research, 2018, vol. 32, # 11, p. 1267 - 1273]

75
[ 556-48-9 ]
[ 1160950-71-9 ]
N-(7-((4-hydroxycyclohexyl)oxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: 1,4-Cyclohexanediol; C₂₅H₂₁NO₆ With tributylphosphine In benzene at 0℃; for 0.0833333h; Stage #2: With diamide at 75℃; for 12h;	3.17 4.3.17 N-(7-((4-Hydroxycyclohexyl)oxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3',6-dimethoxy-[1,1'-biphenyl]-3-carboxamide (15) General procedure: Phenol 9 (0.12g, 0.298mmol), and cyclohexane-1,3-diol (0.128g, 0.597mmol) were dissolved in anhydrous benzene (2mL). Tri-butylphosphine (0.147mL, 0.597mmol) was added dropwise and the reaction was stirred at 0°C. After 5min the mixture was covered and diamide (0.103g, 0.597mmol) was added. The mixture was stirred for 15min and then heated to reflux. The reaction was stirred at reflux for 12h, cooled to rt, concentrated, and purified via column chromatography (SiO2, 1:4, EtOAc: hexane) to afford 12 as a white amorphous solid (35% yield): 1H NMR (500MHz, Chloroform-d) δ 8.80 (s, 1H), 8.70 (d, J=2.8Hz, 1H), 7.93-7.88 (m, 3H), 7.35 (dt, J=15.6, 8.3Hz, 3H), 7.12 (dt, J=7.6, 1.2Hz, 2H), 7.10-7.04 (m, 4H), 6.95-6.87 (m, 3H), 4.81 (dt, J=6.0, 3.2Hz, 1H), 4.39 (tt, J=8.9, 3.8Hz, 1H), 4.14 (ddd, J=14.5, 9.9, 5.8Hz, 1H), 3.90 (s, 4H), 3.86 (s, 4H), 3.83-3.77 (m, 1H), 2.33 (s, 3H), 2.13 (dt, J=12.6, 4.6Hz, 1H), 2.04-1.98 (m, 1H), 1.94-1.86 (m, 2H), 1.70 (ddt, J=21.7, 12.5, 7.0Hz, 3H), 1.60-1.33 (m, 2H). 13C NMR (126MHz, CDCl3) δ 165.67, 159.92, 159.64, 159.47, 157.23, 149.56, 138.75, 131.19, 130.10, 129.31, 128.29, 125.67, 124.43, 122.15, 121.85, 115.39, 113.30, 111.15, 110.90, 75.58, 73.70, 68.47, 67.04, 40.49, 39.11, 34.41, 30.89, 19.27, 8.58. HRMS (ESI+), m/z [M+H+] calculated for C31H31NO7: 530.2179; found 530.2162.

Reference： [1]Forsberg, Leah K.; Davis, Rachel E.; Wimalasena, Virangika K.; Blagg, Brian S.J. [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 12, p. 3096 - 3110]

76
[ 630125-49-4 ]
[ 556-48-9 ]
C₂₀H₁₆F₆N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ethylenediaminetetraacetic acid; dimethyllithium cuprate; caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 210℃; for 0.5h;Inert atmosphere;	First step reaction: Add 5.400 g (20 mmol) to a 250 mL three-necked flask equipped with a mechanical stirring device.<strong>[630125-49-4]3-nitro-5-bromo-trifluorotoluene</strong>,0.0503 g (0.5 mmol) of dimethyl copper lithium,4.8873 g (15 mmol) of cesium carbonate,0.2922g (1mmol) ethylenediaminetetraacetic acid,Add 33 mL of N-methylpyrrolidone as a solvent,Under the protection of agitated and fully argon gas,1.7424 g (15 mmol) of 1,4-dihydroxy-cyclohexane compound was added.Stir at room temperature for 30 min, stirring,Raise the temperature to 210 C under argon protection.The TLC detects that the disappearance of the raw material point is the end of the reaction;After the system is cooled, it is discharged into dichloromethane.Drain filtration, vacuum drying to obtain a crude product,The crude product was passed through a silica gel column of cyclohexane/ethyl acetate = 15/1.get1,4-(3-nitro-5-trifluoromethylphenoxy)cyclohexaneCompound

Reference： [1]Patent: CN109053474,2018,A .Location in patent: Paragraph 0128; 0129

77
[ 630125-49-4 ]
[ 556-48-9 ]
C₂₀H₂₀F₆N₂O₂ [ No CAS ]

Reference： [1]Patent: CN109053474,2018,A

78
[ 32315-10-9 ]
[ 556-48-9 ]
C₇H₁₁ClO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 0℃; for 0.5h;	3.1.5. Synthesis of Phenyl (3-benzyl-5-hydroxyphenyl)carbamate (3a) General procedure: To a solution of phenol (112 mg, 1.2 mmol), triphosgene (178 mg, 0.6 mmol) in CH2Cl2 (10 mL) was added dropwise triethylamine (121 mg, 1.2 mmol) at 0°C. The reaction mixture was stirred for 0.5 h and then 3-amino-5-benzylphenol 8 (119 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 5 h. After the reaction was quenched with water (30 mL), the mixture was extracted with EtOAc (10 mL×3). The combined organic layer was dried over anhydrous Na2SO4, ltered and concentrated in vacuo. The residue was puried by column chromatography (petroleum ether/EtOAc = 4:1) to afford 3a as a white solid (61 mg, 32% yield).

Reference： [1]Cheng, Ya-Juan; Liu, Zhi-Yong; Liang, Hua-Ju; Fang, Cui-Ting; Zhang, Niu-Niu; Zhang, Tian-Yu; Yan, Ming [Molecules, 2019, vol. 24, # 10]

79
[ 556-48-9 ]
[ 39178-35-3 ]
cyclohexane-1,4-diyl diisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.5 g	With pyridine In tetrahydrofuran at 20 - 65℃; for 26h;	2.3. Synthesis of the monomers The synthetic route of LC monomers [1,1′-biphenyl]-4,4′-diyldiisonicotinate (BDI) and cyclohexane-1,4-diyl diisonicotinate (HDI) are shown in Scheme 1. The detailed synthesis and characterization ofBDI were reported in the previous work [33]. The experimental detailsand results of compound BDIwere consistentwith the report. The compoundHDIwas synthesized using cyclohexane-1,4-diol and isonicotinicacid. Isonicotinic acid (36.93 g, 0.3 moL) and thionyl chloride (70 mL)was added into a round flask and stirred at room temperature for 2 h,then heated at 65 °C for 25 h in awater bath. The excess thionyl chloridewas distilled out under reduced pressure to obtain 40.6 g isonicotinoylchloride hydrochloride. Cyclohexane-1,4-diol (8.13 g, 0.07 moL) and20 mL of pyridine were dissolved in 50 mL freshly distilled THF in athree-necked flask. Isonicotinoyl chloride hydrochloride (25 g,0.14 moL) was dissolved in 100 mL of THF and then added dropwiseinto the flask. Subsequently, stirred at room temperature for 2 h, thesemixed solutions reacted at reflux temperature for 24 h. The solventwas removed under reduced pressure after the reaction finished.Then, the mixture was poured into 1000 mL of sodium bicarbonate solution.The precipitates were filtrated and washed with water and recrystallizedin ethanol to obtain 20.5 g white crystals of compoundHDI. Yield: 90%. FTIR (KBr, cm-1): 2935, 2866 (CH2); 1730(C_O); 1594-1399 (C_C, C_N in pyridine); 1264 (CN in pyridine);1176 (COC). Anal. calc. for HDI: C, 66.21%; H, 5.50%; N, 8.52%. 1HNMR (300 MHz, DMSO): δ = 1.46-2.04 (m, 8H,CH2), 4.53-5.07(m, 2H,CHO), 7.89 (d, J = 6 Hz, 4H, pyridyl-H), 8.76 ppm (d, J= 9 Hz, 4H, pyridyl-H). 13C NMR (75 MHz, DMSO): δ = 26.72, 26.86(CH2); 72.45, 72.80 (CHO); 124.04, 124.74 (C_C inpyridyl);141.84, 142.07 (O_CC_C in pyridyl); 148.66, 149.19 (C_N in pyridyl);163.42, 163.59 ppm (O_C).

Reference： [1]Kong, Shengwen; Wang, Xiaodong; Bai, Lu; Song, Ying; Meng, Fanbao [Journal of Molecular Liquids, 2019, vol. 288]

80
[ 556-48-9 ]
[ 35249-73-1 ]
benzyl (4-hydroxycyclohexyl) oxalate [ No CAS ]
dibenzyl O,O'-(cyclohexane-1,4-diyl) dioxalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 35% 2: 25%	With pyridine In diethyl ether at 23℃; for 1h;	3.2. General Procedure B. Synthesis of oxalic acids via alkyl benzyl oxalates. General procedure: B1. Benzyl alcohol (1.0 equiv) in dry Et2O (0.3 M) was added dropwise over 1 h to an ice-cooled solution of oxalyl chloride (2.0 equiv) in dry Et2O (0.6 M). The resulting solution was stirred for 1 h after addition. The reaction mixture was then concentrated to give a slightly yellow oil that was dried in vacuo to remove traces of oxalyl chloride. In a separate round-bottom flask, the substrate alcohol (1.0 equiv) and pyridine (1.2 equiv) were dissolved in dry Et2O (0.1 M). A solution of the benzyl chlorooxoacetate in a minimal amount of Et2O was added dropwise at 23°C, causing the formation of a white precipitate. The resulting mixture was stirred for 1 h. Upon completion, the reaction mixture was transferred to a separatory funnel and washed successively with water and brine. The organic phase was dried over MgSO4, filtered and concentrated to afford the desired alkyl benzyl oxalate, which was purified by flash column chromatography over silica gel.

Reference： [1]González-Esguevillas, María; Miró, Javier; Jeffrey, Jenna L.; MacMillan, David W.C. [Tetrahedron, 2019, vol. 75, # 32, p. 4222 - 4227]

81
[ 637-88-7 ]
cis-4-aminocyclohexanol [ No CAS ]
[ 3114-70-3 ]
[ 556-48-9 ]

Reference： [1]ChemCatChem,2019,vol. 11,p. 5794 - 5799

82
[ 556-48-9 ]
[ 604-69-3 ]
1,4-bis(2’,3’,4’,6’-tetra-O-acetyl-β-D-glucopyranosyloxy)cyclohexane [ No CAS ]
C₂₂H₃₂O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 25% 2: 12%	With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 23h; Inert atmosphere;	3.3.1. Standard O-glucosylation protocol General procedure: β-Glc(OAc)5 1a (3.00 g, 7.68 mmol) and diol or diphenol (HO-X-OH)2 (3.84 mmol) were mixed in anhydrous CH2Cl2 (50 mL). Then BF3OEt2 (0.950 mL, 7.68 mmol) was added dropwise. The molar ratio β-Glc(OAc)5/HO-X-OH/BF3OEt2 is 1:0.5:1. The mixture was stirred at roomtemperature for 23 h under inert atmosphere (nitrogen), and thenquenched by saturated aq. NaHCO3. The organic layer was separated,washed successively with aq. NaHCO3 and (once) with brine solution,dried over MgSO4, and concentrated. BGX(OAc)8 and other products areisolated by column chromatography (eluent CH2Cl2/EA, 7/3) or byrecrystallization (ethanol), depending on the nature of the BGX(OAc)8.Remarks. The glucosylation reactions were also carried out fordifferent quantities up to 15 g. The products were obtained in similaryields and selectivity.

Reference： [1]Patry, Stéphane; Robitzer, Mike; Habas, Jean-Pierre [Carbohydrate Research, 2021, vol. 500]

83
[ 556-48-9 ]
(S)-2-(4-(4-((benzyloxy)carbonyl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid [ No CAS ]
benzyl 4-((S)-6-(2-((4-hydroxycyclohexyl)oxy)-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With toluene-4-sulfonic acid In chloroform at 70℃; for 36h;	27.1 (Step 1) (S)-2-(4-(4-((Benzyloxy)carbonyl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (0.250 g, 0.5 mmol) obtained in step 2 of reference example 26 was dissolved in chloroform (5 mL), then p-toluenesulfonic acid (0.019 g, 0.1 mmol) and trans-1,4-cyclohexanediol (0.290 g, 2.5 mmol) were added to the solution and the mixture was stirred at 70° C. for 36 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (acetonitrile/0.1% formic acid aqueous solution=45/55) to give benzyl 4-((S)-6-(2-(((1r,4S)-4-hydroxycyclohexyl)oxy)-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)benzoate (0.110 g, 37%). ESIMS, (M+H)+, m/z: 599.23.

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - US2021/24540, 2021, A1 Location in patent: Paragraph 1371

84
[ 556-48-9 ]
C₈H₁₇O₅P [ No CAS ]
C₁₄H₂₇O₆P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.1%	With aluminum (III) chloride In toluene at 150℃; for 4h; Inert atmosphere;	8.2 In the second step, 1.0 mol of the above-mentioned butylene glycol methyl propionate phosphinic acid, 1.03 mol of 1,4-cyclohexanediol, 0.34 mol of anhydrous aluminum trichloride and 20 ml of toluene are placed in a three-necked flask In a nitrogen atmosphere, the reaction was mechanically stirred at 150°C for 4 hours, and then distilled under reduced pressure at this temperature for about 1.5 hours until there was no distillate. After that, it was filtered while hot. The filtrate was left to stand and cooled to room temperature and turned into a brown-yellow gelatinous viscous solid. It is the target product, butylene methyl propionate, cyclohexanediol phosphonate, and the yield is about 84.1%.

Reference： [1]Current Patent Assignee: JIANGHAN UNIVERSITY - CN112552340, 2021, A Location in patent: Paragraph 0067; 0070

85
[ 556-48-9 ]
[ 823-78-9 ]
(1R,4R)-4-((3-bromobenzyl)oxy)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.37%	With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 16h;	22.1 To a solution of cyclohexane-1 ,4-diol (2.0 g, 17.22 mmol) and NaH (826.38 mg, 20.66 mmol, 60% purity) in DMF (40 mL) was added 1-bromo-3-(bromomethyl)benzene (5.16 g, 20.66 mmol) at 0 °C, the mixture was stirred at 30 °C for 16 hr. The reaction mixture was poured into NH4CI solution (20 mL) , the solution was extracted with EA (20 mL_ x 3), the combined organic layer was washed with brine (50 mL) , dried over Na2SO4, filtered and concentrated to give a residue in vacuum. The residue was purified by column chromatography (S1O2, PE:EA=10:1-3:1), the solution was concentrated in vacuum to give (0273) Intermediate C (1 .0 g, 3.51 mmol, 20.37% yield) as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ = 7.50 (s, 1 H), 7.41 (br d, J = 7.6 Hz, 1 H), 7.30 - 7.23 (m, 2H), 4.51 (s, 2H), 3.64 - 3.54 (m, 1 H), 3.43 - 3.35 (m, 1 H), 2.05 (br d, J = 11 .7 Hz, 2H), 1 .96 - 1 .89 (m, 2H), 1 .38 - 1 .28 (m, 4H) ppm.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1 Location in patent: Page/Page column 99

86
[ 116-11-0 ]
[ 556-48-9 ]
C₁₂H₂₀O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With 2,6-lutidinium p-toluenesulfonate In tetrahydrofuran at 25℃; for 12h;

Reference： [1]Yu, Na; Xu, Yang; Liu, Tao; Zhong, Haiping; Xu, Zunkai; Ji, Tianjiao; Zou, Hui; Mu, Jingqing; Chen, Ziqi; Liang, Xing-Jie; Shi, Linqi; Kohane, Daniel S.; Guo, Shutao [Nature Communications, 2021, vol. 12, # 1]

87
[ 556-48-9 ]
[ 151266-23-8 ]
[ 862730-10-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran for 5h; Inert atmosphere; Cooling with ethanol-dry ice;	20.1 Step 1: (1s,4s)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohex-1-ol To a dried 500 mL two-necked-flask was added 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.00 g, 19.16mmol), 1,4-cyclohexanediol (cis: trans = 1:0.7, NMR content) (4.45 g, 38.3 mmol), triphenylphosphine (10.05 g, 38.31mmol) and 200 mL ultra dry THF under Ar. The flask was cooled in dry ice-ethanol bath. Diisopropyl azodicarboxylate(7.75 g, 38.31 mmol) was added into the mixture, and reacted for 5 hours. LCMS showed that the reaction was completed.The resulting solution was filtrated to obtain 4.50 g light yellow solid. The mother liquor was concentrated and purifiedwith silica gel column(DCM: MeOH = 100:1) to afford 0.8g product, yield 73%.MS ESI: m/z =360, [M+H]+.
73%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran for 5h; Inert atmosphere; Cooling with ethanol-dry ice;	20.1 Step 1: (1s,4s)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohex-1-ol To a dried 500 mL two-necked-flask was added 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.00 g, 19.16mmol), 1,4-cyclohexanediol (cis: trans = 1:0.7, NMR content) (4.45 g, 38.3 mmol), triphenylphosphine (10.05 g, 38.31mmol) and 200 mL ultra dry THF under Ar. The flask was cooled in dry ice-ethanol bath. Diisopropyl azodicarboxylate(7.75 g, 38.31 mmol) was added into the mixture, and reacted for 5 hours. LCMS showed that the reaction was completed.The resulting solution was filtrated to obtain 4.50 g light yellow solid. The mother liquor was concentrated and purifiedwith silica gel column(DCM: MeOH = 100:1) to afford 0.8g product, yield 73%.MS ESI: m/z =360, [M+H]+.

Reference： [1]Current Patent Assignee: MINGHUI PHARMACEUTICAL HANGZHOU; MINGHUI MEDICINE SHANGHAI; GHUI PHARMACEUTICAL HANGZHOU; MINGHUI PHARMACEUTICAL SHANGHAI - EP3912980, 2021, A1 Location in patent: Paragraph 0250-0252
[2]Current Patent Assignee: MINGHUI PHARMACEUTICAL HANGZHOU; MINGHUI MEDICINE SHANGHAI; GHUI PHARMACEUTICAL HANGZHOU; MINGHUI PHARMACEUTICAL SHANGHAI - EP3912980, 2021, A1 Location in patent: Paragraph 0250-0252

88
[ 110-82-7 ]
[ 556-48-9 ]
[ 13482-22-9 ]
[ 108-94-1 ]
[ 108-93-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; HNO₃; [Cu_0.152Mn_0.848(μ-pyridine-2,6-dicarboxylato)₂{Na₂(μ-H₂O)₄}]n·nH₂O In water monomer; acetonitrile at 75℃; for 8h; Green chemistry;	2.4. Catalytic studies General procedure: The selective peroxidative oxidation of cyclohexane to cyclohexanoland cyclohexanone was carried out under air and atmospheric pressureusing polymer 1 as a catalyst. The desired amount of polymer 1 (0.5-10μmol) was mixed with cyclohexane (1.00 mmol); acetonitrile (3 mL) andHNO3 as an acid promoter (additive) with the molar ratio n(HNO3)/n(catalyst) (0-20) in a 50 mL round bottom flask. An aqueous solution ofH2O2 (30%) as an oxidizing agent with the molar ratio n(H2O2)/n(catalyst) (50-350) was then added. The resulting solution was vigorouslystirred for 1-10 h at 25-105 °C. After completion of the desiredreaction time, 90 μL of cycloheptanone (as GC internal standard) and 10mL of diethyl ether (for substrate and organic product extraction) and1.0 g PPh3 (for reduction of cyclohexyl hydroperoxide to cyclohexanol ifformed) were added to the above-mentioned solution [33,34]. The reactionmixture was stirred with cooling at ca. 0 C and centrifuged foranalysis by GC. Gas chromatographic (GC) measurement was carried outusing a Hewlett-Packard 5890 series II gas chromatograph instrumentequipped with FID detector, and a DB-5 fused silica column (30 m 0.53mm i.d., film thickness 1.5 m). The helium was used as the carrier gas.The Gas Chromatography-Mass Spectrometry (GC-MS) analysis wasperformed on a Varian 3400(He as the carrier gas), equipped with a DB-5 column with the same characteristics that used in the GC instrument. Thecomposition products that were achieved from the catalytic peroxidativeoxidation reactions were characterized by comparing their retentiontimes and matched with those of commercially available materials. Themass spectra of obtained products were confirmed by fragmentationpatterns of the NIST spectral library stored in the computer software.Each test was repeated three times and the average of the results wasreported. Blank experiments were carried out without the catalyst toconfirm the catalytic performance of polymer 1.

Reference： [1]Dusek, Michal; Eigner, Vaclav; Razmara, Zohreh [Journal of Solid State Chemistry, 2022, vol. 311]

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H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 556-48-9 ] {[proInfo.proName]}

Quality Control of [ 556-48-9 ]

Related Doc. of [ 556-48-9 ]

Product Details of [ 556-48-9 ]

Calculated chemistry of [ 556-48-9 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 556-48-9 ]

Application In Synthesis of [ 556-48-9 ]

[ 556-48-9 ] Synthesis Path-Upstream 1~16

[ 556-48-9 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

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Response

Storage

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Physical hazards

Health hazards

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Inquiry