[ CAS No. 5927-18-4 ]

Name: 5927-18-4|Methyl 2-(dimethoxyphosphoryl)acetate|98%
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Quality Control of [ 5927-18-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 5927-18-4 ]

Product Details of [ 5927-18-4 ]

CAS No. :	5927-18-4	MDL No. :	MFCD00008452
Formula :	C₅H₁₁O₅P	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SIGOIUCRXKUEIG-UHFFFAOYSA-N
M.W :	182.11 g/mol	Pubchem ID :	80029
Synonyms :

Calculated chemistry of [ 5927-18-4 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.27
TPSA :	71.64 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) :	-7.84 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.63
Log Po/w (XLOGP3) :	-0.61
Log Po/w (WLOGP) :	0.65
Log Po/w (MLOGP) :	-0.55
Log Po/w (SILICOS-IT) :	-0.57
Consensus Log Po/w :	0.11

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.25
Solubility :	101.0 mg/ml ; 0.556 mol/l
Class :	Very soluble
Log S (Ali) :	-0.42
Solubility :	68.8 mg/ml ; 0.378 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.63
Solubility :	42.3 mg/ml ; 0.232 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.37

Safety of [ 5927-18-4 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P362+P364-P403+P233-P501	UN#:	3082
Hazard Statements:	H302-H315-H318-H335-H411	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 5927-18-4 ]

* 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 [ 5927-18-4 ]
Downstream synthetic route of [ 5927-18-4 ]

[ 5927-18-4 ] Synthesis Path-Upstream 1~19

1
[ 50-00-0 ]
[ 5927-18-4 ]
[ 15484-46-5 ]

Yield	Reaction Conditions	Operation in experiment
44%	With potassium carbonate In water at 20℃; for 2 h;	Example 106: methyl 2-(hydroxymethyl)acrylate44percentA saturated aqueous solution (10 mL) of K₂CO₃ (3.5 g, 117 mmol, 1.6 eq.) was slowly added to a rapidly stirred solution of trimethylphosphonoacetate (5.46 g, 30 mmol, 1.0 eq.) and paraformaldehyde (6.63 g, 48 mmol, 4.0 eq.) at r.t.. After the addition the mixture was stirred for 2 h. Then the mixture was extracted with DCM. The organic layer was concentrated to give the compound (1.5 g, 44percent) as a yellow oil. ¹U NMR (400 MHz, CD₃OD) δ: 6.29 (s, IH), 5.83 (s, IH), 3.75 (s, 3H), 3.72 (s, 2H).

Reference： [1] Angewandte Chemie - International Edition, 2015, vol. 54, # 6, p. 1929 - 1932[2] Angew. Chem., 2015, vol. 127, # 6, p. 1949 - 1952,4
[3] Tetrahedron, 2008, vol. 64, # 17, p. 3701 - 3712
[4] Patent: WO2011/17561, 2011, A1, . Location in patent: Page/Page column 72
[5] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3539 - 3545

2
[ 50-00-0 ]
[ 5927-18-4 ]
[ 15484-46-5 ]
[ 292638-85-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium carbonate In water at 23℃;	Acrylate 20. Synthesized by a method adapted from Villieras and Rambaud.2 To around-bottom flask equipped with a stir bar were added trimethyl phosphonoacetate (S1,9.1 mL, 63 mmol, 1.00 equiv) and formaldehyde (S2, 20.5g, 37percent in water, 252 mmol,4.00 equiv). The flask was lowered into a ambient-temperature water bath. To themixture was added a saturated solution of potassium carbonate in water (15.3 g, 110mmol, 1.75 equiv) dropwise via addition funnel over the course of one hour, and stirringwas continued for an additional hour. The reaction mixture was quenched by addition ofsaturated aqueous ammonium chloride (30 mL), then extracted three times with diethylether. The combined organics were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Methyl acrylate, produced as a side-product,was removed by azeotropic distillation with methanol. The residue was purified byvacuum distillation (~0.5 torr, 44 °C) to afford acrylate 20 as a clear oil (4.07 g, 56percentyield) with minor impurities which were carried forward to the next reaction. Thecharacterization data matched those reported in the literature.3

Reference： [1] Tetrahedron Letters, 2015, vol. 56, # 23, p. 2983 - 2990

3
[ 111-71-7 ]
[ 5927-18-4 ]
[ 111-79-5 ]

Reference： [1] European Journal of Organic Chemistry, 2009, # 4, p. 554 - 563

4
[ 67-56-1 ]
[ 16139-79-0 ]
[ 311-46-6 ]
[ 5927-18-4 ]
[ 625396-69-2 ]
[ 625396-71-6 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 1, p. 131 - 134

5
[ 96-34-4 ]
[ 868-85-9 ]
[ 5927-18-4 ]

Reference： [1] Russian Journal of General Chemistry, 2015, vol. 85, # 10, p. 2441 - 2448[2] Ross. Khim. Zh., 2014, vol. 58, # 1, p. 23 - 30,8

6
[ 67-56-1 ]
[ 88738-78-7 ]
[ 5927-18-4 ]
[ 681123-85-3 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 1, p. 131 - 134

7
[ 6832-16-2 ]
[ 868-85-9 ]
[ 5927-18-4 ]

Reference： [1] Phosphorus, Sulfur and Silicon and the Related Elements, 1992, vol. 73, # 1-4, p. 153 - 160

8
[ 96-32-2 ]
[ 121-45-9 ]
[ 5927-18-4 ]

Reference： [1] Liebigs Annalen der Chemie, 1985, # 2, p. 226 - 238
[2] Canadian Journal of Chemistry, 1968, vol. 46, p. 2225 - 2232

9
[ 96-34-4 ]
[ 121-45-9 ]
[ 5927-18-4 ]

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1996, vol. 35, # 4, p. 312 - 317
[2] Chemische Berichte, 1976, vol. 109, p. 2039 - 2063
[3] Tetrahedron Letters, 1999, vol. 40, # 8, p. 1455 - 1458

10
[ 67-56-1 ]
[ 16139-79-0 ]
[ 311-46-6 ]
[ 5927-18-4 ]
[ 625396-69-2 ]
[ 625396-71-6 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 1, p. 131 - 134

11
[ 67-56-1 ]
[ 42451-44-5 ]
[ 5927-18-4 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1976, vol. 46, p. 529 - 534[2] Zhurnal Obshchei Khimii, 1976, vol. 46, # 3, p. 534 - 540

12
[ 67-56-1 ]
[ 4408-78-0 ]
[ 5927-18-4 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1971, vol. 41, p. 1432 - 1439[2] Zhurnal Obshchei Khimii, 1971, vol. 41, p. 1426 - 1434

13
[ 30361-28-5 ]
[ 5927-18-4 ]
[ 51544-64-0 ]

Reference： [1] Tetrahedron, 2005, vol. 61, # 15, p. 3651 - 3657

14
[ 5927-18-4 ]
[ 33819-10-2 ]
[ 51544-64-0 ]
[ 77761-48-9 ]

Reference： [1] Tetrahedron, 2005, vol. 61, # 15, p. 3651 - 3657

15
[ 5927-18-4 ]
[ 62924-31-6 ]
[ 69877-39-0 ]
[ 69877-38-9 ]

Reference： [1] Journal of Medicinal Chemistry, 1979, vol. 22, # 9, p. 1059 - 1067

16
[ 5927-18-4 ]
[ 1122-91-4 ]
[ 75567-84-9 ]

Reference： [1] Chemistry Letters, 1998, # 3, p. 203 - 204

17
[ 5927-18-4 ]
[ 865-47-4 ]
[ 62327-21-3 ]

Reference： [1] Patent: WO2009/81195, 2009, A1, . Location in patent: Page/Page column 29; 161-162

18
[ 5927-18-4 ]
[ 1095142-51-0 ]
[ 1095142-53-2 ]
[ 1095142-55-4 ]
[ 50650-59-4 ]

Reference： [1] Patent: US2009/5569, 2009, A1, . Location in patent: Page/Page column 7

19
[ 67-56-1 ]
[ 354-32-5 ]
[ 5927-18-4 ]
[ 109-92-2 ]
[ 50650-59-4 ]

Reference： [1] Patent: US2009/5569, 2009, A1, . Location in patent: Page/Page column 6-7

[ 5927-18-4 ] Synthesis Path-Downstream 1~59

1
[ 5927-18-4 ]
[ 53844-02-3 ]
(4aR,4bR,7R,8aR,10aR)-7-Hydroxy-4b-methyl-dodecahydro-phenanthren-2-one [ No CAS ]
[ 14169-97-2 ]

Reference： [1]Patent: US3992437,1976,
Chem.Abstr.,1977,vol. 86

2
[ 104-53-0 ]
[ 5927-18-4 ]
[ 26429-97-0 ]

Yield	Reaction Conditions	Operation in experiment
91.7%		A solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (376 g, 417 mL, 2.07 mol) in THF (750 mL) was stirred at 0 C. in a 3 L 3-neck round bottom flask equipped with a mechanical stirrer and N2 inlet. To the chilled solution, neat tetramethyl guanidine (239 g, 260 mL, 2.07 mol) was added dropwise via an addition funnel. The chilled clear pale yellow solution was stirred for 25 minutes at 0 C. A solution of hydrocinnamaldehyde (90%, 253 g, 248 mL, 1.9 mol) in THF (125 mL) was added dropwise to the reaction solution slowly. Upon completion of addition, the reaction was stirred for 10 h rising to room temperature. GC indicated a 95:5 ratio of product to starting material. 500 ml of water was added to the reaction vessel and the reaction stirred overnight separating into two layers. The organic layer was isolated and the aqueous layer was extracted with t-BuOMe. The organic layers were combined and dried over MgSO4, then concentrated in vacuo to yield an orange oil. The crude product was distilled at 129 C./0.3 mm Hg yielding 360.5 g, 91.7% yield, of a clear slightly yellow oil. [00335] EIMS m/z 190 (13; M+), 159 (410, 158 (39), 131(90), 130(62), 117 (22), 104 (12), 95 (57), 91 (100), 77 (21), 65 (59); HREIMS m/z 190.0998 (C12H14O2 D -0.4 mnu); UV lmax (e) 210 (8400), 260 (230) nm; IR nmax 3027, 2949, 1723, 1658, 1454, 1319, 1203, 978, 700 cm-1; 1H NMR d (CDCl3) 7.15-7.3 (Ph-H5; bm), 7.00 (3-H; dt, 15.6/6.6), 5.84 (2-H; dt, 15.6/1.2), 3.70 (OMe; s), 2.76 (5-H2; t, 7.2), 2.51 (4-H2; bdt, 6.6/7.2); 13C NMR d (CDCl3) 166.9 (1), 148.3 (3), 140.6 (Ph-11'), 128.4/128.2 (Ph2'/3'/5'6'), 126.1 (Ph 4:), 121.4 (2). 51.3 (OMe), 34.2/33.8 (4/5).

Reference： [1]Patent: US6680311,2004,B1 .Location in patent: Page/Page column 47; 53
[2]Journal of the American Chemical Society,1995,vol. 117,p. 2479 - 2490
[3]Angewandte Chemie - International Edition,2014,vol. 53,p. 7634 - 7638
Angew. Chem.,2014,vol. 126,p. 7764 - 7768,5
[4]Chemistry - A European Journal,2016,vol. 22,p. 5767 - 5777
[5]Journal of Organic Chemistry,1990,vol. 55,p. 1928 - 1932
[6]Organic and Biomolecular Chemistry,2015,vol. 13,p. 4255 - 4259
[7]Journal of the American Chemical Society,2019,vol. 141,p. 16983 - 16990

3
[ 60032-57-7 ]
[ 5927-18-4 ]
[ 137146-28-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 1315 - 1324

4
[ 13031-04-4 ]
[ 5927-18-4 ]
[ 86453-60-3 ]
[ 86453-59-0 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 5704 - 5709

5
[ 107-86-8 ]
[ 5927-18-4 ]
[ 52148-91-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 22℃;	To a suspension of NaH (60% in mineral oil, 4.20 g, 24.0 mmol) in anhydrous tetrahydrofuran* (300 mL) cooled to 0 C was added dropwise a solution of trimethylphosphonoacetate (17.0 mL, 19.1 g, 105 mmol) in anhydrous tetrahydrofuran* (40 mL). This solution was stirred at 0 C for 45 min and then treated with 3-methyl-2-butenal (10.0 mL, 8.72 g, 104 mmol) in one portion. The solution was allowed to warm to 22 oC and then stirred for 15 hours. After this time, the reaction mixture was diluted with diethyl ether (300 mL) and 2 N sulfuric acid (100 mL). The organics were separated, washed with saturated aqueous sodium bicarbonate solution (300 mL) and brine (350 mL), dried over magnesium sulfate, filtered and concentrated to a yellow oil. Purification by vacuum distillation afforded 3c (13.32 g, 91 %) of 95% purity by 1H NMR: bp 40-42 C; 1H NMR (500 MHz, CDCl3) d 7.59-7.53 (m, 1H), 5.98 (d, J = 11.6 Hz, 1H), 5.75 (d, J = 15.1 Hz, 1H), 3.73 (s, 3H), 1.88 (q, J = 9.1 Hz, 6H); 13C NMR (125 MHz, CDCl3) delta 168.0, 146.4, 141.1, 123.6, 118.0, 51.3, 26.5, 18.9.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 872 - 874
[2]Heterocycles,1984,vol. 21,p. 309 - 324

6
[ 5927-18-4 ]
[ 5077-67-8 ]
[ 1575-44-6 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 2839 - 2840

7
[ 5927-18-4 ]
[ 51716-63-3 ]
7-((methoxycarbonyl)methylene)-cis-bicyclo<3.3.0>octan-3-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1995,vol. 117,p. 6732 - 6738

8
[ 5927-18-4 ]
[ 53844-02-3 ]
(4aR,4bR,7R,8aR,10aR)-7-Hydroxy-4b-methyl-dodecahydro-phenanthren-2-one [ No CAS ]
[ 14169-96-1 ]

Reference： [1]Journal of medicinal chemistry,1967,vol. 10,p. 582 - 593

9
[ 5927-18-4 ]
[ 128461-65-4 ]
[ 201667-72-3 ]

Yield	Reaction Conditions	Operation in experiment
98%		<strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (5.46 g, 4.9 mL, 30 mmol) was added to a solution of K2CO3(8.3 g, 60 mmol) in water (8.3 mL), cooled at 0 C. The reaction mixture was stirred for 15min, and a solution of the 3-(4-methoxybenzyloxy)propionaldehyde1 (4.9 g, 25 mmol) indiethyl ether (10 mL) was then added. The heterogeneous mixture was stirred overnight atroom temperature and then extracted with diethyl ether. The organic phase was dried withanhydrous Na2SO4 and concentrated to give (E)-methyl 5-(4-methoxybenzyloxy)pent-2-enoate (6.1 g, 98%) as a yellow oil, which was used in the next step without any furtherpurification.

Reference： [1]European Journal of Organic Chemistry,2002,p. 1941 - 1951
[2]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 2446 - 2450
[3]Angewandte Chemie - International Edition,1998,vol. 37,p. 1724 - 1726
[4]Organic Letters,2000,vol. 2,p. 2475 - 2477
[5]Journal of the Brazilian Chemical Society,2012,vol. 23,p. 344 - 348

10
[ 30361-28-5 ]
[ 5927-18-4 ]
[ 51544-64-0 ]
methyl (E,E,E)-2,4,6-decatrienoate [ No CAS ]

Reference： [1]Tetrahedron,2005,vol. 61,p. 3651 - 3657

11
[ 5927-18-4 ]
[ 33819-10-2 ]
[ 51544-64-0 ]
[ 77761-48-9 ]
Me deca-cis-2, trans-4, trans-6-trienoate [ No CAS ]
methyl (E,E,E)-2,4,6-decatrienoate [ No CAS ]

Reference： [1]Tetrahedron,2005,vol. 61,p. 3651 - 3657

12
[ 777089-26-6 ]
[ 5927-18-4 ]
[ 777089-28-8 ]

Yield	Reaction Conditions	Operation in experiment
87%		Sodium hydride (0.513 g of a 60% dispersion, 12.8 mmol) was placed in a flask and washed three times with hexane. The resulting solid was suspended in DMF (10 mL) and cooled to 0 C. TRIMETHYL phosphonoacetate (2.2 mL, 13.5 mmol) was added dropwise to this suspension to give a clear homogeneous solution. After stirring for another 15 minutes at 0 C, a solution of benzyl 3-fluoro-4- FORMYLPHENYLCARBAMATE (3.5 g, 12.8 mmol) in DMF (10 mL) was added dropwise. The resulting orange suspension was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was poured into 0.5 N HCL and extracted with three portions of dichloromethane. Combined organic phases were washed with saturated NAHC03, H2O, brine, and dried (MGS04) filtered and concentrated. The resulting orange solid was washed sequentially with hexane and then 30% ethyl acetate-hexane to provide the title compound as a yellow-orange solid (2.7 g). The washings were concentrated and purified by column chromatography (0-30% ethyl acetate-hexane) to provide an additional 0.95 g of the product. Yield 3.66 g (87%). H NMR (300 MHz, d6-DMSO): 3.71 (s, 3H), 5.17 (s, 2H), 6. 55 (dd, J = 16, 1 Hz, 1H), 7.26 (d, J= 9 Hz, 1H), 7. 35-7. 50 (m, 6H), 7.63 (d, J= 16 Hz, 1H), 7.79 (t, J =9HZ, 1H), 10.3 (bs, 1 H) MP= 157-158 C.
72%		Sodium hydride (7.2 g of a 60% dispersion, 0. 188 mol) was placed in a flask and washed three times with hexane. The resulting solid was suspended in DMF (140 mL) and cooled to 0 C. <strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (30.7 ML, 0.190 mol) was added dropwise to this suspension to give a clear homogeneous solution. After stirring for another 20 minutes at 0 C, a solution of benzyl 3-fluoro-4- FORMYLPHENYLCARBAMATE (2) (48 g, 0.176 mol) in DMF (140 mL) was added dropwise. The resulting orange suspension was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was poured into 0.5 N HCI (1.5 L) and extracted with three 300 mL portions of dichloromethane. Combined organic phases were washed with saturated NaHCO3, twice with H20, brine, and dried (Na2S04). While concentrating the solution on a rotary evaporator, the product precipitated from solution and these solids were collected on a filter (33.4 g). The filtrate was concentrated to give more solids that were washed with ether (additional 8.4 g obtained). Yield 41.8 g (72%). 'H NMR (300 MHz, d6-DMSO): 3.71 (s, 3H), 5.17 (s, 2H), 6.55 (dd, J= 16,1 Hz, 1H), 7.26 (d, J = 9 Hz, 1H), 7. 35-7. 50 (m, 6H), 7.63 (d, J = 16 Hz, 1H), 7.79 (t, J = 9 Hz, 1H), 10.3 (bs, 1 H) MP= 157-158 C.

Reference： [1]Patent: WO2004/89943,2004,A1 .Location in patent: Page 54
[2]Organic Letters,2005,vol. 7,p. 2627 - 2630
[3]Patent: WO2004/89943,2004,A1 .Location in patent: Page 100

13
[ 498-62-4 ]
[ 5927-18-4 ]
[ 75754-85-7 ]

Yield	Reaction Conditions	Operation in experiment
94%		EXAMPLE 10 3-Thiophen-3-yl-acrylic Acid Methyl Ester To a suspension of sodium hydride (3.65 g 91.22 mmol) in anhydrous THF (250 ML) was added trimethylphosphono acetate (10.16 ML, 62.77 mmol) in THF (50 ML) dropwise.. The thick reaction mixture was then stirred for 1 hour. 3 thiophene carboxaldehyde (5.00 ML, 57.01 mmol) was dissolved in THF (50 ML) and added dropwise, and the reaction stirred at room temp for 18 hours.. The reaction was quenched with half saturated NH4Cl (120 ML).. The layers were separated and the aqueous layer extracted with EtOAc (2*100 ML).. The combined organics were washed with brine (100 ML), dried over MgSO4, filtered and concentrated.. The crude material was chromatographed on silica eluding with hexanes, then 15% EtOAc/heavens to give the title compound 10 as an oil that crystallizes upon standing (9.05 g, 94%). 1H NMR(400MHz, CDCl3) delta7.64(d, 1H, J=15.7 Hz), 7.46 (d, 1H, J=1.47 Hz), 7.30 (dd, 1H, J=5.13, 2.69 Hz), 7.26 (d, 1H, J=5.13 Hz), 6.22 (d, 1H, J=16.1 Hz), 3.76 (s, 3H). MS (APCI) m/z 169 (M++1). Analysis calculated for C8H8O2S: C, 57.12; H, 4.79; S, 19.06. Found: C,57.20; H, 4.77; S, 19.10.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2329 - 2332
[2]Patent: US6710190,2004,B1 .Location in patent: Page column 22
[3]Organic Letters,2016,vol. 18,p. 5716 - 5719

14
[ 870837-70-0 ]
[ 5927-18-4 ]
(E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl)acrylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Dimethylphosphonoacetic acid methyl ester (3.80 mL) and lithium hydroxide monohydrate (1.20 g) were added one by one to a THF (20 mL) solution of the crude aldehyde compound (4.76 g) obtained above, and the reaction solution was agitated overnight at the room temperature. 2N sodium hydroxide solution was added to the reaction solution after confirming disappearance of the starting materials (20 mL), and the reaction solution was agitated at 50 C. for 2 hours. The reaction solution was cooled to 0 C., 2N hydrochloric acid was added to the reaction solution (20 mL), and deposited precipitation was separated by filtering with Kiriyama funnel. The obtained precipitation was washed with water and ethyl acetate, and 4.2 g of the title compound was obtained. The physical properties of the compound are as follows. 1H-NMR (DMSO-d6) delta (ppm): 7.96 (s, 1H), 7.63 (d, J=16 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.39 (dd, J=1.6, 8.0 Hz, 1H), 7.06 (s, 1H), 6.68 (d, J=16 Hz, 1H), 3.90 (s, 3H).

Reference： [1]Patent: US2006/4013,2006,A1 .Location in patent: Page/Page column 77

15
[ 5927-18-4 ]
[ 34841-47-9 ]
[ 154349-03-8 ]

Yield	Reaction Conditions	Operation in experiment
57%		Stage 2 - Preparation of {4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}acetic acid; To stage 1 product (1.03g, 6.3mmol) in water (10OmL) were added K2CO3 (2.61g, 18.9mmol) then trimethylphosphonoacetate (1.23mL, 7.6mmol) at O0C. Addition was carried out over 10 minutes to avoid the reaction temperature rising above 15C. The reaction mixture was then stirred at RT for 72h. A solution of 1 M HCI was added until pH - 1. The white precipitate was isolated by filtration, washed with water (10OmL), concentrated and dried on the freeze drier to afford the desired product as a white solid (784 mg, 57%). 1H NMR (300MHz, Cf6-DMSO) delta: 12.46 (1 H, br s), 7.69-7.63 (2H, m), 7.31 (2H, d, J=8.1 Hz), 6.74 (1 H, d, J=16.0Hz), 6.63 (1 H, d, J=16.0Hz), 3.72 (3H, s), 3.62 (2H, s).

Reference： [1]Patent: WO2008/40934,2008,A1 .Location in patent: Page/Page column 73

16
[ 5927-18-4 ]
[ 126430-46-4 ]
C₁₆H₂₃O₇P [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2007,vol. 349,p. 432 - 440

17
[ 5927-18-4 ]
[ 73291-09-5 ]
[ 731846-75-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4481 - 4486

18
[ 5927-18-4 ]
[ 1134-43-6 ]
[ 863885-81-8 ]

Yield	Reaction Conditions	Operation in experiment
99%		Step 4; Sodium hydride (95% dry powder; 158 mg; 6.25 mmol) was suspended in anhydrousTHF (10 mL) and <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (0.945 mL; 5.84 mmol) added dropwiseat 0C under a nitrogen atmosphere resulting in a solid white mass which could not bestirred. A solution of the aldehyde 4-4 from above (950 mg; 4.87 mmol) in THF (7 mL+ 3 mL rinse) was then added dropwise resulting in a yellow colour and slowdissolution of the white solid mass. After the addition, the reaction was allowed towarm to ambient temperature. After 15 h, the cloudy reaction mixture was evaporatedto a pale yellow solid which was extracted with ethyl acetate (2 x 50 mL) and washed with saturated NaHCO3 (3 x 75 ml). The combined extracts were dried over MgSO4and evaporated to afford the cinnamate ester 4-5 as pale yellow solid (1.212 g; 99 %)which was used without further purification.
	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 15h;	Step 4:; Sodium hydride (95% dry powder; 158 mg; 6.25 mmol) was suspended in anhydrous THF (10 mL) and <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (0.945 mL; 5.84 mmol) added dropwise at 0C under a nitrogen atmosphere resulting in a solid white mass which could not be stirred. A solution of the aldehyde 12-4 from step 3 (950 mg; 4.87 mmol) in THF (7 mL + 3 mL rinse) was then added dropwise resulting in a yellow colour and slow dissolution of the white solid mass. After the addition, the reaction was allowed to warm to ambient temperature. After 15 h, the cloudy reaction mixture was evaporated to a pale yellow solid which was extracted with ethyl acetate (2 x 50 mL) and washed with saturated NaHC03 (3 x 75 mL). The combined extracts were dried over MgS04 and evaporated to afford the cinnamate ester 12-5 as pale yellow solid (1.212 g; 99 %) which was used in step 5 without further purification.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 10130 - 10143
[2]Patent: WO2006/7693,2006,A1 .Location in patent: Page/Page column 48; 49
[3]Patent: WO2005/80388,2005,A1 .Location in patent: Page/Page column 65-66

19
[ 5927-18-4 ]
[ 79099-07-3 ]
[ 169206-65-9 ]

Yield	Reaction Conditions	Operation in experiment
94%		60% NaH (3.06 g) was washed with dry hexane (2 x 20 mL) and the clear solution was syringed out under N2 atmosphere. The washed NaH was suspended in dry DMF (100 mL) and cooled to 0 C. To this suspension was added slowly <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (14.1 mL) over a period of 20 minutes. Compound HI (14. Og, 78 mmol) in dry DMF (15 mL) was slowly added to the solution. The temperature was maintained at 0 C over a period of 20 minutes, then allowed to stir while warming to RT for 3h. At this point the reaction was diluted with Et20 (250 mL) and washed with water (100 mL). The aqueous layer was back extracted with additional diethyl ether (40 mL), then the combined organic extract was washed with water (4 x 50 mL) and brine (30 mL). The separated organic layer was dried over MgS04,filtered and the solvent was removed under reduced pressure to yield the product as a crystalline solid. Isolated 16.95g (94% yield).
92%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	Methyl dimethylphosphonoacetate (1.8 ml) was dissolved in tetrahydrofuran (40 ml). Under ice cooling, sodium hydride (60% in oil, 450 mg) was added and the resulting mixture was stirred as was. A tetrahydrofuran solution (tetrahydrofuran: 10 ml) of 1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) was added. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate, followed by the addition of 2N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue thus obtained was purified by chromatography (hexane:ethyl acetate = 6:1) on a silica gel column, whereby the title compound (2.35 g, 92%) was obtained.1H-NMR(CDCl3) delta: 1.47(9H,s), 2.28(2H,t,J=5.9Hz), 2.94(2H,t,J=5.9Hz), 3.48(2H,t,J=5.9Hz), 3.50(2H,t,J=5.9Hz), 3.70(3H,s), 5.72(1H,s).
92%		tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-l-carboxylate.; Sodium hydride in mineral oil (60%, 7.92 g, 198.02 mmoles) was washed with hexanes then suspended in dimethylformamide (220 mL). The mixture was cooled to 0C.<strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (29.0 mL, 189.82 mmoles) was added dropwise to the stirred reaction mixture. After 20 min at 0C, a solution of N-tert-butoxycarbonyl-4- piperidone (30.41 g, 152.62 mmoles) in dimethylformamide (80 mL) was added to the mixture dropwise. The reaction was stirred at room temperature for 3 h and then diluted with diethyl ether (650 mL). The mixture was washed once with water and the aqueous layer was extracted once with diethyl ether. The combined organic layers were washed 4 times with water and the aqueous phase was discarded. The organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated to dryness. The title compound was obtained as a white solid in 92% yield. XH-NMR (300 MHz, CDC13): delta = 5.68 (s, 1 H), 3.66 (s, 3 H), 3.40-3.51 (m, 4 H), 2.90 (t, J= 5.49, 2 H), 2.25 (t, J= 5.49, 2 H), 1.44 (s, 9 H).

78.1%		To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.0 g, 15 mmol) in DMF (30 mL) in two neck RB was wadded NaH (56-60 %) (0.54 g, 22.5 mmol) portion wise at 0 C and stirred for 30 mins at RT then methyl 2-(dimethoxyphosphoryl)acetate (3.29 g, 18 mmol) was added and stirred for 16 h at RT. The reaction mixture was quenched with cold water and extracted with ethyl acetate (2 X 100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chomatography using 80 % ethyl acetate in hexane as eluent to afford the title compound (3.0 g, 78.1 %) 1H NMR (400 MHz, DMSO-d6): d 5.77 (s, 1H), 3.61 (s, 3H), 3.41-3.33 (m, 4H), 2.82 (t, / = 6.0 Hz, 2H), 2.26 (t, / = 5.6 Hz, 2H), 1.44 (s, 9H). LC-MS: m/z 255.1 (M+l)+.
72.9%		Sodium hydride in mineral oil (60%, 11.9 g, 297 mmol) was dissolved in DMF (200mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286 mmol) was added dropwise at 0CC. The reaction mixture was stirred at 0 00 for 20 mm then tert-butyl 4-oxopiperidine-1-carboxylate (45.5 g, 228 mmol) in DMF (100 mL) was added drop wiseat 0 00 The reaction mixture was stirred at rt for 2 h, then diluted with ice water (20 mL), filtered and the solvents were removed in vacuo to give tert-butyl 4-(2-methoxy-2- oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) as a yellow solid.LCMS (Method F): mlz 256 (M+H) (ES), at 2.47 mi UV active
72.9%		Sodium hydride in mineral oil (60%, 1 1.9 g, 297 mmol) was dissolved in DMF (200 mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286 mmol) was added drop wise at 0 C. The reaction mixture was stirred at 0 C for 20 min then te/f-butyl 4- oxopiperidine-1-carboxylate (45.5 g, 228 mmol) in DMF (100 mL) was added drop wise at 0C. The reaction mixture was stirred at rt for 2 h, then diluted with ice water (20 mL), filtered and the solvents were removed in vacuo to give te/f-butyl 4-(2-methoxy-2- oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) as a yellow solid. LCMS (Method F): m/z 256 (M+H)+ (ES+), at 2.47 min, UV active
		Intermediate 2a: tert-butyl 4-((methoxycarbonyl)methylene)piperidine-1-carboxylate Sodium hydroxide (4.56 g, 0.114 mol) was dissolved in ethanol (210 mL), and <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (11.4 g, 0.062 mol) added with stirring. The mixture was stirred for 30 min at room temperature. Tert-butyl 4-oxopiperidine-1-carboxylate (11.35 g, 0.057 mol) was added with stirring at room temperature, and the reaction was allowed to stand overnight. Then, the mixture was acidified with diluted hydrochloric acid until the pH was 4, filtered, concentrated, and partitioned into water and chloroform. Phases were separated. The aqueous phase was extracted once with chloroform. Chloroform phases were combined, washed once with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound.
		Sodium hydride (60% in mineral oil, 4.8 g, 120 mmol) was washed with hexanes and then suspended in N,N-dimethylformamide (100 mL). The mixture was cooled to 0 C. <strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (17.0 mL, 111 mmol) was added to the mixture dropwise. The reaction was held at 0 C. for 45 minutes. A solution of N-tert-butoxycarbonyl-4-piperidone (18.5 g, 92.6 mmol) in N,N-dimethylformamide (25 mL) was added to the reaction mixture dropwise. The mixture was held at 0 C. for 1 h and then warmed to room temperature where it was held for 1 h. The reaction was quenched with 1 N hydrochloric acid. The mixture was extracted with diethyl ether (2×). Combined organic layers were washed with water (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in 1:1 ethyl acetate/methanol (60 mL). A catalytic amount of palladium (10% on charcoal) was added to the mixture. The reaction vessel was placed on a Parr apparatus, charged with 55 psi of hydrogen, and shaken at room temperature for 18 h. The reaction mixture was removed from the Parr apparatus and filtered. The filtrate was concentrated in vacuo to give the title compound as lightly colored oil in 94% yield. 1H NMR (300 MHz, CDCl3): delta 4.04 (d, J=10.25, 2H), 3.64 (s, 3H), 2.68 (t, J=14.44, 2H), 2.21 (d, J=6.95, 2H), 1.99-1.80 (m, 1H), 1.64 (d, J=13.54, 2H), 1.41 (s, 9H), 1.25-1.03 (m, 2H).
		Preparation of 2a: tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1- carboxylate Sodium hydroxide (4.56 g, 0.114 mol) was dissolved in alcohol (210 ml), and alcohol solution containing dimethoxy phosphoryl methyl acetate (11.4g, 0.062mol) added with stirring. The mixture was stirred for 30 min at room temperature. 1-(tert-butoxy carboxyl)piperidyl-4-one (11.35g, 0.057mol) was added with stirring at room temperature, and the reaction was allowed to stand overnight. Then, the mixture was acidized with diluted hydrochloric acid until the pH value was 4, filtered, concentrated, dissolved with water and chloroform. The chloroform phase was obtained after layer separation. The water phase was extracted once with chloroform. The chloroform phase was combined, washed once with saturated salt water, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give the title compound.
		Step A: tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine- 1 -carboxylate: A mixture of 60%sodium hydride (1.30 g, 33 mmol) in 145 mL of DMF was cooled to 0C, methyl 2-(dimethoxyphosphoryl)acetate (4.8 mL, 31 mmol) was then added dropwise. After 20 minutes at0C, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25 mmol) in 13 mL of DMFwas added dropwise. The reaction mixture was stirred at r.t. for 3 hours, and then diluted with EtOAc, washed with water; the organic layer was separated and washed with brine, dried over Na2504, filtered and concentrated to afford the title compound. ?H-NMR (400 MHz, CDC13) oe ppm 5.70 (s, 1H), 3.67 (s, 3H), 3.40-3.53 (m, 4H), 2.85-2.95 (t, J= 6.0 Hz, 2H), 2.20-2.30 (t, J=5.2 Hz, 2H), 1.45 (s, 9H).

Reference： [1]Patent: WO2013/166282,2013,A2 .Location in patent: Page/Page column 95
[2]Patent: EP1577302,2005,A1 .Location in patent: Page/Page column 121
[3]Patent: WO2011/123232,2011,A1 .Location in patent: Page/Page column 9
[4]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3157 - 3161
[5]Patent: WO2019/207538,2019,A1 .Location in patent: Page/Page column 73-74
[6]Patent: WO2015/140559,2015,A1 .Location in patent: Page/Page column 41
[7]Patent: WO2016/147011,2016,A1 .Location in patent: Page/Page column 46-47
[8]Patent: US2009/105247,2009,A1 .Location in patent: Page/Page column 12
[9]Patent: US2005/215576,2005,A1 .Location in patent: Page/Page column 49
[10]Patent: EP2045245,2009,A1 .Location in patent: Page/Page column 19
[11]Patent: WO2016/127358,2016,A1 .Location in patent: Page/Page column 54

20
[ 37674-72-9 ]
[ 5927-18-4 ]
6-chloro-3,4-dihydro-2H-1-benzopyran-4-ylidene-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	EXAMPLE 17 In a flame dried flask under nitrogen equipped with a mechanical stirrer, trimethyl phosphonoacetate (10.9 g.) was added dropwise to a slurry of 50% sodium hydride (2.9 g.) in 300 ml. freshly dried tetrahydrofuran and stirred at room temperature for 1 hour. A solution of <strong>[37674-72-9]6-chloro-3,4-dihydro-2H-1-benzopyran-4-one</strong> (10 g.) in 100 ml. of freshly dried tetrahydrofuran was added dropwise, keeping the temperature below 30 C. during the addition. The solution was then heated at reflux for 5 hours and stirred at room temperature for 12 hours. The solution was poured into ice-water, extracted with diethyl ether, washed with water and dried over magnesium suflate. The solution was treated with activated charcoal and evaporated under vacuum to yield a yellow oil (6.3 g.). Chromatography on silica gel (900 ml.) eluted with 1:1 hexane:ethyl acetate yielded 6-chloro-3,4-dihydro-2H-1-benzopyran-4-ylidene-acetic acid methyl ester, (1.6 g., 12%), m.p. 113-115 C.

Reference： [1]Patent: US4210663,1980,A

21
[ 4746-97-8 ]
[ 5927-18-4 ]
[ 172270-85-8 ]

Yield	Reaction Conditions	Operation in experiment
87%		To a DMF (50 mL) solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (26 mL), sodium hydride (purity: 55% or higher, 7.03 g) was added in small portions at 0C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A DMF (50 mL) solution of 1,4-cyclohexanedione monoethylene ketal (25.2 g) was added thereto in small portions at room temperature. This suspension was stirred for 19 hours and diluted with a saturated aqueous solution of ammonium chloride, followed by two extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (29.7 g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta (ppm) = 5.75-5.65 (1H, m), 3.99 (4H, s), 3.70 (3H, s), 3.01 (2H, t, J = 6.7 Hz), 2.39 (2H, t, J = 6.7 Hz), 1.81-1.75 (4H, m);. MS (EI) m/z: 212 (M)+.
87%		(1a) (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester To a DMF (50 mL) solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (26 mL), sodium hydride (purity: 55% or higher, 7.03 g) was added in small portions at 0C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A DMF (50 mL) solution of 1,4-cyclohexanedione monoethylene ketal (25.2 g) was added thereto in small portions at room temperature. This suspension was stirred for 19 hours and diluted with a saturated aqueous solution of ammonium chloride, followed by two extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (29.7 g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta (ppm) = 5.75-5.65 (1H, m), 3.99 (4H, s), 3.70 (3H, s), 3.01 (2H, t, J = 6.7 Hz), 2.39 (2H, t, J = 6.7 Hz), 1.81-1.75 (4H, m) MS (EI) m/z: 212 (M)+.
	With sodium hydride; In tetrahydrofuran; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; at 0 - 20℃; for 12.0833h;	a). To a 0 C. solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (4.8 mL, 34 mmol) in DMPU (12 mL) and THF (30 mL) was added a suspension of NaH (0.74 g, 31 mmol) in THF (45 mL). To the resulting mixture was added a solution 1,4-dioxaspiro[4.5]decane-8-one (4.7 g, 30 mL) in THF (30 mL). After stirring at 0 C. for 5 min the suspension was allowed to reach room temperature and stirred for 12 h. The resulting solution was poured into water (900 mL) and extracted with Et2O (2×200 mL). The combined organics were washed with brine and dried over MgSO4, and organics were removed in vacuo. Silica gel chromatography (gradient of 5 to 7% ethyl acetate in hexanes) afforded the product.

NaH (9.2 g, 384 mmol, 1.5 eq) was suspended in THF (850 ml). This was cooled to C. and trimethylphosphonoacetate (40 ml, 277 mmol, 1.1 eq) was added dropwise keeping T<10 C. Mixture was then recooled to 0 C. and stirred for 15 min. Then compound 1 (40 g, 256 mmol, 1.0 eq) in THF (300 ml) was added dropwise. The reaction mixture was stirred over night allowing it to warm to room temperature. The mixture was poured into water (500 ml) and EtOAc (300 ml) were added, the layers were separated. The aqueous layer was extracted with EtOAc (400 ml). The combined organic layers were dried (Na2SO4) and evaporated. Yield: 51.6 g of methyl 2-(4-(1,3-dioxalane)cyclohexylidene)acetate; 1H NMR (CDCl3, 300 MHz) delta 1.78 (q, 4H), 2.37 (t, 2H), 2.99 (t, 2H), 3.68 (s, 3H), 3.99 (s, 4H), 5.65 (s, 1H)

Reference： [1]Patent: EP2256105,2010,A1 .Location in patent: Page/Page column 25
[2]Patent: EP2471777,2012,A1 .Location in patent: Page/Page column 10
[3]Patent: US2006/293392,2006,A1 .Location in patent: Page/Page column 62-63
[4]Patent: US2009/36425,2009,A1 .Location in patent: Page/Page column 17-18

22
[ 877267-79-3 ]
[ 5927-18-4 ]
[ 877269-51-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2, 1-a][2]benzazepine-10-carboxylate; A stirred suspension of methyl 11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.61 g, 10 mmol), Cs2CO3 (3.91 g, 12 mmol) and trimethyl 2-phosphonoacetate (2.86g, 14 mmol) in an. DMF (40 mL) was heated at 60 C. under nitrogen for 3 h. The resultant yellow suspension was cooled to rt and water was added with vigorous stirring. A yellow precipitate formed which was collected by filtration. The solid was washed with water, and then air dried overnight to afford the title compound as a yellow powder (4.124 g, 96%). LC/MS: m/e 430 (MH+); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.30-1.46 (m, J=14.86 Hz, 2 H) 1.55 (s, 2 H) 1.77 (s, 2 H) 1.85-2.18 (m, 4 H) 2.76-2.89 (m, 1 H) 3.84 (s, 3 H) 3.95 (s, 3 H) 4.19 (s, 1 H) 5.68 (s, 1 H) 7.38-7.63 (m, 4 H) 7.74 (dd, J=8.44, 1.39 Hz, 1 H) 7.81-7.98 (m, 2 H) 8.29 (d, J=1.0l Hz, 1 H).
96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate.; A stirred suspension of methyl 11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.61 g, 10 mmol), Cs2CO3 (3.91 g, 12 mmol) and trimethyl 2-phosphonoacetate (2.86 g, 14 mmol) in an. DMF (40 mL) was heated at 60 C. under nitrogen for 3 h. The resultant yellow suspension was cooled to rt and water was added with vigorous stirring. A yellow precipitate formed which was collected by filtration. The filtrand was washed with water, and then air dried overnight to afford the title compound as a yellow powder (4.124 g, 96%). LC/MS: m/e 430 (MH+); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.30-1.46 (m, J=14.86 Hz, 2H) 1.55 (s, 2H) 1.77 (s, 2H) 1.85-2.18 (m, 4H) 2.76-2.89 (m, 1H) 3.84 (s, 3H) 3.95 (s, 3H) 4.19 (s, 1H) 5.68 (s, 1H) 7.38-7.63 (m, 4H) 7.74 (dd, J=8.44, 1.39 Hz, 1H) 7.81-7.98 (m, 2H) 8.29 (d, J=1.01 Hz, 1H).
96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Methyl 13-cyclohexyl-6-(methoxycarbonyl)- 7H-indolo[2, 1-a] [2]benzazepine- 10-carboxylate (5; Ri = Rs - Me, R2 = H). A stirred suspension of methyl 11- cyclohexyl-6-hydroxy-6H-isoindolo[2,l-a]indole-3-carboxylate (3.61 g, lOrnmol), Cs2CO3 (3.91 g, 12 mrnol) and trimethyl 2-phosphonoacetate (2.86g, 14 mmol) in an. DMF (40 mL) was heated at 60 0C under nitrogen for 3 h. Resultant yellow suspension was cooled to rt and water was added with vigorous stirring. The yellow precipitate was filtered off , washed with water and then air dried overnight to afford the designated compound (4.124g, 96%). LC/MS: m/e 430 (MH+); IH NMR (400 MHz, CHLOROFORM-D) 6 ppm 1.30 - 1.46 (m, J=14.86 Hz, 2 H) 1.55 (s, 2 H) 1.77 (s, 2 H) 1.85 - 2.18 (m, 4 H) 2.76 - 2.89 (m, 1 H) 3.84 (s, 3 H) 3.95 (s, 3 H) 4.19 (s, 1 H) 5.68 (s, 1 H) 7.38 - 7.63 (m, 4 H) 7.74 (dd, J=8.44, 1.39 Hz, 1 H) 7.81 - 7.98 (m, 2 H) 8.29 (d, J=LOl Hz, I H).

96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate.; A stirred suspension of methyl 11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.61 g, 10 mmol), Cs2CO3 (3.91 g, 12 mmol) and trimethyl 2-phosphonoacetate (2.86 g, 14 mmol) in an. DMF (40 mL) was heated at 60 C. under nitrogen for 3 h. The resultant yellow suspension was cooled to rt and water was added with vigorous stirring. A yellow precipitate formed which was collected by filtration. The solid was washed with water, and then air dried overnight to afford the title compound as a yellow powder (4.124 g, 96%). LC/MS: m/e 430 (MH+); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.30-1.46 (m, J=14.86 Hz, 2 H) 1.55 (s, 2 H) 1.77 (s, 2 H) 1.85-2.18 (m, 4 H) 2.76-2.89 (m, 1 H) 3.84 (s, 3 H) 3.95 (s, 3 H) 4.19 (s, 1 H) 5.68 (s, 1 H) 7.38-7.63 (m, 4 H) 7.74 (dd, J=8.44, 1.39 Hz, 1 H) 7.81-7.98 (m, 2 H) 8.29 (d, J=1.01 Hz, 1 H).
96%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	Intermediate 23 Methyl 13-cyclohexyl-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate. A stirred suspension of methyl 11-cyclohexyl-6-hydroxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.61 g, 10 mmol), Cs2CO3 (3.91 g, 12 mmol) and trimethyl 2-phosphonoacetate (2.86 g, 14 mmol) in an. DMF (40 mL) was heated at 60 C. under nitrogen for 3 h. The resultant yellow suspension was cooled to rt and water was added with vigorous stirring. A yellow precipitate formed which was collected by filtration. The solid was washed with water, and then air dried overnight to afford the title compound as a yellow powder (4.124 g, 96%). LC/MS: m/e 430 (MH+); 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.30-1.46 (m, J=14.86 Hz, 2H) 1.55 (s, 2H) 1.77 (s, 2H) 1.85-2.18 (m, 4H) 2.76-2.89 (m, 1 H) 3.84 (s, 3H) 3.95 (s, 3H) 4.19 (s, 1H) 5.68 (s, 1H) 7.38-7.63 (m, 4H) 7.74 (dd, J=8.44, 1.39 Hz, 1H) 7.81-7.98 (m, 2H) 8.29 (d, J=11.1 Hz, 1H).

Reference： [1]Patent: US2007/78122,2007,A1 .Location in patent: Page/Page column 176
[2]Patent: US2007/60565,2007,A1 .Location in patent: Page/Page column 72
[3]Patent: WO2007/92000,2007,A1 .Location in patent: Page/Page column 143
[4]Patent: US2008/188458,2008,A1 .Location in patent: Page/Page column 34
[5]Patent: US2008/171015,2008,A1 .Location in patent: Page/Page column 25

23
[ 71690-05-6 ]
[ 5927-18-4 ]
[ 955029-08-0 ]

Yield	Reaction Conditions	Operation in experiment
		2) To a solution of methyl (dimethoxyphosphoryl) acetate (3.4mL) in toluene (103mL) was added portionwise 60% NaH (0.96g) at 20 to 300C under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise above Solution A at 0 to 100C and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into a mixture of AcOEt and water and adjusted to pH 2 with IN- HCl aq. The separated organic layer was washed with saturated sodium hydrogen carbonate aq., dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give methyl (2E) -3- (5, 6-dichloropyridin-3-yl) acrylate (2.83g).

Reference： [1]Patent: WO2008/75757,2008,A1 .Location in patent: Page/Page column 36

24
[ 879016-22-5 ]
[ 5927-18-4 ]
[ 942316-72-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		Methyl 2-(dimethoxyphosphoryl)acetate (1.402 ml,9.72 mmol) was added dropwise to a stirred, 0 C. suspension of sodium hydride (0.359 g, 8.97 mmol) in TRF (60 mE). The reaction mixture was allowed to warm up to room temperature and the stirred for 1 hour. A solution of 5-chloro-2-(1R- tetrazol-1-yl)benzaldehyde (1.56 g, 7.48 mmol) in TRF (10 mE) was then added. The mixture was stirred vigorously for 30 minutes. The mixture was poured into a cold saturated NR4C1 solution. The resulting mixture was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate. The solid was collected and dried in vacuo to give 1.78 g (90%) of (E)-methyl 3-(5-chioro-2- (1 R-tetrazol-1 -yl)phenyl)acrylate as an off white solid.
57%		ID. (E)-3-(5-chloro-2-tetrazol-l-yl-phenyl)-acrylic acid methyl ester: To a cooled (0 C) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to room temperature and stirred at room temperature for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2- tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid (1.76 g). The solid was redissolved in EtOAc and filtered through a plug of silica gel and eluted with EtOAc. The filtrate was concentrated to give a greenish solid (1.36 g). Recrystallization from EtOAc gave an off-white solid (0.476 g). Additional product was obtained by concentrating the filtrate, adding methanol, sonicating, and collecting the resulting solid by filtration. A total of 0.829 g (57%) of ID was obtained. LCMS m/z 265.1 (M+H)+; 287.2(M+Na)+. 1HNMR (500 MHz, CDCl3) delta: 8.80 (s, IH), 7.78 (d, J= 2.2 Hz, IH), 7.58(dd, J= 8.8, 2.2 Hz, IH), 7.42 (d, J= 8.2 Hz, IH), 7.25 (d, J= 16.0 Hz, IH), 6.45 (d,J= 16.0 Hz, IH), 3.78 (s, 3H).
57%		To a cooled(0 0C) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to rt and stirred at rt for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2-tetrazol-l-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid weighing 1.76 g. The solid was dissolved in EtOAc and filtered through a plug of silica gel, eluting with EtOAc. The green filtrate was concentrated to give a greenish solid weighing 1.36 g. Recrystallization from EtOAc gave an off- white solid weighing 0.476 g. Additional product was obtained by concentrating the filtrate from recrystallization, adding methanol, sonicating, and collecting the solid product by filtration. A total of 0.829 g (57%) of (E)-3-(5-chloro-2-tetrazol-l-yl- phenyl)-acrylic acid methyl ester was obtained. LCMS m/z 265.1 (M+H)+; 287.2 (M+Na)+. 1H NMR (CDCl3, 500 MHz) delta: 8.80 (s, IH), 7.78 (d, J= 2.2 Hz, IH), 7.58 (dd, J= 8.8, 2.2 Hz, IH), 7.42 (d, J= 8.2 Hz, IH), 7.25 (d, J= 16.0 Hz, IH), 6.45 (d, J= 16.0 Hz, IH), 3.78 (s, 3H). To a white suspension of this ester (0.140 g, 0.529 mmol) in MeOH (3.0 mL) was added 1.0 M sodium hydroxide (1.587 ml, 1.587 <n="105"/>mmol). The resulting suspension was stirred vigorously at rt for 2.5 h. The yellow suspension was neutralized with 1.0 N HCl (1.60 mL), and concentrated to give a beige solid. The solid was partitioned between 1.0 N HCl and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 0.137 g (100%) of (E)-3-(5-chloro-2-tetrazol-l-yl- phenyl)-acrylic acid as a white solid. LCMS m/z 251.1 (M+H)+. 1H NMR (SOO MHz, DMSO-d6) delta: 12.72 (s, IH), 9.87 (s, IH), 8.24 (d, J= 2.2 Hz, IH), 7.77 (dd, J= 8.8, 2.2 Hz, IH), 7.73 (d, J= 8.2 Hz, IH), 6.98 (d, J= 16.0 Hz, IH), 6.70 (d, J= 16.0 Hz, IH).

57%		1D. (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid methyl ester To a cooled (0 C.) suspension of NaH. (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to room temperature and stirred at room temperature for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2-tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid (1.76 g). The solid was redissolved in EtOAc and filtered through a plug of silica gel and eluted with EtOAc. The filtrate was concentrated to give a greenish solid (1.36 g). Recrystallization from EtOAc gave an off-white solid (0.476 g). Additional product was obtained by concentrating the filtrate, adding methanol, sonicating, and collecting the resulting solid by filtration. A total of 0.829 g (57%) of ID was obtained. LCMS m/z 265.1 (M+H)+; 287.2 (M+Na)+. 1H-NMR (500 MHz, CDCl3) delta: 8.80 (s, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.58 (dd, J=8.8, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.25 (d, J=16.0 Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 3.78 (s, 3H).
57%		To a cooled (0 C) suspension of NaH (0.262 g, 6.56 mmol) inTHF (27.3 mL) was added drop wise methyl 2-(dimethoxyphosphoryl)acetate (1.15 mL, 7.10 mmol). The resulting thick, white suspensionwas diluted with additional THF (15 mL) to facilitatemixing, and then the reaction was allowed to warm to rt. After45 min, a slightly cloudy blue solution of 5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)benzaldehyde39 (1.14 g, 5.46 mmol) in THF (8 mL)was added. The yellow-green suspension was stirred vigorously.After 30 min, the reaction was poured into cold sat. NH4Cl andextracted with EtOAc. The organic layers were combined andwashed with brine, dried over Na2SO4, filtered and concentratedto give a green-blue solid (1.76 g). The solid was dissolved inEtOAc and filtered through a plug of silica gel and eluted withEtOAc. The filtrate was concentrated to give a greenish solid(1.36 g). Recrystallization from EtOAc gave an off-white solid(0.476 g). Additional product was obtained by concentrating thefiltrate, adding methanol, sonicating, and collecting the resultingsolid by filtration. A total of 0.829 g (57% yield) of methyl (2E)-3-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enoate wasobtained. LCMS: 265.1 (M+H)+; 287.2 (M+Na)+. 1H NMR(500 MHz, CDCl3) d: 8.80 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.58 (dd,J = 8.8, 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 16.0 Hz,1H), 6.45 (d, J = 16.0 Hz, 1H), 3.78 (s, 3H)
57%		Intermediate 1; (E)-2,5-Dioxopyrrolidin- 1 -yl 3-(5-chloro-2-(l H-tetrazol-1 -yi)phenyl)acrylate; [00261] Intermediate IA. (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid methyl ester: To a cooled (0 C) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing. The reaction was allowed to warm to rt and stir for 45 min. Next, a solution of 5-cliloro-2-tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem. 2006, 49:1346), in THF (8 mL) was added. The resulting suspension was stirred vigorously. After 30 min, the reaction was poured into cold saturated ammonium chloride and extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated to give a green/blue solid weighing 1.76 g. The solid was dissolved in EtOAc and filtered through a plug of silica gel, eluting with EtOAc. The green filtrate was concentrated to give a greenish solid weighing 1.36 g. Recrystallization from EtOAc gave an off- white solid weighing 0.476 g. Additional product was obtained by concentrating the filtrate from the recrystallization, adding methanol, sonicating, and collecting the solid by filtration. A total of 0.829 g (57%) of Intermediate IA was obtained. 1H NMR(500 MHz, CDCl3) delta: 8.80 (s, 1H), 7.78 (d, J= 2.2 Hz, 1H)5 7.58 (dd, J= 8.8, 2.2 Hz, 1H), 7.42 (d, J= 8.2 Hz, 1H), 7.25 (d, J= 16.0 Hz, 1H), 6.45 (d, J= 16.0 Hz, 1H), 3.78 (s, 3H). MS m/z: 265.1 (M+H)+ and 287.2 (M+Na)+.
		Step 4: (E)-methyl 3-(5-chloro-2-(lH-tetrazol-l-yl)phenyl)acrylate. Methyl 2- (dimethoxyphosphoryl)acetate (1.402 ml, 9.72 mmol) was added dropwise to a stirred, 0 C suspension of sodium hydride (0.359 g, 8.97 mmol) in THF (60 mL). The reaction mixture was allowed to warm up to room temperature and the stirred for 1 hour. A solution of 5-chloro-2-(lH- tetrazol-l-yl)benzaldehyde (1.56 g, 7.48 mmol) in THF (10 mL) was then added. The mixture was stirred vigorously for 30 minutes. The mixture was poured into a cold saturated NH4C1 solution. The resulting mixture was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over MgS04, filtered and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate. The solid was collected and dried in vacuo to give (E)-methyl 3-(5-chloro-2-(lH-tetrazol-l -yl)phenyl)acrylate as an off white solid.

Reference： [1]Patent: US2016/229839,2016,A1 .Location in patent: Paragraph 0296
[2]Patent: WO2008/76805,2008,A2 .Location in patent: Page/Page column 118
[3]Patent: WO2008/157162,2008,A1 .Location in patent: Page/Page column 102-103
[4]Patent: US2010/16316,2010,A1 .Location in patent: Page/Page column 60
[5]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 2257 - 2272
[6]Journal of Medicinal Chemistry,2017,vol. 60,p. 9703 - 9723
[7]Patent: WO2009/114677,2009,A1 .Location in patent: Page/Page column 108
[8]Patent: WO2015/54087,2015,A1 .Location in patent: Page/Page column 67

25
[ 5927-18-4 ]
[ 105640-07-1 ]
[ 701232-66-8 ]

Yield	Reaction Conditions	Operation in experiment
97%		60% suspension mixed with NaH mineral oil (7.6 g, 0.19 mol) was added to <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (22.8 mL, 0.15 mol) solution dissolved in anhydrous tetrahydrofuran (655mL) under 0 ? nitrogen gas. 4-(4-hydroxyphenyl)cyclohexanone (25 g, 0.13 mol) solution dissolved in tetrahydrofuran (525 mL) was slowly added thereto at 25?. Then, the reaction mixture was stirred at room temperature for 5 hours, cooled with water, and extracted with ethyl acetate. The mixed organic phase was washed with brine and dried with Na2SO4. The solvent was reduced under reduced pressure to obtain [4-(4-hydroxyphenyl)cyclohexylidene]acetic acid methyl ester as a white solid (31.3 g, 97 %). 1H NMR (300 MHz, DMSO-d6) : delta 9. 14 (s, 1H), 7.00 (d, J = 8 Hz, 2H), 6.65 (d, J = 7.8 Hz), 5.69 (s, 1H), 3.86-3.76 (m, 1H), 3.60 (s, 3H), 2.76- 2.63 (m, 1H), 2.42- 2.24 (m, 2H), 2.07 -1.86 (m, 3 H), 1.57 -1.33 (m, 2H).
94%		a) Methyl 2-r4-(4-hvdroxyphenyl)cvclohexylidenelacetate; <strong>[5927-18-4]Trimethyl phosphonoacetate</strong> (170 mL, 1.05 mol) was added dropwise to a stirred suspension of sodium hydride (60 % in mineral oil, 27.5 g, 1.14 mol) in THF (3.5 L) cooled to 12C. After completion of addition, the reaction mixture was allowed to warm to ambient temperature and stirred for I h. In a separate vessel, N,N-tetramethyl guanidine (144 mL, 1.14 mol) was added to a suspension of 4-(4-hydroxyphenyl)cyclohexan-l-one (235 g, 0.95 mol) in THF (1.2 L) and the reaction mixture was stirred for 1 h at ambient temperature. The phosphonoacetate mixture was cooled to 100C and the guanidine solution added slowly, controlling the temperature between 8 and 120C until no residual exotherm was observed. The temperature was allowed to rise to ambient temperature and the reaction mixture was stirred for 16 h. The mixture was partitioned between a dilute aqueous solution of ammonium chloride (2.4 L) and ethyl acetate (2.4 L). The aqueous phase was separated and extracted with ethyl acetate (1.2 L). The organic phases were combined and washed with brine (2.4 L), dried (MgSO4) and concentrated in vacuo to leave an off- white solid. The solid was slurried in a mixture of ether and hexane (2:1; 470 <n="35"/>mL), filtered and washed with a mixture of ether and isohexane (2:1; 240 mL) to give the product as a white solid (285 g, 94%). 1R NMR delta 1.35 - 1.55 (2H, m), 1.85 - 2.05 (4H, m), 2.25-2.40 (2H, m), 2.65 - 2.75 (IH, m), 3.60 (3H, s), 3.80 (IH, m), 6.66 (2H, d), 6.99 (2H, d), 9.10 (IH, s)
	With sodium hydride; In tetrahydrofuran; mineral oil; at 4 - 20℃; for 18h;Inert atmosphere;	5.1 Synthesis of methyl r4-(4-hydroxyphenyl)cvclohexylidenelacetate 1.69 g of 4-(4-hydroxyphenyl)cyclohexanone (77.22 mmol, 1 eq.) are placed in 100 mL of THF in a 250 mL round-bottomed flask under nitrogen. The solution is cooled to 4C on an ice bath and 3 g of 60% sodium hydride (75.04 mmol, 0.97 eq.) are added portionwise. 16.88 g of methyl dimethylphosphoacetate (92.67 mmol, 1.2 eq.) are placed in 100 mL of THF in another 500 mL round-bottomed flask under nitrogen. This second solution is cooled on an ice bath and 4.41 g of 60% sodium hydride (1 10.30 mmol, 1 .42 eq.) are added portionwise. The ice baths are removed and the media are stirred at room temperature for 30 minutes. The 4-(4-hydroxy- phenyl)cyclohexanone solution is added to the methyl dimethylphosphoacetate solution. The reaction medium is stirred for 18 h. 100 mL of a saturated aqueous ammonium chloride solution is added and the reaction medium is extracted three times with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated to give 17.16 g of methyl [4-(4-hydroxyphenyl)cyclo- hexylidene]acetate.M+H+ = 247.

		Step A: methyl [4~( -hvdroxyphenyl)cyclohexylidene]acetate. A 2 L 4-neck round- bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of sodium hydride (60% in mineral oil, 42.5 g, 1.1 mol, 1.0 equiv) in tetrahydrofuran (500 mL). This was followed by the addition of a solution of 4-(4-hydroxyphenyl)cyclohexanone (200 g, 1.05 mol, LOO equiv) in tetrahydrofuran (1000 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. The resulting solution was assigned as solution A. Into a 5 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (63 g, 1.7 equiv, 60%) in tetrahydrofuran (1000 mL). This was followed by the addition of a solution of methyl 2- (dimethoxyphosphoryl)acetate (229.7 g 1.2 equiv) in tetrahydrofuran (1500 mL) dropwise with stirring at 0C. The resulting solution was stirred for 2 h at room temperature. To this reaction mixture was added solution A dropwise with stirring. The resulting solution was stirred for 1 h at room temperature, then quenched by the addition of water/ice. The resulting solution was extracted with 3 500 mL of ethyl acetate. The combined organic layers were washed with brine (1 L), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by recrystallization from ether to afford the title compound as a white solid.
		Methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate. Sodium hydride (60% suspension in mineral oil, 1.2 g, 30 mmol) was added to a solution of 4-(4- hydroxyphenyl)cyclohexanone (5.7 g, 30 mmol) in anhydrous THF (100 mL) at 0 C under a nitrogen atmosphere. In a separate flask, <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (5.83 mL, 36 mmol) was added to a suspension of sodium hydride (1.8 g, 45 mmol) in anhydrous THF (100 mL) at 0 C under a nitrogen atmosphere. After 30 min., the two mixtures were allowed to warm to rt and were stirred for 30 min. The solution containing the ketone was added to the phosphonate solution via cannula. The reaction mixture was stirred overnight at rt. Water (150 mL) was added, the organic layer was separated, and aqueous phase was extracted with EtOAc (2 x 120 mL). The combined organic layers were washed with brine, dried (MgS04), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (10-20% EtOAc/Hexanes) yielded the title compound as a white solid. :H NMR (DMSO-d6) delta 9.12 (s, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 5.70 (s, 1H), 3.82 (m, 1H), 3.61 (s, 3H), 2.70 (m, 1H), 2.33 (m, 2H), 2.03 (m, 1H), 1.92 (m, 2H), 1.48 (m,2H); (M+l 247.2).
		A 2 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of sodium hydride (60% in mineral oil, 42.5 g, 1.1 mol, 1.0 equiv) in tetrahydrofuran (500 mL). This was followed by the addition of a solution of 4-(4-hydroxyphenyl)cyclohexanone (200 g, 1.05 mol, 1.00 equiv) in tetrahydrofuran (1000 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. The resulting solution was assigned as solution A. Into a 5 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (63 g, 1.7 equiv, 60%) in tetrahydrofuran (1000 mL). This mixture was treated with a solution of methyl 2-(dimethoxyphosphoryl)acetate (229.7 g 1.2 equiv) in tetrahydrofuran (1500 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. To this reaction mixture was added solution A dropwise with stirring. The resulting solution was stirred for 1 h at room temperature then quenched by the addition of water/ice. The resulting solution was extracted with 3x500 mL of ethyl acetate. The combined organic layers were washed with brine (1 L), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by recrystallization from ether to afford the title compound as a white solid.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10610 - 10629
[2]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 544 - 549
[3]Patent: EP2842938,2015,A1 .Location in patent: Paragraph 0056-0058
[4]Patent: WO2008/129319,2008,A1 .Location in patent: Page/Page column 33-34
[5]Patent: WO2012/11081,2012,A1 .Location in patent: Page/Page column 29-30
[6]Patent: WO2012/122075,2012,A1 .Location in patent: Page/Page column 33
[7]Patent: WO2012/138648,2012,A1 .Location in patent: Page/Page column 75
[8]Patent: WO2013/68439,2013,A1 .Location in patent: Page/Page column 34-35
[9]Journal of labelled compounds and radiopharmaceuticals,2014,vol. 57,p. 670 - 673

26
[ 5927-18-4 ]
[ 17429-02-6 ]
[ 1108195-95-4 ]

Yield	Reaction Conditions	Operation in experiment
69%		(4-Methoxy-4 methyl-cyclohexylidene)-acetic acid methyl ester A mixture of trimethyl phosphonoacetate (9.11 mL, 56 mmol) and (40 mL, 64 mmol) of n-BuLi (1.6N) in DME (60 mL) is stirred for 10 minutes at 0 C. <strong>[17429-02-6]4-Hydroxy-4-methyl-cyclohexanon</strong>e (8 g, 56 mmol) was added and the mixture stirred 2.5 hours at 0 C. until TCL indicated complexion of the reaction. Product was obtained after extraction with dichloromethane (7.71 g, 69%).

Reference： [1]Patent: US2009/29977,2009,A1 .Location in patent: Page/Page column 44

27
[ 5927-18-4 ]
[ 845823-12-3 ]
(E)-3-(3,5-difluoro-phenyl)-4,4,4-trifluoro-but-2-enoic acid methyl ester [ No CAS ]
(Z)-3-(3,5-difluoro-phenyl)-4,4,4-trifluoro-but-2-enoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1,3,3-tetramethylguanidine; In dichloromethane; at 0 - 20℃; for 22h;	1-(3,5-Difluorophenyl)-2,2,2-trifluoroethanone (1.0 g, 4.8 mmol) was added to CH2Cl2 (5 mL). Trimethylphosphonoacetate (0.87 g, 4.8 mmol) was added and the mixture was cooled to 0 C. Tetramethylguanidine (0.72 mL, 5.7 mmol) was added dropwise by syringe. The mixture was allowed to attain room temperature slowly and was stirred 22 hours. The reaction mixture was poured into a separatory funnel containing CH2Cl2 (40 mL). The organic phase was washed with distilled water (3*), brine, and then dried over Na2SO4. The solution was filtered and the solvents concentrated to a crude oil, which was flash chromatographed using CH2Cl2 as eluent. This gave the desired product as a yellow oil (1.13 g, 89%; mixture of E/Z isomers).

Reference： [1]Patent: US2009/23801,2009,A1 .Location in patent: Page/Page column 25

28
[ 5927-18-4 ]
[ 386704-12-7 ]
[ 1119807-17-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 24h;	26A. (E)-Methyl 3-(6-(trifluoromethyl)pyridin-3-yl)acrylate To a stirring solution of trimethyl phosphonoacetate (0.510 mL, 3.14 mmol) in THF (15 mL) at 0 C. was added NaH (88.0 mg, 3.3 mmol). After stirring for ca. 20 min, the slurry was allowed to warm to ambient temperature for 10 min, then cooled again to 0 C. To this was added dropwise 6-(trifluoro-methyl)nicotinaldehyde (500 mg, 2.86 mmol), which is commercially available from Oakwood Products, Inc. (1741 Old Dunbar Rd., West Columbia, S.C. 29172), in THF (5 mL) over 2 min. The bath was allowed to expire and the reaction stirred at ambient temperature for ca. 24 h. The reaction was quenched with H2O (50 mL) then diluted with EtOAc (100 mL). The phases were separated and the organics further washed with H2O (2×20 mL), brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 670 mg 26A in ca. 85% purity as a white solid (86% yield). This was taken forward without further purification. m/z (ES+) M+1=232. 1; HPLC tR=1.07 min. 1H NMR (500 MHz, CDCl3) delta 8.84 (dd, J=2.1, 0.6 Hz, 1H), 7.99 (dt, J=8.2, 1.2 Hz, 1H), 7.77-7.65 (m, 2H), 6.59 (d, J=16.2 Hz, 1H), 3.85 (s, 3H).

Reference： [1]Patent: US2009/76020,2009,A1 .Location in patent: Page/Page column 41

29
[ 5927-18-4 ]
[ 865-47-4 ]
[ 62327-21-3 ]

Yield	Reaction Conditions	Operation in experiment
	In 2-MeTHF; at 5 - 20℃;	Intermediate 64-8: Methyl 2-fn r.4rWU4-f4A5.5-tetramethyl-T .3.2-rtioxahorolan-2- vDnhenylkvclohexyDacetateTrimethylphosphonoacetate (1.05X-1.06X) was added dropwise to a suspended solution of t-BuOK (0.70X-0.71X) in 2-MeTHF (10 vol) at 5-1O0C. The resulting solution was stirred at 15-2O0C for 3.5-4.0 hours. The reaction mixture was cooled to 5-1O0C and DIPEA (0.81-0.82X) was added to the reaction at 10-150C. 4-(4-Hydroxyphenyl)cyclohexanone (1.0 X) was added in portions to the above reaction mixture at 10-150C and the resulting solution was stirred at 15-2O0C for 3-6 hours and then sampled for HPLC analysis. NH4C1- sol (5.0X-6.0X) was added to the reaction mixture at 0-150C, and the reaction was quenched. The organic layer was separated and the aqueous layer was extracted with 2- MeTHF (2.5X-3.0X). The two organic extracts were combined and washed with NaHSO3 aq. and then NaCl-solution (2.5X-3.0X) twice. The organic layer was concentrated to 2~3 vol and n-heptane was added to give a suspended solution, and the above mixture was <n="163"/>concentrated to below 3percent of 2-MeTHF residue to give a suspended solution. The mixture was cooled to 0-5 0C, stirred for 1.0-2.0 h, filtered and the cake washed with n-heptane (2 vol X2). Dry in vacuum at below 450C to give the desired phenoxyacrylate product.

Reference： [1]Patent: WO2009/81195,2009,A1 .Location in patent: Page/Page column 29; 161-162

30
[ 111-71-7 ]
[ 5927-18-4 ]
[ 111-79-5 ]

Reference： [1]European Journal of Organic Chemistry,2009,p. 554 - 563

31
[ 5927-18-4 ]
[ 14615-72-6 ]
[ 64793-98-2 ]

Reference： [1]Chemistry - A European Journal,2009,vol. 15,p. 2278 - 2288

32
[ 5927-18-4 ]
[ 22515-18-0 ]
[ 1189770-25-9 ]

Yield	Reaction Conditions	Operation in experiment
95%		400 mg (10.0 mmol) sodium hydride (60 % in mineral oil) was suspended in 10 ml THF and cooled to 4C. While being stirred, a solution of 1.3 ml (8.99 mmol) trimethylphosphono acetate in 10 ml THF was added. The mixture was stirred for 1 h at the same temperature. After this, a solution of 4,4-difluorocyclohexanone in 10 ml THF was added at 00C. The mixture was allowed to warm to room temperature and stirred for 14 h. THF and water was added and the THF evaporated. The remainder was diluted with ethyl acetate, washed with water and saturated sodium hydrogen carbonate solution and evaporated to yield 1.49 g (95 %) of the product. <n="152"/>MS (El): m/z = 190 (M)
57%		To a stirred suspension of 60% NaH (0.4 g, 10 mmol) in THF (10 mL), methyl 2-(dimethoxyphosphoryl)acetate (1.3 mL, 9 mmol) in 10 mL THF was added at 0C and stirred for lh at 0-5 0C. 4,4-difluorocyclohexanone 67 (1 g, 7.5 mmol) in 10 mL THF was then added slowly at 0C and allowed to stir at room temperature for about 1 5h. The reaction mixture was diluted with 20 mL THF and 50 mL ice-water, THF layer was separated and concentrated, residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), saturated NaHCO3 solution (10 mL) and dried over Na2SO4 andconcentrated under reduced ?pressure to obtain methyl 2-(4,4-difluorocyclohexylidene)acetate 68 as light brown liquid (0.8 g, 57% yield). ?HNMR (400 MHz, CDC13): oe 5.73 (s, 1H), 3.70 (s, 3H), 3.04 (t, 2H), 2.41 (t, 2H), 2.09-1.97 (m, 4H).
		Example 1F 400 mg (10.0 mmol) NaH suspended in 30 mL THF were cooled to 5 C. and 1.30 mL (9.00 mmol) methyl-2-(dimethoxyphosphoryl)acetate were added. The reaction mixture was stirred for 1 h at this temperature. 1.00 g (7.50 mmol) 4,4-difluorocyclohexanone was added to the mixture. The reaction mixture was warmed to room temperature and stirred over night at ambient temperature. The mixture was hydrolysed with water and THF and concentrated under reduced pressure. The product was obtained as an oil.

Reference： [1]Patent: WO2009/121919,2009,A1 .Location in patent: Page/Page column 149-150
[2]Patent: WO2015/25197,2015,A1 .Location in patent: Paragraph 000141
[3]Patent: US2012/115863,2012,A1 .Location in patent: Page/Page column 39

33
[ 5927-18-4 ]
[ 99-61-6 ]
[ 659-04-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium methylate; In N,N-dimethyl-formamide;	Step 95a: (E)-Methyl 3-(3-(chlorosulfonyl)phenyl)acrylate (1006-218)To a solution of 3-nitro-benzaldehyde (15 g, 0.1 mol), (dimethoxy- phosphoryl)-acetic acid methyl ester (27 g, 0.148 mol) in DMF (100 ml) was added NaOMe (10.7 g 0.198 mol). The reaction was mornitored by TLC. After reaction was completed, the reaction mixture was adjusted to pH = 1 with aquous HCl solution and evaporated. The resulting solid was washed with water to afford (E)-methyl 3-(3-nitrophenyl)acrylate as a yellow solid (20.14 g, 98%).
98%	With sodium methylate; In N,N-dimethyl-formamide;	Step 95a: (E)-Methyl 3-(3-(chlorosulfonyl)phenyl)acrylate (1006-218)[0624]To a solution of 3-nitro-benzaldehyde (15 g, 0.1 mol), (dimethoxy-phosphoryl)-acetic acid methyl ester (27 g, 0.148 mol) in DMF (100 ml) was added NaOMe (10.7 g 0.198 mol). The reaction was monitored by TLC. After reaction was completed, the reaction mixture was adjusted to pH=1 with aqueous HCl solution and evaporated. The resulting solid was washed with water to afford (E)-methyl 3-(3-nitrophenyl)acrylate as a yellow solid (20.14 g, 98%).
85 g	With potassium carbonate; In water; at 20℃; for 1h;	To a mixture of compound 115 (82.4 g, 452 mmol) and K2CO3 (96 g, 696 mmol) in H20 (160 mL) was added compound 114 (52.4 g, 348 mmol). The reaction was stirred at room temperature for 1 hour. Then the solution was filtered and the filter cake was washed with 1 N HCl and water, and the solid was concentrated to give compound 116 (85 g, crude) as a white solid. The product was used directly in the next step without further purification. (0943) NMR: H20619-001-1Q1 (DMSO- 6, 400 MHz) delta 8.56 (s, 1 H), 8.25-8.19 (m, 2 H), 7.80 (d, J=16 Hz, 1 H), 7.71 (t, J=8 Hz, 1 H), 6.86 (d, J=16 Hz, 1 H), 3.75 (s, 3 H).

183.5 g

A mixture of methanol (450 ml), 3-nitrobenzaldehyde (150 gms) and methyl-2- (dimethoxyphosphoryl)acetate (234.9 gms) was stirred for 10 minutes at 25-30C. Cooled the reaction mixture to 15-20C. Triethyl amine (276 ml) was slowly added to the reaction mixture at 15-20C. Heated the reaction mixture to 60-65C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 25-30C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 183.5 gms; M.R: 120-127C.

Reference： [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 238
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0623; 0624
[3]Synthetic Communications,2010,vol. 40,p. 2520 - 2524
[4]Patent: WO2015/138969,2015,A1 .Location in patent: Page/Page column 120
[5]Patent: WO2018/29699,2018,A1 .Location in patent: Page/Page column 14

34
[ 5927-18-4 ]
[ 81172-89-6 ]
[ 7560-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; lithium bromide; In tetrahydrofuran; at 5 - 25℃;	Intermediate 29; Methyl (2£)-3-(4-formylphenyl)acrylateLithium bromide (159g, 2.5eq) was dissolved in THF (2L) and cooled to <;5C. Trimethyl phosphonoacetate (1.3eq, 138mL) then triethylamine (204mL, 2eq) were charged at <;10C. 4-Diethoxybenzaldehyde (152.8g, 1eq) was charged over25mins and the reaction allowed to warm to 20 +/- 5C, then the cooling was removed. After 1 h 40min, the reaction was quenched with water, separated, and the aqueous layer extracted with EtOAc. The combined organic phases were washed three times with brine then concentrated to dryness in vacuo. Methanol (0.5L) was charged to the residue and again concentrated to dryness. Methanol (0.75L) and 1 N HCI (0.75L) were charged to the residue and stirred at ambient temperature for 45 min. Water (0.75L) was charged and the product isolated by filtration (128.5g). 1H NMR (30OMHz1CDCI3) delta(ppm): 10.06 (1 H, s), 7.93 (2H, d), 7.71 (3H, m), 6.58 (1 H, d), 3.85 (3H, s).

Reference： [1]Patent: WO2010/97586,2010,A1 .Location in patent: Page/Page column 45

35
[ 5927-18-4 ]
[ 1243634-45-8 ]
[ 1243634-46-9 ]

Yield	Reaction Conditions	Operation in experiment
95%		[00207] In a 50 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed trimethylphosphonoacetate (2.11 g, 11.60 mmol) in anhydrous acetonitrile (20 mL) under argon. To this solution 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (1.76 g, 11.60 mmol) was added at room temperature and stirred for 15 minutes. At this time, a solution of (4) (1.89 g, 5.80 mmol) in dry acetonitrile (20 mL) was added to the above reaction mixture via cannula and monitored for completion by checking TLC (typically 2 hours). At this time the reaction mixture was quenched by addition of water (80 mL), the phases were separated, and the aqueous phase was extracted with EtOAc (4 x 60 mL). Combined organic phases were washed with brine (2 x 100 mL), dried (MgS04), and concentrated. Chromatography (80% EtOAc-hexanes) afforded 2.10 g (95%) of a colorless oil. IR (film) 3440,1720,1660 cm"1; [oc]20D +34.95 (c 1.07, CHC13); 1H NMR (CDC13) delta 1.31 (s, 3H), 1.57 (m, 1H), 1.74 (m, 2H), 1.84 (m, 1H), 2.30 (m, 1H), 2.39 (s, 3H), 3.49 (m, 1H), 3.71 (s, 3H), 3.94 (m, 4H), 4.07 (d, J= 8.0 Hz, 1H), 5.80 (td, J= 1.6 Hz, J= 15.2 Hz, 1H), 6.80 (td, J= 7.2 Hz, J= 15.6 Hz, 1H), 7.27 (bd, J- 8.0 Hz, 2H), 7.56 (td, J= 2.0 Hz, J= 8.4 Hz, 2H); 13C NMR (CDC13) delta 21.2, 23.8, 29.7, 35.0, 39.0, 51.4, 53.2, 64.5, 64.6, 109.6, 123.9, 125.5, 129.4, 141.2, 141.9, 144.2, 166.4; HRMS calcd for C19H28N05S (M+H) 382.1683. Found 382.1695.

Reference： [1]Organic Letters,2010,vol. 12,p. 4118 - 4121
[2]Journal of Organic Chemistry,2012,vol. 77,p. 2345 - 2359
[3]Patent: WO2012/9263,2012,A1 .Location in patent: Page/Page column 77

36
[ 5927-18-4 ]
[ 100-06-1 ]
[ 99142-77-5 ]

Yield	Reaction Conditions	Operation in experiment
83%		NaH (0.37 g, 60% dispersion in oil, 9.19 mmol) was suspended in anhydrous hexane (10 mL), stirred under a nitrogen atmosphere for 10 minutes, and the solvent was removed. THF (4 mL) was added to oil-free NaH and cooled to 0. Trimethylphosphonoacetates (1.55 ml, 9.59 mmol) were dipped and the reaction mixture was stirred for 30 minutes. 4- methoxy acetophenone (compound 15) (1.20 g, 7.99 mmol) solution among the drying THF (5 mL) was dipped to the reaction mixture and the mixture was heated at the room temperature and it was stirred for 14 hours. The saturation NH 4 Cl aqueous solution was gradually added after the completion of reaction and it extracted in the EtOAc (2 × 40 mL). It dried to the anhydrous Na 2 SO 4 and the mixed organic solvent layer was the vacuum concentration to the saline solution (25 mL), and the purified water (25 mL) after doing washing. The crude product was refined to the column chromatography (EtOAc/Hexane=1/20) and pure products (1.37 g, 83%) of the oil phase were obtained.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 50 - 53
[2]Patent: KR101799305,2017,B1 .Location in patent: Paragraph 0106; 0107
[3]Journal of Organic Chemistry,2010,vol. 75,p. 8319 - 8321
[4]Organic Letters,2016,vol. 18,p. 4451 - 4453
[5]Chinese Journal of Chemistry,2017,vol. 35,p. 397 - 400
[6]Chemical Communications,2017,vol. 53,p. 9258 - 9261

37
[ 5927-18-4 ]
[ 60032-63-5 ]
methyl 4-hydroxy-3-iodocinnamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; In methanol; at 70℃; for 24h;	Na (5.0 mmol) was dissolved in dry MeOH (7 ml) and to the resulting solution methyl trimethylphosphonacetate (3.0 mmol) and a solution of the aldehyde (1.0 mmol) in dry MeOH (1 ml) were added in sequence. The resulting mixture was allowed to react for 24 h at 70 C. The solution was then acidified with HCl (aq) 10%, and extracted with Et2O (3 x 10 ml). The combined organic phases were dried over Na2SO4 and evaporated to dryness yielding the desired product that was used for the next reaction without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 769 - 772

38
[ 5927-18-4 ]
[ 156866-52-3 ]
3-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-acrylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		To a solution of trimethyl phosphino acetate (4.64 mL, 23.5 mmol) in dry DMF (20 mL) was added potassium tert-butoxide (2.14 g, 19.13 mmol) at 0° C. and the mixture was stirred at same temperature over a period of 15 min.To the above mixture a solution of <strong>[156866-52-3](4-Formyl-benzyl)-carbamic acid tert-butyl ester</strong> (3.0 g, 12.75 mmol) in DMF (10 mL) was added drop wise at ice temperature.The reaction mixture was stirred at ice temperature over a period of 45 min.The resulting reaction mixture diluted with ethyl acetate, washed with water, brine and dried over sodium sulfate.The residue obtained upon evaporation of volatiles was purified by column chromatography to give 3-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-acrylic acid methyl ester as colourless solid (1.5 g, 40percent).

Reference： [1]Patent: US2012/101099,2012,A1 .Location in patent: Page/Page column 18-20

39
[ 5927-18-4 ]
[ 35344-95-7 ]
[ 1295583-21-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃;	(E)-methyl 3-(l -methyl- lH-pyrazol-4-yl)acrylateCs2C03 (1.304g, 4 mmol) was added to a solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100°C overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3 -(1 -methyl- lH-pyrazol-4- yl)acrylate (0.278 g). ES+ (M+H)+ 167
0.278 g	With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃;	Cs2CO3 (1.304 g, 4 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364 g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100° C. overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3-(1-methyl-1H-pyrazol-4-yl)acrylate (0.278 g). ES+(M+H)+167

Reference： [1]Patent: WO2012/118782,2012,A1 .Location in patent: Page/Page column 74-75
[2]Patent: US2013/317003,2013,A1 .Location in patent: Paragraph 0429

40
[ 790667-49-1 ]
[ 5927-18-4 ]
[ 1338821-09-2 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2. Synthesis of tert-butyl (2S,4E)- and tert-butyl (2S,4Z)-4-(2-methoxy-2-oxoethylidene)-2-methylpiperidine-1-carboxylate (C20) Sodium hydride (60% in mineral oil, 1.35 g, 33.6 mmol) was washed with hexanes (25 mL), suspended in N,N-dimethylformamide (40 mL) and cooled to 0 C. Methyl (dimethoxyphosphoryl)acetate (4.66 mL, 32.3 mmol) was added to the reaction in a drop-wise manner, and the mixture was held at 0 C. with vigorous stirring for 20 minutes. A solution of <strong>[790667-49-1]ter<strong>[790667-49-1]t-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate</strong></strong> (C19) (5.52 g from the previous experiment, ?24.3 mmol) in N,N-dimethylformamide (10 mL) was added drop-wise, and the resulting solution was allowed to warm to room temperature over 16 hours. The reaction was then diluted with diethyl ether (400 mL) and washed with water (300 mL). The aqueous layer was extracted with diethyl ether (200 mL) and the combined organic layers were washed with water (4200 mL) and saturated aqueous sodium chloride solution (200 mL), then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was obtained as a colorless oil, composed of a roughly 1:1 mixture of olefin isomers. Yield: 6.63 g, 24.6 mmol, quantitative. 1H NMR (400 MHz, CDCl3) delta 5.83 and 5.72 (2 br s, 1H), 4.44-4.61 (m, 1H), 3.98-4.14 (m, 1H), 3.71 and 3.70 (2 s, 3H), 3.58-3.70 (m, 1H), 2.93-3.03 (m, 1H), 2.06-2.11, 2.18-2.33 and 2.53-2.59 (multiplets, total 3H), 1.47 (2 s, 9H), 1.08 (d, J=6.7 Hz) and 1.07 (d, J=6.9 Hz, total 3H).

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256
[2]Patent: US2013/150376,2013,A1 .Location in patent: Paragraph 0271

41
[ 5927-18-4 ]
N-acetoxymethyl-N-(N-fluorenylmethyloxycarbonyl-L-leucyl)-4-oxo-L-homoalanine methyl ester [ No CAS ]
dimethyl N-acetoxymethyl-N-(N-fluorenylmethyloxycarbonyl-L-leucyl)-N-acetoxymethyl-4,5-dehydro-L-homoglutamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		[0103] Dimethyl N-Acetoxymethyl-N-(N-fluorenylmethyloxycarbonyl-L-leucyl)-N-acetoxymethyl-4,5-dehydro-L-homoglutamate(60). A suspension of sodium hydride (60 % in mineral oil, 6 mg, 0.15 mmol) in dry THF (1.5 mL) was cooledto -10 C and a solution of methyl 2-(dimethoxyphosphoryl)acetate (27 mg, 0.15 mmol) in dry THF (1 mL) was addeddropwise. The mixture was stirred for 45 minutes, and then a solution of the aldehyde (41) (54 mg, 0.10 mmol) in dryTHF (1 mL) was slowly added, while the temperature was mantained at -10 C for 35 minutes. The reaction mixture waspoured into water and extracted with diethyl ether. The organic layer was dried, filtered and evaporated as usual, andthe residue was purified by rotatory chromatography (hexane/EtOAc, 80:20), affording the olefin (60) (49 mg, 82%) asa yellowish slurry: [alpha]D = -22.30 (c 0.38, CHCl3); IR (CHCl3) vmax. 3431, 1745, 1721, 1674, 1511 cm-1; 1H NMR (500MHz, CDCl3, 26 C) deltaH 0.94 (3H, d, J = 6.7 Hz, Me), 0.98 (3H, d, J = 6.6 Hz, Me), 1.42-1.56 (2H, m, 3?-H2), 1.70 (1 H,m, 4?-H), 2.10 (3H, s, Ac), 2.92 (2H, dd, J = 7.3, 7.4 Hz, 3-H2), 3.67 (3H, s, OMe), 3.68 (3H, s, OMe), 4.21 (1 H, dd, J =7.2, 7.2 Hz, CHFmoc), 4.34 (1 H, dd, J = 7.0, 10.6 Hz, OCHa-fluorenyl), 4.40 (1 H, dd, J = 7.4, 10.6 Hz, OCHb-fluorenyl),4.55 (1 H, dd, J = 7.0, 8.3 Hz, 2-H), 4.83 (1 H, ddd, J = 4.2, 9.1, 9.4 Hz, 2?-H), 5.34 (1 H, d, J = 9.1 Hz, NH), 5.43 (1 H, d, J = 12.4 Hz, NCHaO), 5.55 (1 H, d, J = 12.4 Hz, NCHbO), 5.85 (1 H, d, J = 15.6 Hz, 5-H), 6.80 (1 H, ddd, J = 7.6, 8.1,15.6 Hz, 4-H), 7.30 (2H, dd, J = 7.5, 7.5 Hz, Ar), 7.39 (2H, dd, J = 7.4, 7.5 Hz, Ar), 7.58 (1 H, d, J = 7.5 Hz, Ar), 7.75 (1H, d, J = 7.6 Hz, Ar); 13C NMR (125.7 MHz, CDCl3, 26 C) deltaC 20.6 (CH3), 21.6 (CH3), 23.2 (CH3), 24.7 (CH), 31.6 (CH2),42.9 (CH2), 47.2 (CH), 49.9 (CH), 51.4 (CH3), 52.6 (CH3), 59.6 (CH), 67.1 (CH2), 71.7 (CH2), 120.0 (2 x CH), 124.0(CH), 125.1 (2 x CH), 127.0 (2 x CH), 127.7 (2 x CH), 141.3 (2 x C), 143.8 (CH), 143.9 (2 x C), 156.5 (C), 166.3 (C),169.9 (C), 170.5 (C), 174.9 (C); MS (EI) m/z (relative intensity) 594 (M+, <1), 339 (M+ - fluorenylmethyl -OCO - HOMe,<1), 308 ([Fmoc-NH-CHCH2CHMe2]+, 3), 279 ([Fmoc-NH-CHCO]+, 3), 200 ([CH2=NH-CH(CO2Me)CH2CH=CHCO2Me+ H]+, 6), 179 ([fluorenyl-CH2]+, 60), 178 ([fluorenyl-CH2 - H]+, 100), 165 ([fluorenyl]+, 25); HRMS calcd for C32H38N2O9,594.2577, found 594.2573; calculated for C16H23N2O6, 339.1556, found 339.1564; calculated for C20H22NO2, 308.1651,found 308.1647; calculated for C14H11, 179.0861, found 179.0857; calculated for C14H10, 178.0783, found 178.0790;calculated for C13H9, 165.0704, found 165.0707. Elemental analysis: Calculated for C32H38N2O9: C, 64.63; H, 6.44; N,4.71; found C, 64.75; H, 6.68; N, 4.88.

Reference： [1]Organic Letters,2013,vol. 15,p. 5778 - 5781
[2]Journal of Organic Chemistry,2015,vol. 80,p. 9379 - 9391
[3]Patent: EP2957555,2015,A1 .Location in patent: Paragraph 0098; 0103

42
[ 5927-18-4 ]
[ 43192-33-2 ]
[ 1528736-48-2 ]

Yield	Reaction Conditions	Operation in experiment
56%		General procedure: To a suspension of potassium tert-butoxide (7.83g, 70mmol, 3.0equiv) in THF (300mL) at 0C was added trimethyl phosphonoacetate (10.6g, 58mmol, 2.5equiv). The resulting clear yellow solution was stirred for 15min at 0C, then a solution of (4-bromo-2-methoxy)benzaldehyde (31b; 5.00g, 23mmol) in THF (20mL) was added dropwise. The resulting mixture was warmed from 0C to room temperature over 16h. The solvent was removed under vacuum, then the crude mixture was diluted with water (50mL) and extracted with EtOAc (2×100mL). The combined organic extracts were washed with water (1×50mL), brine (1×50mL), dried (MgSO4), filtered, and concentrated to provide a dark residue. The residue was purified by flash chromatography using 5% EtOAc in hexanes to obtain 3.53g (56%) of product as a white solid: Rf 0.19 (5% EtOAc/hexane; 1H NMR (CDCl3) delta 8.02 (d, 1H), 7.47 (dd, 1H), 7.26-7.22 (m, 1H), 6.93 (t, 1H), 6.84 (d, 1H), 6.62 (d, 1H), 6.2 (s, 1H), 3.83 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 419 - 434

43
[ 5927-18-4 ]
[ 82257-15-6 ]
[ 1528736-54-0 ]

Yield	Reaction Conditions	Operation in experiment
65%		To a suspension of potassium t-butoxide (819 mg, 7.3 mmol, 2.5 equiv) in THF (20 mL) at 0 C was added trimethyl phosphonoacetate (1.30 g, 7.3 mmol, 2.5 equiv). The clear yellow solution was stirred for 10 minutes at 0 C, then <strong>[82257-15-6]4-methoxynicotinaldehyde</strong> (400 mg, 2.92 mmol) was added over 5 min. The resulting suspension was allowed to warm to room temperature over 1.5 h.. The mixture was then diluted with water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated to yield a crude solid that was purified by flash chromatography (1:1 hexanes:EtOAc). Product-containing fractions were combined, evaporated and dried under high vacuum to yield 368 mg (65%) of product as a pale yellow oil: Rf 0.33 (1:1 hexane:EtOAc); 1H NMR (CDCl3) delta 8.58 (s, 1H), 8.46 (d, 1H), 7.81 (d, 1H), 6.85 (d, 1H), 6.60 (d, 1H), 3.96 (s, 3H), 3.82 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 419 - 434

44
[ 5927-18-4 ]
[ 53581-86-5 ]
methyl 3-(4-chloro-2-methoxyphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a suspension of potassium tert-butoxide (7.83g, 70mmol, 3.0equiv) in THF (300mL) at 0C was added trimethyl phosphonoacetate (10.6g, 58mmol, 2.5equiv). The resulting clear yellow solution was stirred for 15min at 0C, then a solution of (4-bromo-2-methoxy)benzaldehyde (31b; 5.00g, 23mmol) in THF (20mL) was added dropwise. The resulting mixture was warmed from 0C to room temperature over 16h. The solvent was removed under vacuum, then the crude mixture was diluted with water (50mL) and extracted with EtOAc (2×100mL). The combined organic extracts were washed with water (1×50mL), brine (1×50mL), dried (MgSO4), filtered, and concentrated to provide a dark residue. The residue was purified by flash chromatography using 5% EtOAc in hexanes to obtain 3.53g (56%) of product as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 419 - 434

45
[ 5927-18-4 ]
[ 3453-33-6 ]
[ 744241-46-1 ]

Yield	Reaction Conditions	Operation in experiment
92%		To the Trimethyl phosphonoacetate (55.6 mL, 381 mmol) in 250 mL anhydrous CH2Cl2 cooled to 0 C. was added DBU (48.8 mL, 322 mmol) and the mixture was stirred for 15 min. Aldehyde 59 (40.0 g, 215 mmol) in 50 mL CH2Cl2 was added dropwise. The temperature of the reaction mixture brought to rt and resulting reaction mixture was stirred at rt for 16 h, and then quenched with 100 mL of Water. The mixture was partitioned, and the aq. layer was extracted with CH2Cl2 (3×150 mL). The combined organics were washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel column chromatography (10:1 hexanes/ethyl acetate) to give the desired trans-alpha,beta-unsaturated ester 62 (48.0 g, 92%) as a white solid.

Reference： [1]Patent: US2014/171447,2014,A1 .Location in patent: Paragraph 0321; 0323

46
[ 20098-14-0 ]
[ 5927-18-4 ]
[ 110511-31-4 ]

Yield	Reaction Conditions	Operation in experiment
90%		To a solution of trimethyl phosponoacetate 21 (699.58 mg, 3.842 mmol) in anhydrous tetrahydrofuran (15 mL) 60% suspension in minral oil of sodium hydride (200 mg, 4.802 mmol) was added at 0 C under nitrogen atmosphere and stirred for 1 h at the same temperature. Added solution of 5-hydroxy-2-adamantanone 20 (500 mg, 3.201 mmol) in tetrahydrofuran (5 mL) slowly at room temperature. The reaction mixture was stirred for 5 h, quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to provide (5-hydroxy-adamantan-2-ylidene)acetic acid methyl ester 22 (641 mg, 90%). 1H NMR (300 MHz, DMSO-d6): delta 5.60 (s, 1H), 4.53 (s, 1H), 3.58 (s, 3H), 2.67-2.54 (m, 1H), 2.16-2.08 (m, 1H), 1.80-1.52 (m, 11H); LC-MS (m/z): 223 [M+H]+.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 101,p. 716 - 735

47
[ 5927-18-4 ]
[ 1550-35-2 ]
[ 186758-21-4 ]

Yield	Reaction Conditions	Operation in experiment
99%		(E)-Methyl 3-(2,4-difluorophenyl)acrylateTo a solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (1.425 mL, 8.80 mmol) in THF (30 mL) was added KOtBu (0.987 g, 8.80 mmol) and stirred at RT for 10 min before was added 2,4-difluorobenzaldehyde (0.875 mL, 8 mmol) in THF (5 mL). The resulting reaction mixture was stirred at RT for 160 min. To the reaction mixture was added more <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (0.648 mL, 4.00 mmol) then KOtBu (0.449 g, 4.00 mmol). The resulting reaction mixture was stirred at RT for 30 min. To the reaction mixture was added H20 (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over MgS04, filtered, evaporated down under vacuum to afford desired intermediate (E)-methyl 3-(2,4-difluorophenyl)acrylate (1.5710 g, 7.93 mmol, 99 % yield). LC-MS m/z 199.1 (M+H)+, 0.94 min (ret. time).
86%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 5.5h;	Step1 To a stirred solution of methyl (dimethoxyphosphoryl) acetate (12.8 mL, 77.46 mmol, 1.1 eq) in THF (70.0 mL)) was added KOtBu (8.69 g, 77.46 mmol, 1.1 eq) at RT and the reaction mixture was stirred for 10 min. Then 2,4-difluorobenzaldehyde (10.0 g, 70.42 mmol, 1.0 eq) in THF (20 mL) was added drop wise stirred at RT for 2 h. Methyl (dimethoxyphosphoryl) acetate (5.8 mL, 35.21 mmol, 0.5) and KOtBu (3.95 g, 35.21 mmol, and 0.5 eq) was added as lot-2 and stirred for 30 minutes. After 3 h, reaction mixture was diluted with water (200 mL) extracted with EtOAc (2*100 mL), organic layer was dried over anhydrous Na2SO4, and evaporated under reduced pressure gave crude compound, which was purified by column chromatography on silica gel (100-200 mesh) using EtOAc/pet ether (1:9) as eluent to get (E)-methyl 3-(2,4-difluorophenyl)acrylate (12.0 g, 86%) as a white solid. TLC system: EtOAc: Pet ether (1:9), Rf: 0.5.

Reference： [1]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 566
[2]Patent: WO2016/202253,2016,A1 .Location in patent: Page/Page column 314; 315
[3]Patent: US2018/78541,2018,A1 .Location in patent: Paragraph 0377; 0379

48
[ 499770-67-1 ]
[ 5927-18-4 ]
methyl (2E)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)prop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere;	(E)-3-(1 -Methyl-1 H-benzotriazol-5-yl)-acrylic acid methyl esterA stirred solution of t-BuOK (2.10 g, 18.6 mmol) in THF (100 ml_) at 0 C under N2was treated with trimethyl phosphonoacetate (4.30 g, 23.3 mmol). After 30 mins, 1- methyl-1 H-1 ,2,3-benzotriazole-5-carbaldehyde (2.50 g, 15.5 mmol) was added slowly in portions. After 1 h, the mixture was treated with NH4CI (aq., sat.), diluted with water and then extracted with n-heptane (x3), resulting in a precipitate which was isolated by filtration. The combined organic layers were washed with water and brine, dried over MgS04, filtered and concentrated to dryness, giving a beige solid which was washed with toluene and dried under vacuum. This material was combined with the precipitate above to give the product as a beige solid (3.1 g, 92%). LCMS (M+H)+218, RT 1.12 min.
92%		Intermediate 2 (E)-3-(1 -Methyl-1 H-benzotriazol-5-yl)-acrylic acid methyl ester A stirred solution of t-BuOK (2.10 g, 18.6 mmol) in THF (100 ml) at 0C under N2 was treated with trimethyl phosphonoacetate (4.30 g, 23.3 mmol). After 30 mins, 1 -methyl-1 H-1 ,2,3- benzotriazole-5-carbaldehyde (2.50 g, 15.5 mmol) was added slowly in portions. After 1 hour, the mixture was treated with NH4CI (aq., sat.), diluted with water and then extracted with n- heptane (x3), resulting in a precipitate which was isolated by filtration. The combined organic layers were washed with water and brine, dried over MgS04, filtered and concentrated to dryness, giving a beige solid which was washed with toluene and dried under vacuum. This material was combined with the precipitate above to give the product as a beige solid (3.1 g, 92%). LC-MS m/z 218 (M+H)+ 1 .12 min (ret. time).

Reference： [1]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 135; 278; 328; 329
[2]Patent: WO2016/203400,2016,A1 .Location in patent: Page/Page column 44; 45
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 3991 - 4006

49
[ 5927-18-4 ]
[ 711-33-1 ]
3-(4-trifluoromethylphenyl)pent-2-enoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		Example 21 Preparation of Compound AA [3-(4-Trifluoromethylphenyl)-pentanamide] To a chilled (0 C.) solution of lithium bis(trimethylsilyl)amide (1.0 M, 50 mL) was dropwise added a solution of trimethylphosphonoacetate, keeping the temperature below 10 C. The solution was then allowed to warm to room temperature and stirred for an additional five minutes, after which a solution of <strong>[711-33-1]4'-(trifluoromethyl)propiophenone</strong> in THF (25 mL) was added in one portion. The solution was slowly heated to 50 C. for eight hours. The solution was cooled to room temperature, then diluted with a 10% NH4Cl solution (100 mL), and extracted with ethyl acetate (2*100 mL). The organic layers were combined and dried over MgSO4, filtered, and the filtrate concentrated to a white solid which was recrystallized from hexane/ethyl acetate to give 5.42 grams of 3-(4-trifluoromethylphenyl)pent-2-enoic acid methyl ester intermediate (85% yield).

Reference： [1]Patent: US9206143,2015,B2 .Location in patent: Page/Page column 26

50
[ 5927-18-4 ]
[ 52010-98-7 ]
C₁₁H₁₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride; In acetonitrile; at 0 - 20℃; for 17.33h;	Lithium chloride (1.1906 g, 1.56 eq.) in acetonitrile (20 mL) solution of 3-hydroxy-methyl-benzaldehyde (2.4528 g) in acetonitrile (10 mL) , phosphonoacetic acid trimethyl (5.1150g, 1.56 eq.) in acetonitrile (10 mL) was mixed at room temperature, the resulting mixed solution, 0 C. with DBU (1,8-diazabicyclo [5.4.0] -7-undecene) (4.2682g, 1.56 eq) in acetonitrile (10 mL ) solution was added over a period of 2 minutes, 20 minutes at 0 C, and the mixture was stirred at room temperature for 17 hours. Was added water (50 mL), extracted with ethyl acetate (250 mL), the organic layer was washed with brine (100 mL), dried over magnesium sulfate. The residue obtained by distilling off the solvent, column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (2.5720 g, 74%, colorless oil)
74%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride; In acetonitrile; at 0 - 20℃; for 17.36h;	Lithium chloride (1.1906 g, 1.56 eq.) In acetonitrile (20 mL) solution of acetonitrile (10 mL) solution of <strong>[52010-98-7]3-hydroxymethyl benzaldehyde</strong> (2.4528 g), trimethyl phosphonoacetate (5.1150g, 1.56 eq.) In acetonitrile (10 mL) was mixed at room temperature, the resulting mixed solution, 0 C. with DBU (1,8-diazabicyclo [5.4.0] -7-undecene) (4.2682g, acetonitrile (10 mL of 1.56 eq.)) the solution was added over a period of 2 minutes, 20 minutes at 0 , and the mixture was stirred at room temperature for 17 hours. Was added water (50 mL), extracted with ethyl acetate (250 mL), the organic layer was washed with brine (100 mL), dried over magnesium sulfate. The residue obtained by distilling off the solvent, column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (2.5720 g, 74%, colorless oil).

Reference： [1]Patent: JP2016/17036,2016,A .Location in patent: Paragraph 0351; 0353-0355
[2]Patent: JP2016/17037,2016,A .Location in patent: Paragraph 0307

51
[ 5927-18-4 ]
[ 130753-13-8 ]
benzyl 3-(2-methoxy-2-oxoethylidene)-8-azabicyclo[3,2,1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.6%		Sodium hydride (0.344g, 8.60mmol, 60%) in tetrahydrofuran (20.0mL) suspension of trimethyl phosphono acetic acid (0.908mL, 5.61mmol) was added at 0C. After stirring for 20 minutes at the same temperature, <strong>[130753-13-8]benzyl 3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate</strong> (0.970g, 3.74mmol) in tetrahydrofuran(20.0mL) was added a solution of room temperature and the mixture was stirred after raising the temperature 22 hours.Distilled water was added to the reaction mixture, and the mixture was distilled off under reduced pressure of tetrahydrofuran,and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by column chromatography (silica gel, nhexane/ ethylacetate = 94 / 665/ 35), 3(2methoxy2oxoethylidene)8azabicyclo[3,2,1] octane8carboxylicacid benzyl (below,reference example compound of 13) (0.645g, 2.05mmol, 54.6%) was obtained as a colorless oily product.

Reference： [1]Patent: JP2015/124178,2015,A .Location in patent: Paragraph 0145

52
[ 60032-57-7 ]
[ 5927-18-4 ]
[ 137146-28-2 ]

Yield	Reaction Conditions	Operation in experiment
75%		Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (60%, 1.09 g, 1.10 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of methyl 2-(dimethoxyphosphoryl)acetate (5.41 g, 29.71 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 30 min at 0 C. To this was added a solution of <strong>[60032-57-7]2-methylpyridine-3-carbaldehyde</strong> (3 g, 24.77 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 100 mL of water, extracted with 2×300 mL of ethyl acetate, washed with 1×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). The collected fraction was concentrated under vacuum to give (E)-methyl 3-(2-methylpyridin-3-yl)acrylate (3.3 g, 75%) as yellow oil. MS: (ES, m/z): 178[M+H]+.

Reference： [1]Patent: US2016/264518,2016,A1 .Location in patent: Paragraph 0862; 0863

53
[ 13490-32-9 ]
[ 5927-18-4 ]
2-(4-amino-1,2,5-oxadiazol-3-yl)-4-dimethoxyphosphoryl-1,4-dihydroimidazol-5-one [ No CAS ]
3-amino-3-(4-amino-1,2,5-oxadiazol-3-yl)-4-dimethoxyphosphoryl-isoxazolidin-5-one [ No CAS ]
4-amino-N'-methoxy-1,2,5-oxadiazole-3-carboxamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%; 30%; 15%	With sodium hydride; In toluene; for 6h;Reflux;	General procedure: Trialkylphosphonoacetate (2a or b) (1 mmol) was dissolved inrigorously dried toluene (25 mL) then sodium hydride (1mmol)was added carefully with stirring. Thence, the startingmaterial 1(1 mmol) was added to the mixture which then was refluxed for6 h., the volatile materials were evaporated under reduced pressureand the remaining residue was purified on silica gel columnchromatograph to give compounds 5a,b, 6a,b, and 7a,b

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2016,vol. 191,p. 1000 - 1008

54
[ 5927-18-4 ]
[ 24078-12-4 ]
methyl (E)-3-(4-bromo-2-methylphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; at 20℃; for 19h;	To a mixture of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (5.87 mL, 44 mmol, 1 equiv.) and trimethyl phosphonoacetate (7.62 mL, 53 mL, 1.2 equiv.) was added potassium carbonate (12.1 g, 88 mmol, 2 equiv.) and DBU (0.2 mL, 1.3 mmol, 0.03 equiv.). The reaction was stirred at room temperature for 19 h before being quenched with water. It was extracted three times with ether, the combined organic extracts were dried over sodium sulfate and the solvent was evaporated. The residue was purified by bulb-to-bulb distillation (135-140C, 0.15 mbar) to afford methyl (E)-3-(4-bromo-2-methylphenyl)acrylate (10.3 g, 92 % yield).1H NMR: 2.40 (s, 3H), 3.81 (s, 3H), 6.34 (d, / = 15.9, 1H), 7.32.7.40 (m, 3H), 7.87 (d, / =15.9, 1H). 13C NMR: 167.2 (s), 141.3 (d), 139.6 (s), 133.6 (d), 132.4 (s), 129.6 (d), 127.8 (d), 124.1 (s), 119.5 (d), 51.8 (q), 19.6 (q).

Reference： [1]Patent: WO2017/9175,2017,A1 .Location in patent: Page/Page column 15

55
[ 256417-10-4 ]
[ 5927-18-4 ]
(E)-methyl 3-(2,6-difluoro-4-methoxyphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 24h;	Step1 To a stirred solution of <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (5 g, 29.05 mmol, 1 eq) in THF (100 mL) was added trimethylphosphonoacetate (5.03 mL, 34.86 mmol, 1.2eq) and DBU (5.65 mL, 37.76 mmol, 1.3eq). The solution was stirred at RT for 24 h. It was then concentrated in vacuo and dissolved in 1:2 EtOAc/Hexane (250 mL). The resulting solution was washed sequentially with 1 N aq. HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and finally with brine (100 mL). The organic phase was then dried over sodium sulfate, filtered and evaporated under reduced pressure to yield the crude (E)-methyl 3-(2,6-difluoro-4-methoxyphenyl)acrylate as off white solid (5.8 g, 87%). It was used for the next step without further purification.

Reference： [1]Patent: US2018/78541,2018,A1 .Location in patent: Paragraph 0355; 0357

56
[ 189442-92-0 ]
[ 5927-18-4 ]
(E)-tert-butyl 4-(3-methoxy-3-oxoprop-1-enyl)-4-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		A mixture of methyl 2- (dimethoxyphosphoryl) acetate (1.82 g, 10 mmol) and t-BuOK (1.2 g, 10 mmol) in dry THF (15 mL) was stirred at 0 for 2h under N2. Then a solution of <strong>[189442-92-0]tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate</strong> (2.2 g, 9 mmol) was added to the mixture at 0 under N2. And the resulting mixture was stirred at rt overnight, quenched with aq. NH4Cl (100 mL) and extracted with EtOAc (100 mL × 3) . The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The crude compound was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc20/1 to 5/1) to give (E) -tert-butyl 4- (3-methoxy-3-oxoprop-1-enyl) -4-methylpiperidine-1-carboxylate (2 g, 78) . LRMS m/z (M-55) 228.2 found, 228.1 required

Reference： [1]Patent: WO2018/68297,2018,A1 .Location in patent: Page/Page column 95

57
[ 5927-18-4 ]
[ 304873-65-2 ]
C₁₄H₁₈N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.62%	With potassium carbonate; In tetrahydrofuran; for 15h;Inert atmosphere;	To a mixture of compound 21.8 (2.50 g, 11.25 mmol, 1 eq) and methyl 2- dimethoxyphosphorylacetate 21.7 (2.05 g, 11.25 mmol, 1.63 mL, 1 eq) in THF (30 mL) was added K2C03 (3.11 g, 22.50 mmol, 2 eq) in one portion at 50C under N2. The mixture was stirred at 50 C for 15 hours. The reaction mixture was diluted with H20 30 mL and extracted with EtOAc 90 mL (30 mL x 3). The combined organic layers were washed with brine 50 mL(50 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=5:1) to give compound 21.6 (2.40 g, 8.62 mmol, 76.62% yield) as a white solid.[02921 LCMS (ESI): m/z: [M + H] calcd for C14H18N204: 278; found 279; RTO.739 mm.

Reference： [1]Patent: WO2018/209132,2018,A1 .Location in patent: Paragraph 0291; 0292

58
[ 5927-18-4 ]
[ 13670-99-0 ]
C₁₁H₁₀F₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		General procedure: Trimethyl phosphonacetate (5.21 mmol) was added dropwise to a suspension of NaH (5.21 mmol) in dry THF (8 mL) at 0 C under inert atmosphere (N2). After 30 min, the appropriate ketone(4.17 mmol) was added to the reaction mixture. The reaction mixture was let to warm slowly to room temperature. The system was kept stirring at room temperature overnight. The next morning the reaction was quenched by addition 1M NH4Cl (10 mL) and the product was extracted with Et2O (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography eluting with n-hexane: EtOAc, 50:1 to give the pure 3a-d, 3f-l.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 163,p. 722 - 735

59
[ 53590-49-1 ]
[ 5927-18-4 ]
C₁₂H₁₀ClNO₂ [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 5026 - 5029

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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. 5927-18-4 ]

Quality Control of [ 5927-18-4 ]

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[ 5927-18-4 ] Synthesis Path-Upstream 1~19

[ 5927-18-4 ] Synthesis Path-Downstream 1~59

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[ 5927-18-4 ]