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[ CAS No. 29941-82-0 ] {[proInfo.proName]}

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Quality Control of [ 29941-82-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 29941-82-0 ]

CAS No. :	29941-82-0	MDL No. :	MFCD00013782
Formula :	C₈H₁₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PJLUWPNLDKJSCF-UHFFFAOYSA-N
M.W :	140.18	Pubchem ID :	121598
Synonyms :

Calculated chemistry of [ 29941-82-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.62
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.27
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.86
Log Po/w (XLOGP3) :	1.44
Log Po/w (WLOGP) :	1.66
Log Po/w (MLOGP) :	0.65
Log Po/w (SILICOS-IT) :	1.93
Consensus Log Po/w :	1.51

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.48
Solubility :	4.6 mg/ml ; 0.0328 mol/l
Class :	Very soluble
Log S (Ali) :	-1.6
Solubility :	3.54 mg/ml ; 0.0252 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.69
Solubility :	2.85 mg/ml ; 0.0203 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.4

Safety of [ 29941-82-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 29941-82-0 ]

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

Downstream synthetic route of [ 29941-82-0 ]

[ 29941-82-0 ] Synthesis Path-Downstream 1~50

1
[ 69545-46-6 ]
[ 29941-82-0 ]
[ 73922-19-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; lithium diisopropyl amide 1.) THF, -78 deg C, 2.) methanol, reflux; Multistep reaction;

Reference： [1]Stork, Gilbert; Logusch, E. W. [Journal of the American Chemical Society, 1980, vol. 102, # 3, p. 1218 - 1219]

2
2-(2-Iodo-ethoxy)-cyclohex-2-enone [ No CAS ]
[ 29941-82-0 ]
1-Oxa-spiro[3.5]nonan-5-one [ No CAS ]
(3aR,7aS)-Hexahydro-benzofuran-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 18 % Chromat. 2: 72%	With tri-n-butyl-tin hydride In benzene at 80℃;
1: 72 % Chromat. 2: 18 % Chromat.	With tri-n-butyl-tin hydride In benzene at 80℃;

Reference： [1]Ponaras, Anthony A.; Zaim, Oemer [Tetrahedron Letters, 1993, vol. 34, # 18, p. 2879 - 2882]
[2]Ponaras, Anthony A.; Zaim, Oemer [Tetrahedron Letters, 1993, vol. 34, # 18, p. 2879 - 2882]

3
[ 106-39-8 ]
[ 29941-82-0 ]
3-(4-Chloro-phenyl)-2-ethoxy-cyclohex-2-enone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With water; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 48h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

4
[ 108-86-1 ]
[ 29941-82-0 ]
[ 89114-51-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With water; N-ethyl-N,N-diisopropylamine; triphenylphosphine In N,N-dimethyl-formamide at 100℃; for 16h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

5
[ 108-37-2 ]
[ 29941-82-0 ]
3-(3-Chloro-phenyl)-2-ethoxy-cyclohex-2-enone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With water; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 48h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

6
[ 2398-37-0 ]
[ 29941-82-0 ]
2-Ethoxy-3-(3-methoxy-phenyl)-cyclohex-2-enone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With water; N-ethyl-N,N-diisopropylamine; triphenylphosphine In N,N-dimethyl-formamide at 100℃; for 48h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

7
[ 64-17-5 ]
[ 10316-66-2 ]
[ 29941-82-0 ]

Yield	Reaction Conditions	Operation in experiment
42%	With toluene-4-sulfonic acid In benzene for 16h; Heating;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

8
[ 694-80-4 ]
[ 29941-82-0 ]
3-(2-Chloro-phenyl)-2-ethoxy-cyclohex-2-enone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With water; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 96h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

9
[ 591-17-3 ]
[ 29941-82-0 ]
2-ethoxy-3-(3-methylphenyl)-2-cyclohexenone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With water; N-ethyl-N,N-diisopropylamine; triphenylphosphine In N,N-dimethyl-formamide at 100℃; for 16h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

10
[ 106-38-7 ]
[ 29941-82-0 ]
2-Ethoxy-3-p-tolyl-cyclohex-2-enone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With water; N-ethyl-N,N-diisopropylamine; triphenylphosphine In N,N-dimethyl-formamide at 100℃; for 48h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

11
[ 29941-82-0 ]
[ 402-43-7 ]
[ 207682-54-0 ]

Yield	Reaction Conditions	Operation in experiment
76%	With water; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 60h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

12
[ 29941-82-0 ]
[ 2142-63-4 ]
3-(3-Acetyl-phenyl)-2-ethoxy-cyclohex-2-enone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With water; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 16h;

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

13
[ 29941-82-0 ]
[ 106-95-6 ]
5-allyl-2-ethoxy-cyclohex-2-enone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With manganese triacetate In benzene for 11h; Heating;

Reference： [1]Tanyeli, Cihangir; Özdemirhan, Devrim [Tetrahedron, 2005, vol. 61, # 34, p. 8212 - 8217]

14
[ 29941-82-0 ]
[ 70871-45-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 86 percent / iPr₂NEt, Ph₃P, H₂O / Pd(OAc)2 / dimethylformamide / 16 h / 100 °C 2: 84 percent / BBr₃ / CH₂Cl₂ / 1.) -78 deg C, 1 h, 2.) -12 deg C, 3 h

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

15
[ 29941-82-0 ]
2-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-cyclohexen-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 76 percent / iPr₂NEt, (o-Tol)3P, H₂O / Pd(OAc)2 / dimethylformamide / 60 h / 100 °C 2: 90 percent / BBr₃ / CH₂Cl₂ / 1.) -78 deg C, 1 h, 2.) -12 deg C, 3 h

Reference： [1]Garg, Neeraj; Larhed, Mats; Hallberg, Anders [Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4158 - 4162]

16
[ 29941-82-0 ]
[ 73922-20-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1.) LDA, 2.) NaOMe / 1.) THF, -78 deg C, 2.) methanol, reflux 2: H⁺

Reference： [1]Stork, Gilbert; Logusch, E. W. [Journal of the American Chemical Society, 1980, vol. 102, # 3, p. 1218 - 1219]

17
[ 29941-82-0 ]
[ 73922-25-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) LDA, 2.) NaOMe / 1.) THF, -78 deg C, 2.) methanol, reflux 2: H⁺ 3: 1.) Li / 1.) ammonia-THF, reflux

Reference： [1]Stork, Gilbert; Logusch, E. W. [Journal of the American Chemical Society, 1980, vol. 102, # 3, p. 1218 - 1219]

18
[ 29941-82-0 ]
(4aS,8S,8aR)-8-Allyl-8-methyl-octahydro-naphthalene-1,7-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) LDA, 2.) NaOMe / 1.) THF, -78 deg C, 2.) methanol, reflux 2: H⁺ 3: 1.) Li / 1.) ammonia-THF, reflux

Reference： [1]Stork, Gilbert; Logusch, E. W. [Journal of the American Chemical Society, 1980, vol. 102, # 3, p. 1218 - 1219]

19
[ 29941-82-0 ]
(4aS,8R,8aR)-8-Allyl-8-methyl-octahydro-naphthalene-1,7-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) LDA, 2.) NaOMe / 1.) THF, -78 deg C, 2.) methanol, reflux 2: H⁺ 3: 1.) Li / 1.) ammonia-THF, reflux

Reference： [1]Stork, Gilbert; Logusch, E. W. [Journal of the American Chemical Society, 1980, vol. 102, # 3, p. 1218 - 1219]

20
[ 29941-82-0 ]
C₁₂H₁₅⁽²⁾H₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) LDA, 2.) NaOMe / 1.) THF, -78 deg C, 2.) methanol, reflux 2: H⁺ 3: 1.) Li / 1.) ammonia-THF, reflux

Reference： [1]Stork, Gilbert; Logusch, E. W. [Journal of the American Chemical Society, 1980, vol. 102, # 3, p. 1218 - 1219]

21
[ 29941-82-0 ]
C₁₂H₁₅⁽²⁾H₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) LDA, 2.) NaOMe / 1.) THF, -78 deg C, 2.) methanol, reflux 2: H⁺ 3: 1.) Li / 1.) ammonia-THF, reflux

Reference： [1]Stork, Gilbert; Logusch, E. W. [Journal of the American Chemical Society, 1980, vol. 102, # 3, p. 1218 - 1219]

22
[ 29941-82-0 ]
[ 4637-24-5 ]
6-[(dimethylamino)methylene]-2-ethoxycyclohex-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In DMF (N,N-dimethyl-formamide) at 60℃; for 2h;	41.1 STEP 1. 6- [ (DIMETHYLAMINO) METHYLENE]-2-ETHOXYEYELOHEX-2-EN-L-ONE 3.4 g (0.02 mmol) of 2-ETHOXYCYCLOHEX-2-EN-1-ONE were dissolved in 30 mL of dry dimethylformamide and 30 mL (0.05 mmol) of dimethylformamide dimethyl acetale were added. The solution was stirred at 60°C for 2 hours. The solvent was then evaporated under vacuum, the residue triturated with diethyl ether and collected by filtration to give 6.6 g of the title compound (80% yield).

Reference： [1]Current Patent Assignee: NERVIANO MEDICAL SCIENCES S.R.L. - WO2004/104007, 2004, A1 Location in patent: Page 127-128

23
[ 64-17-5 ]
[ 765-87-7 ]
[ 29941-82-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With toluene-4-sulfonic acid Reflux;	44.1 Step 1: 2-Et oxycyclohex-2-eKoae Step 1: 2-Et oxycyclohex-2-eKoae A flask with stir bar and distillation apparatus was charged with cyclohexane-l ,2-dione (5.00 g, 44.6 mmol), EtOH (75 mL) and 4-methylbenzenesulfonic acid hydrate (0.848 g, 4.46 mmol). 'The mixture was heated to reflux until about 30 mL of solvent was distilled off. The flask was charged with EtOH (50 mL) then reheated to reflux until about 50 mL of solvent was distilled of. The flask was charged with EtOH (100 mL) then reheated to reflux until about 100 mL of solvent was distilled off. The mixture was cooled then concentrated under reduce pressure. The material was purified via flash chromatography on silica gel (0-100% EtOAc/heptane) to give the title compound (6.14 g, 98%); LC/MS (Table A, Method i) Re = 0.53 min; MS m/z: 141 ( M i l ) .
69%	With toluene-4-sulfonic acid In toluene for 48h; Reflux;	5n General Procedure 5n [Int-5.32] 2-ethoxycyclohex-2-en-1-one : General procedure: In a round-bottom flask, at room temperature, 1,2-Cyclohexandione (14) (1 g, 8.9 mmol) was dissolved in a mixture of toluene (20 ml) and ethanol (10 ml). p-Toluenesulfonic acid (204 mg, 1.07 mmol) was added and the solution heated under reflux for 2 days. The solvent was then evaporated and the residue dissolved with dichloromethane (20 ml) and washed with a saturated solution of NaHCO3 (20 ml). The organic layer was dried over Na2SO4 and concentrated. The crude was purified by chromatography on a silica gel column with 10% AcOEt in Cyclohexane as solvent to give 15a as a brown oil (858 mg, 69%): 1H NMR (400 MHz, DMSO-d6) δ 5.99 (t, J = 4.6 Hz, 1H), 3.68 (q, J = 7.0 Hz, 2H), 2.46 - 2.25 (m, 4H), 1.99 - 1.75 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H). UPLC-MS: tR = 1.34 min (Generic method); MS (ESI) m/z calcd for C8H13O2 (M+H)+: 141.1, found: 141.4.
66%	With toluene-4-sulfonic acid In toluene for 48h; Reflux;

66%	With toluene-4-sulfonic acid In toluene for 48h; Heating / reflux;	1 Example 1; 2-ETHOXYCYCLOHEX-2-EN-1-ONE 50 g (0.45 mol) of 1,2-dicyclohexandione were dissolved in a mixture of 1 L of toluene and 0.5 L of ethanol. 10 g of p-toluenesulfonic acid were added and the solution heated at reflux for 2 days. (TLC chloroform/methanol 6/1). The solvent was then evaporated, the residue redissolved with dichloromethane and washed with a saturated solution of NaHCO3. The organic layer was dried over NA2S04 and concentrated. The crude was purified by chromatography on a silica gel column by eluting with a mixture of cyclohexane/ethyl acetate 98/2 (66 % yield as an oil). 'H NMR (400 MHz, DMSO-D6) 8 ppm 1. 20 (t, 3 ET) 2. 33-2.39 (m, 6 H) 3.67 (q, 2 H) 5.97 (t, 1 H).
60%	With iodine; copper(II) oxide at 100℃; for 4h;
	With toluene-4-sulfonic acid In toluene at 90℃; for 48h;	8.1 Step 1. Synthesis of 2-ethoxycyclohex-2-en-1 -one A solution of cyclohexane- 1 , 2-dione (50 g, 446 mmol) and 4- methylbenzenesulfonic acid (10 g, 58.1 mmol) in EtOH (200 ml_) and toluene (400 ml_) was stirred at 90 °C for 2 days. The reaction was concentrated under vacuum. The resulting residue was purified by silica gel column with (0713) PE:EA=90:10 to yield 2-ethoxycyclohex-2-en-1-one. Mass spectrum (ESI, m/z): Calculated for C8H13O2, 141.1 (M+H), found 141.2.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/168633, 2016, A1 Location in patent: Page/Page column 200-201
[2]Current Patent Assignee: FONDAZIONE PER LA RICERCA SULLA FIBROSI CISTICA ONLUS; FONDAZIONE PER LA RICERCA SULLA FIBROSI CISTICA; ISTITUTO GIANNINA GASLINI; ISTITUTO ITALIANO DI TECNOLOGIA - WO2018/167690, 2018, A1 Location in patent: Page/Page column 154
[3]Location in patent: experimental part Brasca, Maria Gabriella; Amboldi, Nadia; Ballinari, Dario; Cameron, Alexander; Casale, Elena; Cervi, Giovanni; Colombo, Maristella; Colotta, Francesco; Croci, Valter; D'Alessio, Roberto; Fiorentini, Francesco; Isacchi, Antonella; Mercurio, Ciro; Moretti, Walter; Panzeri, Achille; Pastori, Wilma; Pevarello, Paolo; Quartieri, Francesca; Roletto, Fulvia; Traquandi, Gabriella; Vianello, Paola; Vulpetti, Anna; Ciomei, Marina [Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5152 - 5163]
[4]Current Patent Assignee: NERVIANO MEDICAL SCIENCES S.R.L. - WO2004/104007, 2004, A1 Location in patent: Page 68-69
[5]Yan, Yizhe; Li, Shaoqing; Wang, Jianyong [European Journal of Organic Chemistry, 2020, vol. 2020, # 41, p. 6474 - 6477]
[6]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/8317, 2020, A1 Location in patent: Page/Page column 130

24
[ 29941-82-0 ]
[ 95-92-1 ]
[ 802541-12-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 2-ethoxycyclohex-2-en-1-one With lithium hexamethyldisilazane In tetrahydrofuran; diethyl ether at -50℃; for 0.5h; Stage #2: oxalic acid diethyl ester In tetrahydrofuran; diethyl ether at -50 - 20℃;

Reference： [1]Location in patent: experimental part Brasca, Maria Gabriella; Amboldi, Nadia; Ballinari, Dario; Cameron, Alexander; Casale, Elena; Cervi, Giovanni; Colombo, Maristella; Colotta, Francesco; Croci, Valter; D'Alessio, Roberto; Fiorentini, Francesco; Isacchi, Antonella; Mercurio, Ciro; Moretti, Walter; Panzeri, Achille; Pastori, Wilma; Pevarello, Paolo; Quartieri, Francesca; Roletto, Fulvia; Traquandi, Gabriella; Vianello, Paola; Vulpetti, Anna; Ciomei, Marina [Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5152 - 5163]

25
[ 29941-82-0 ]
[ 4637-24-5 ]
[ 1105665-33-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	In N,N-dimethyl-formamide at 130℃; for 21h;	44.2 Siep 2; (£)-6-((Dimethylamino)meth lcne)-2-ethoxyc clohex-2-cnone Siep 2; (£)-6-((Dimethylamino)meth lcne)-2-ethoxyc clohex-2-cnone 2-Ethoxycyclohex-2-enone (6.14 g, 43.8 mol) in DMF (30 mL) with l , l-dimethoxy-N,N- dimethylmethanamine (60 mL, 450 mmol) was heated to about 130 °C for about 3 h. The flask was charged with 1 , 1 -ditnethoxy-NN-dirnethylmethanamine (15 mL, 110 mmol) then the mixture was heated at about 130 °C for about 18 h. The mixture was cooled then concentrated under reduced pressure to give the title compound (8.1 g, 95%); LC/MS (Table A, Method i) Rt = 0.77 min; MS m/z: 196 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/168633, 2016, A1 Location in patent: Page/Page column 201

26
[ 29941-82-0 ]
[ 4637-24-5 ]
3-(hydroxymethylene)cyclohexane-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 90℃;	8.2 Step 2. Synthesis of 3-(hvdroxymethylene)cvclohexane-1 , 2-dione A solution of 2-ethoxycyclohex-2-en-1-one (23 g, 0.164 mol) in N,N- dimethylformamide dimethyl acetal (200 ml_) was stirred overnight at 90 °C. The resulting solution was concentrated under vacuum and the resulting residue was stirred vigorously in C^Ch/aq. HCI (2 N) at room temperature for 6 hours. The resulting mixture was extracted with CH2CI2. The organic layers were combined, dried over Na2S04 and concentrated under vacuum to yield 3- (hydroxymethylene)cyclohexane-l , 2-dione as yellow oil. Mass spectrum (ESI, m/z): Calculated for C7H9O3, 141.0 (M+H), found 140.8.
	Stage #1: 2-ethoxycyclohex-2-en-1-one; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 90℃; for 16h; Stage #2: With hydrogenchloride In dichloromethane; water monomer at 20℃; for 6h;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/8317, 2020, A1 Location in patent: Page/Page column 130
[2]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

27
[ 2356-16-3 ]
[ 29941-82-0 ]
ethyl 2-(2-ethoxycyclohex-2-en-1-ylidene)-2-fluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: ethyl(diethylphosphono)(fluoro)acetate With n-butyllithium In tetrahydrofuran at -78℃; for 2h; Stage #2: 2-ethoxycyclohex-2-en-1-one In tetrahydrofuran at -78 - 20℃;
	Stage #1: ethyl(diethylphosphono)(fluoro)acetate With n-butyllithium In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; Stage #2: 2-ethoxycyclohex-2-en-1-one In tetrahydrofuran at -78 - 20℃; Inert atmosphere;	13.1 Step 1. Synthesis of ethyl 2-(2-ethoxycvclohex-2-en-1-ylidene)-2-fluoroacetate To a solution of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (17.1 g, 70.6 mmol) in THF (100 ml_) at -78°C under nitrogen was added n-BuLi (28.3 ml_, 70.8 mmol). The reaction was stirred for 2 h at -78°C before 2- ethoxycyclohex-2-en-1-one (3.30 g, 23.5 mmol) was added. The reaction was stirred for 30 min at -78°C and was then warmed to room temperature and stirred overnight. The reaction was quenched with H2O. The resulting mixture was extracted with EtOAc, and the organic layers were combined and concentrated under vacuum. The resulting residue was purified by silica gel column with PE:EA=70:30 to yield ethyl 2-(2-ethoxycyclohex-2-en-1-ylidene)-2- fluoroacetate. 1H NMR (300 MHz, CDCb) 6:5.17 (m, 1 H), 4.14 - 4.21 (m, 2H), 3.61 - 3.68 (m, 2H), 2.36 - 2.41 (m, 2H), 2.09 - 2.15 (m, 2H), 1.57 - 1.65 (m, 2H), 1.13 - 1.31 (m, 6H).

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/8317, 2020, A1 Location in patent: Page/Page column 154

28
[ 454-31-9 ]
[ 29941-82-0 ]
6-(2,2-difluoroacetyl)-2-ethoxy-cyclohex-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-ethoxycyclohex-2-en-1-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.25h; Stage #2: ethyl difluoroacetate In tetrahydrofuran at -78 - 20℃; for 2.5h;	19.1 Step 1. Synthesis of 6-(2.2-difluoroacetyl)-2-ethoxycvclohex-2-en-1-one To a solution of 2-ethoxycyclohex-2-en-1-one (1000 mg, 7.13 mmol) in THF (40 ml_) at -78°C was added LiHMDS (1.0 M in THF, 8.56 ml_, 8.56 mmol). The reaction was stirred at -78°C for 15 min before ethyl 2,2-difluoroacetate (0.975 ml_, 9.27 mmol) was added. The reaction was kept at -78°C for 30 min and was then warmed up to room temperature and stirred for 2 h. The reaction was quenched with aq. 1 N HCI, and the mixture was extracted with EtOAc. (1072) The organic layer was washed with sat. aq. NaCI, dried over Na2S04 and concentrated to yield 6-(2,2-difluoroacetyl)-2-ethoxycyclohex-2-en-1-one.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/8317, 2020, A1 Location in patent: Page/Page column 172

29
[ 29941-82-0 ]
ethyl 2-fluoro-2-(2-oxocyclohexylidene)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C / Inert atmosphere 2.1: hydrogenchloride / dichloromethane; water monomer / 20 °C
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C 1.2: -78 - 20 °C 2.1: hydrogenchloride / dichloromethane; water monomer / 20 °C

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/8317, 2020, A1
[2]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

30
[ 29941-82-0 ]
ethyl 2-(3-((dimethylamino)methylene)-2-oxocyclohexylidene)-2-fluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C / Inert atmosphere 2.1: hydrogenchloride / dichloromethane; water monomer / 20 °C 3.1: N,N-dimethyl-formamide / 2 h / 90 °C
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C 1.2: -78 - 20 °C 2.1: hydrogenchloride / dichloromethane; water monomer / 20 °C 3.1: N,N-dimethyl-formamide / 2 h / 90 °C

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/8317, 2020, A1
[2]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

31
[ 29941-82-0 ]
1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 90 °C 2: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C
	Multi-step reaction with 2 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/8317, 2020, A1
[2]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

32
[ 64-17-5 ]
[ 108-94-1 ]
[ 29941-82-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With iodine; copper(II) oxide at 100℃; for 12h;

Reference： [1]Yan, Yizhe; Li, Shaoqing; Wang, Jianyong [European Journal of Organic Chemistry, 2020, vol. 2020, # 41, p. 6474 - 6477]

33
[ 29941-82-0 ]
(Z)-4-chloro-N-((2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroethyl)carbamoyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C 6.1: hydrazine / methanol / 1 h / 20 °C 7.1: dichloromethane / 0.33 h / 0 °C

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

34
[ 29941-82-0 ]
(Z)-3-chloro-N-((2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroethyl)carbamoyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C 6.1: hydrazine / methanol / 1 h / 20 °C 7.1: triethylamine / tetrahydrofuran / 16 h / 20 °C 7.2: 1 h / 100 °C / Microwave irradiation

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

35
[ 29941-82-0 ]
(Z)-5-chloro-N-((2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroethyl)carbamoyl)-2-methoxybenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C 6.1: hydrazine / methanol / 1 h / 20 °C 7.1: triethylamine / tetrahydrofuran / 16 h / 20 °C 7.2: 1 h / 100 °C / Microwave irradiation

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

36
[ 29941-82-0 ]
(Z)-3-chloro-N-((2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroethyl)carbamoyl)-4-methoxybenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C 6.1: hydrazine / methanol / 1 h / 20 °C 7.1: triethylamine / tetrahydrofuran / 16 h / 20 °C 7.2: 1 h / 100 °C / Microwave irradiation

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

37
[ 29941-82-0 ]
(Z)-4,5-dichloro-N-((2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroethyl)carbamoyl)thiophene-2-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C 6.1: hydrazine / methanol / 1 h / 20 °C 7.1: triethylamine / tetrahydrofuran / 16 h / 20 °C 7.2: 1 h / 100 °C / Microwave irradiation

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

38
[ 29941-82-0 ]
(Z)-5-chloro-N-((2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroethyl)carbamoyl)-4-methylthiophene-2-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C 6.1: hydrazine / methanol / 1 h / 20 °C 7.1: triethylamine / tetrahydrofuran / 16 h / 20 °C 7.2: 1 h / 100 °C / Microwave irradiation

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

39
[ 29941-82-0 ]
(Z)-N-((2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroethyl)carbamoyl)benzo[b]thiophene-2-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C 6.1: hydrazine / methanol / 1 h / 20 °C 7.1: triethylamine / tetrahydrofuran / 16 h / 20 °C 7.2: 1 h / 100 °C / Microwave irradiation

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

40
[ 29941-82-0 ]
(Z)-4,5-dichloro-N-((2-fluoro-2-(1-(4-(trifluoromethyl)phenyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)ethyl)carbamoyl)thiophene-2-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C 1.2: -78 - 20 °C 2.1: hydrogenchloride / dichloromethane; water monomer / 20 °C 3.1: N,N-dimethyl-formamide / 2 h / 90 °C 4.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 5.1: diisobutylaluminium hydride / tetrahydrofuran / 2 h / -78 - 0 °C 6.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 20 °C 7.1: hydrazine hydrate monohydrate / methanol / 2 h / 20 °C 8.1: triethylamine / tetrahydrofuran / 16 h / 20 °C 8.2: 1 h / 100 °C / Microwave irradiation

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

41
[ 29941-82-0 ]
ethyl (Z)-2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroacetate [ No CAS ]
ethyl (E)-2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

42
[ 29941-82-0 ]
(Z)-2-(1-(2,4-dichlorobenzyl)-1,4,5,6-tetrahydro-7H-indazol-7-ylidene)-2-fluoroethan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

43
[ 29941-82-0 ]
(Z)-2-(1-(2,4-dichlorobenzyl)-1 ,4,5,6-tetrahydro-7H-indazol- 7-ylidene)-2-fluoroethan-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C 6.1: hydrazine / methanol / 1 h / 20 °C

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

44
[ 29941-82-0 ]
ethyl 2-fluoro-2-(1-(4-(trifluoromethyl)phenyl)-5,6-dihydro-1H-indazol-7(4H)-ylidene)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C 1.2: -78 - 20 °C 2.1: hydrogenchloride / dichloromethane; water monomer / 20 °C 3.1: N,N-dimethyl-formamide / 2 h / 90 °C 4.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

45
[ 29941-82-0 ]
(Z)-2-fluoro-2-(1-(4-(trifluoromethyl)phenyl)-5,6-dihydro-1H-indazol-7(4H)-ylidene)ethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C 1.2: -78 - 20 °C 2.1: hydrogenchloride / dichloromethane; water monomer / 20 °C 3.1: N,N-dimethyl-formamide / 2 h / 90 °C 4.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 5.1: diisobutylaluminium hydride / tetrahydrofuran / 2 h / -78 - 0 °C 6.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 20 °C 7.1: hydrazine hydrate monohydrate / methanol / 2 h / 20 °C

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

46
[ 29941-82-0 ]
(Z)-2-(2-(1-(2,4-dichlorobenzyl)-5,6-dihydro-1H-indazol-7(4H)-ylidene)-2-fluoroethyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: 16 h / 90 °C 1.2: 6 h / 20 °C 2.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 3.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 3.2: 16.5 h / -78 - 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran / 3.5 h / -78 - 0 °C / Inert atmosphere 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 20 °C

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

47
[ 29941-82-0 ]
(Z)-2-(2-fluoro-2-(1-(4-(trifluoromethyl)phenyl)-5,6-dihydro-1H-indazol-7(4H)-ylidene)ethyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C 1.2: -78 - 20 °C 2.1: hydrogenchloride / dichloromethane; water monomer / 20 °C 3.1: N,N-dimethyl-formamide / 2 h / 90 °C 4.1: trifluoroacetic acid / 1,4-dioxane / 2 h / 60 °C 5.1: diisobutylaluminium hydride / tetrahydrofuran / 2 h / -78 - 0 °C 6.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 20 °C

Reference： [1]Bakaj, Ivona; Guo, Lili; Ho, George; Lee, Seunghun P.; Macielag, Mark; Norquay, Lisa; Rankin, Matthew; Zhang, Xuqing; Zhu, Bin [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 1, p. 111 - 117]

48
[ 765-87-7 ]
[ 29941-82-0 ]

Yield	Reaction Conditions	Operation in experiment
	With p-toluenesulfonic acid monohydrate	1.1.1 1 1 : 2-ethoxycyclohex-2-en-1-one (2a) 1,2-Cyclohexanedione 1a (90 g, 803.2 mmol) and p-toluenesulfonic acid monohydrate (15.3 g, 80.3 mmol) were suspended in toluene/ethanol (2: 1, 1000 mL), the suspension was heated to reflux and the reaction continued for 36 hours. After the reaction solution was cooled to room temperature, most of the solvent was removed by distillation under reduced pressure. Then, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution (500 mL), and extracted three times with dichloromethane (200 mL). The organic layers were combined, dried (anhydrous sodium sulfate), suction filtered, and concentrated. The resulting residue was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=20: 1) to afford a light yellow oily product, which was the title compound 2a (91.1 g, 650.6 mmol, 81%).

Reference： [1]Current Patent Assignee: CHENGDU SYNOWEST BIOTECHNOLOGY; CHENGDU SING BIOMEDICAL SCIENCE AND TECH; CHENGDU CYNOGEN BIO PHARMACEUTICAL TECH - EP3992196, 2022, A1

49
[ 534-15-6 ]
[ 29941-82-0 ]
8-ethoxy-2-methoxy-5,6-dihydroquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.1.2 2 2 : 8-ethoxy-2-methoxy-5,6-dihydroquinazoline (3a) The solution of compound 2a (21 g, 150.0 mmol) and N,N-dimethylformamide dimethylacetal (99.3 mL, 750.0 mol, 5 equiv.) in N,N-dimethylformamide (300 mL) was stirred at 120 °C for 13 hours. After the mixture was cooled to room temperature, the brown oily product obtained by vacuum concentration was enamine intermediate. The crude product can be directly used in the next reaction without further purification. LC-MS (ESI), C13H20N3O [M+H]+: m/z = 234.2.

Reference： [1]Current Patent Assignee: CHENGDU SYNOWEST BIOTECHNOLOGY; CHENGDU SING BIOMEDICAL SCIENCE AND TECH; CHENGDU CYNOGEN BIO PHARMACEUTICAL TECH - EP3992196, 2022, A1

50
[ 29941-82-0 ]
[ 52328-05-9 ]
[ 4637-24-5 ]
8-ethoxy-2-methoxy-5,6-dihydroquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-ethoxycyclohex-2-en-1-one; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In N,N-dimethyl-formamide at 120℃; for 13h; Stage #2: O-methylisourea hydrogen sulfate With anhydrous Sodium acetate In N,N-dimethyl-formamide at 80℃; for 24h;	1.1.2 2): 8-ethoxy-2-methoxy-5,6-dihydroquinazoline (3a) The solution of compound 2a (21 g, 150.0 mmol) and N,N-dimethylformamide dimethylacetal (99.3 mL, 750.0 mol, 5 equiv.) in N,N-dimethylformamide (300 mL) was stirred at 120 °C for 13 hours. After the mixture was cooled to room temperature, the brown oily product obtained by vacuum concentration was enamine intermediate. The crude product can be directly used in the next reaction without further purification. LC-MS (ESI), C13H20N3O [M+H]+: m/z = 234.2.The crude product obtained in the above step, O-methylisourea sulfate (73.9 g, 300.0 mmol) and anhydrous sodium acetate (49.2 g, 600.0 mmol) were suspended in N, N-dimethylformamide (500 ml). The temperature of the mixture was raised to 80°C and the reaction was continued for 24 hours. After the mixture was cooled to room temperature, the mixture was diluted with dichloromethane (500 mL), suction filtered, and concentrated. The resulting residue was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1) to afford light yellow solid product which was the title compound 3a (16.4 g, 79.5 mmol, 53%). 1H NMR (400 MHz, chloroform-d, ppm) δ 8.20 (s, 1H), 5.46 (t, J = 4.7 Hz, 1H), 3.99 (s, 3H), 3.92 (q, J = 7.0 Hz, 2H), 2.70 (t, J = 7.9 Hz, 2H), 2.40 (td, J= 7.9, 4.8 Hz, 2H), 1.44 (t, J= 7.0 Hz, 3H).

Reference： [1]Current Patent Assignee: CHENGDU SYNOWEST BIOTECHNOLOGY; CHENGDU SING BIOMEDICAL SCIENCE AND TECH; CHENGDU CYNOGEN BIO PHARMACEUTICAL TECH - EP3992196, 2022, A1 Location in patent: Paragraph 0129; 0131-0132

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
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