[ CAS No. 1450-75-5 ] {[proInfo.proName]}

Name: 1450-75-5|1-(5-Bromo-2-hydroxyphenyl)ethanone|98%
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Quality Control of [ 1450-75-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1450-75-5 ]

Product Details of [ 1450-75-5 ]

CAS No. :	1450-75-5	MDL No. :	MFCD00191850
Formula :	C₈H₇BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HQCCNFFIOWYINW-UHFFFAOYSA-N
M.W :	215.04	Pubchem ID :	95991
Synonyms :

Calculated chemistry of [ 1450-75-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.36
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.69 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.04
Log Po/w (XLOGP3) :	2.7
Log Po/w (WLOGP) :	2.36
Log Po/w (MLOGP) :	1.86
Log Po/w (SILICOS-IT) :	2.35
Consensus Log Po/w :	2.26

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.21
Solubility :	0.132 mg/ml ; 0.000614 mol/l
Class :	Soluble
Log S (Ali) :	-3.14
Solubility :	0.157 mg/ml ; 0.000731 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.02
Solubility :	0.207 mg/ml ; 0.000962 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.36

Safety of [ 1450-75-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1450-75-5 ]

* 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 [ 1450-75-5 ]
Downstream synthetic route of [ 1450-75-5 ]

[ 1450-75-5 ] Synthesis Path-Upstream 1~21

1
[ 1450-75-5 ]
[ 5676-56-2 ]
[ 42524-21-0 ]

Yield	Reaction Conditions	Operation in experiment
65%	With acetylhydroxamic acid; sulfuric acid In acetonitrile at 80℃; for 0.166667 h; Microwave irradiation	General procedure: 2-Hydroxy acetophenone 4a (1.0 g, 7.4 mmol), acetohydroxamic acid (0.83 g, 11.0 mmol), acetonitrile (3 ml), and conc. H₂SO₄ (0.2 ml) were taken into a 10 ml pressure tube and subjected to microwave heating (CEM discover, 360 W, 80 °C, 25 psi) for 8 min. Next, the reaction mixture was diluted with ethyl acetate (3 ml) and to this; saturated sodium bicarbonate solution (5 ml) was added drop-wise. The mixture was extracted with ethyl acetate (2 .x. 10 ml) and the combined organic layer was washed with saturated NaCl solution, dried over anhy. Na₂SO_4, and concentrated under reduced pressure. Purification of the mixture by normal column chromatography (silica gel 60-120 mesh, ethyl acetate/hexane: 1:9) gave benzoxazole 5a (0.67 g, 70percent) in the form of a yellow oil and 2-hydroxy acetophenone oxime 6a (68 mg, 6percent, mp 104-107 °C) in the form of a white powder.

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 46, p. 6103 - 6107
[2] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946

2
[ 1450-75-5 ]
[ 5676-56-2 ]

Reference： [1] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667

3
[ 1450-75-5 ]
[ 5676-56-2 ]

Reference： [1] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667
[2] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946

4
[ 1450-75-5 ]
[ 5676-56-2 ]
[ 42524-21-0 ]
[ 6329-74-4 ]

Reference： [1] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946

5
[ 1450-75-5 ]
[ 5676-56-2 ]
[ 6329-74-4 ]

Reference： [1] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946

6
[ 1450-75-5 ]
[ 14733-73-4 ]

Reference： [1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 18, p. 3591 - 3596

7
[ 118-93-4 ]
[ 1450-75-5 ]
[ 2491-36-3 ]

Reference： [1] Polish Journal of Chemistry, 1983, vol. 57, # 1/3, p. 49 - 56

8
[ 1450-75-5 ]
[ 35794-84-4 ]

Reference： [1] Patent: US2002/45650, 2002, A1,

9
[ 1450-75-5 ]
[ 35794-84-4 ]

Reference： [1] Chemical Communications, 2016, vol. 52, # 83, p. 12306 - 12309

10
[ 1450-75-5 ]
[ 74-88-4 ]
[ 16740-73-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate In acetone	1-(5-Bromo-2-methoxy-phenyl)-ethanone A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 47 mmol), methyl iodide (3.5 mL, 56 mmol), and potassium carbonate (10 g, 73 mmol) in acetone (80 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and the resulting white solid filtered and washed thoroughly with ethyl acetate. The filtrate was washed with water, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to provide the title compound (10 g, 94percent) as a white solid.
91%	Stage #1: With potassium carbonate In [⁽²⁾H₆]acetone at 20℃; for 1 h; Stage #2: at 20℃; for 20 h;	Potassium carbonate (9.6 g) was added to a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et₂O and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91percent yield). LC-MS (Method 1): m/z [M+H]⁺=229.1 (MW calc.=229.07); R_t=3.30 min.
91%	Stage #1: With potassium carbonate In acetone at 20℃; for 1 h; Stage #2: at 20℃; for 20 h;	Intermediate 7a) Potassium carbonate (9.6 g) was added to a solution of 1 -(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et₂0 and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91 percent yield). LC-MS (Method 1): m/z [M+H]⁺ = 229.1 (MW calc. = 229.07); R, = 3.30 min.

89%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	A mixture of 5-Bromo-2-hydroxyacetophenone 2a (10g, 46.5mmol, 1 eq), potassium carbonate (9.62g, 69.75mmol, 1.5 eq) and iodomethane (5.8mL, 93mmol, 2 eq) in DMF (120mL) were stirred overnight in a sealed round bottom flask at room temperature. DMF was removed under reduced pression and the residue was partitioned between water and EtOAc. The combined EtOAc extracts were washed with brine, 0.5M NaOH and then three times with water. The organic layer was dried over MgSO₄ and the solvent evaporated. The product was obtained as an off-white solid (9.5g, 89percent). m.p. 31–32°C. SM (ESI): m/z 251–253 [M+Na]⁺. ¹H NMR (δ ppm): 2.54 (s, 3H, COCH₃), 3.90 (s, 3H, OCH₃), 7.18 (d, J_ortho=8.9Hz, 1H, CHar), 7.66 (d, J_meta=2.6Hz, 1H, CHar), 7.72 (dd, J_ortho=8.9Hz, J_meta=2.6Hz, 1H, CHar).
75%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 12 h; Inert atmosphere	To a stirred solution of 1 -(5-bromo-2-hydroxyphenyl)ethan- 1-one 1 (10 g, 46.51 mmol) in DMF (100 mL) were added K2C03 (9.63 g, 69.77 mmol) and Mel (5.8 mL, 93.02 mmol) at 0°C under Ar. The mixture was stirred at RT for 12 h then quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure to afford compound 2 (8.8 g, 75percent) as pale yellow liquid. ‘H NIVIR (500MHz, DMSO-d6): 7.70 (dd, J 9.0, 2.6 Hz, 1H), 7.64 (d, J= 2.6 Hz, 1H), 7.16 (d, J= 9.0 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H); LC-MS (ESI):m/z 228.8 (M + Hf).

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2561 - 2563
[2] Tetrahedron, 2001, vol. 57, # 24, p. 5027 - 5038
[3] Chemistry - A European Journal, 2016, vol. 22, # 30, p. 10415 - 10419
[4] Patent: US2003/187007, 2003, A1,
[5] Patent: US2014/194443, 2014, A1, . Location in patent: Paragraph 0427-0429
[6] Patent: WO2014/108337, 2014, A1, . Location in patent: Page/Page column 56; 57
[7] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 774 - 796
[8] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 8, p. 1115 - 1123
[9] Patent: WO2017/15221, 2017, A1, . Location in patent: Paragraph 00255
[10] Organic and Biomolecular Chemistry, 2005, vol. 3, # 24, p. 4432 - 4443
[11] Advanced Synthesis and Catalysis, 2018, vol. 360, # 8, p. 1634 - 1638

11
[ 2142-63-4 ]
[ 1836-06-2 ]
[ 1450-75-5 ]

Yield	Reaction Conditions	Operation in experiment
15%	With (difluoroboryl)dimethylglyoximatocobalt(II) bis(acetonitrile); water; 3-cyano-1-methylquinolinium cation In acetonitrile at 20℃; for 5 h; Inert atmosphere; Irradiation; Green chemistry	1-methyl-3-cyanoquinoline salt as a photosensitizer, Cobalt oxime complex 2 as a cobalt catalyst, 5mL acetonitrile was added2.69 mg (1 × 10 -2 mmol) photosensitizer and 2.80 mg (6 × 10 -3 mmol) cobalt catalyst, Replacing the atmosphere with Ar atmosphereAnd then0.2 mmol of 3'-bromoacetophenone (R1 is COCH3, R3 is Br, R2, R4 are independently H) and 2 mmol of H2O. Room temperature, high pressureMercury lamp irradiation 5h. After the reaction was completed, the H2 production was detected by GC (TCD) and the conversion of benzene by GC (FID), And then separated by column. 1H NMR and MS identified products were 3'-bromo-2-hydroxyacetophenone, 3'-bromo-4-hydroxyacetophenone and 3'-bromo-6-hydroxyacetophenone. The conversion of 3'-bromoacetophenone was 32percent, the yield of coupling products was 2percent, 15percent and 15percent, respectively, and the yield of H2 was 8percent.

Reference： [1] Patent: CN107324975, 2017, A, . Location in patent: Paragraph 0130-0131

12
[ 118-93-4 ]
[ 1836-05-1 ]
[ 1450-75-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With Oxone; ammonium bromide In methanol at 20℃; for 4.5 h;	General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH₄Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3.x.25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of ¹H NMR and mass spectral data.

Reference： [1] Tetrahedron Letters, 2012, vol. 53, # 2, p. 191 - 195

13
[ 118-93-4 ]
[ 22362-66-9 ]
[ 1836-05-1 ]
[ 1450-75-5 ]

Yield	Reaction Conditions	Operation in experiment
19 %Chromat.	With N-Bromosuccinimide In acetonitrile at 20℃; for 2 h;	General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na₂S₂O₃ (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na₂S₂O₃ (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na₂SO₄ and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF₂₅₄ coated plate (5percent CH₂Cl₂/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, ¹H and ¹³C NMR. Their spectroscopic data are in agreement with those reported in the literature.

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5823 - 5828
[2] Tetrahedron, 2017, vol. 73, # 46, p. 6564 - 6572

14
[ 67-56-1 ]
[ 201230-82-2 ]
[ 1450-75-5 ]
[ 57009-12-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	at 100℃;	A solution of l-(5-bromo-2-hydroxyphenyl)ethanone (20.0 g, 93.0 mmol, 1.00 equiv) in methanol (500 mL), Pd(dppf)₂Cl₂ (4 g, 4.7 mmol, 0.05 equiv) and triethylamine (20 g, 200.00 mmol, 2.00 equiv) were stirred overnight at 100°C under an atmosphere of CO (g). The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was diluted with 200 mL of H₂0 and the resulting solution was extracted with 5x50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solids were filtered off. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 15 g (83percent) of methyl 3-acetyl-4-hydroxybenzoate as a light yellow solid. H NMR (300 MHz, CDC1₃): 12.68 (s, 1 H), 8.49 (d, 1H), 8.14 (dd, / = 2.1 Hz, l H), 7.02 (d, / = 9.6 Hz,l H), 3.93 (s, 3 H), 2.71 (s,3 H)

Reference： [1] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175

15
[ 1450-75-5 ]
[ 33839-11-1 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1969, p. 781 - 787

16
[ 1450-75-5 ]
[ 70978-54-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With nitric acid In tetrachloromethane	1I 5-Bromo-2-hydroxy-3-nitroacetophenone A solution of 5-bromo-2-hydroxyacetophenone (23.7 g, 0.110 mol) in carbon tetrachloride (90 ml) was added with concentrated nitric acid (17.2 ml). The mixture was left under stirring at 75° C. for 50 minutes, then left to cool at room temperature. The precipitated solid was recovered by filtration washing with cold carbon tetrachloride. After drying under vacuum, 20.9 g of the title product were obtained as a light yellow solid (73percent yield). ¹ H N.M.R. (300 MHz, CDCl₃) δ ppm: 2.73 (s, 3H); 8.14 (d, 1H); 8.31 (d, 1H); 12.92 (s, 1H).

Reference： [1] Patent: US5990142, 1999, A,
[2] Patent: EP1391451, 2004, A1, . Location in patent: Page 113
[3] Patent: WO2017/221002, 2017, A1, . Location in patent: Page/Page column 92

17
[ 1450-75-5 ]
[ 5676-56-2 ]
[ 42524-21-0 ]
[ 6329-74-4 ]

Reference： [1] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946

18
[ 1450-75-5 ]
[ 5676-56-2 ]
[ 6329-74-4 ]

Reference： [1] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946

19
[ 1450-75-5 ]
[ 55580-08-0 ]

Reference： [1] Patent: US2011/76291, 2011, A1,
[2] Patent: WO2012/162330, 2012, A1,
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640

20
[ 1450-75-5 ]
[ 79099-07-3 ]
[ 690632-38-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: With pyrrolidine In methanol Stage #2: at 80℃;	To a stirred solution of pyrrolidine (1.07g, 15 mmol) in MeOH (150 mL) was added 5-bromo-2-hydroxy acetophenone (6.45g, 30 mmol) (solution turned yellow). Then 4-t- butoxycarbonyl-piperidone (5.98g, 30 mmol) was added (solution turned brown). The reaction was heated at 80 ⁰C overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (300 mL). The mixture was washed with 1 N HCl (150 mL), IN NaOH (150 mL x 2), water and brine. The organic layer was dried (Na₂SO₄), filtered and concentrated to give compound 8A (11.7g, 99percent). ¹H-NMR (CDCl₃) δ 7.95 (d, J = 2.7 Hz, IH), 7.55 (dd, J = 8.7, 2.7 Hz, IH), 6.88 (d, J = 8.7 Hz, IH), 3.84 (br s, 2H), 3.21-3.13 (m, 2H), 2.03-1.95 (m, 2H), 1.64-1.55 (m, 2H), 1.44 (s, 9H).
97%	Stage #1: With pyrrolidine In toluene at 20℃; for 0.333333 h; Stage #2: for 15 h; Reflux	Example 13Preparation of Compound 17 Step 1A mixture of compound 13a (11.1 g, 52 mmol) and pyrrolidine (5.6 mL, 67 mmol) in toluene (200 mL) was stirred at 20° C. for 20 minutes. The mixture was then treated with 1-BOC-4-piperidone 13b (13.4 g, 67 mmol) and refluxed for about 15 hours. The reaction mixture was then cooled to room temperature, washed sequentially with 10percent aqueous NaOH and H₂O, dried over MgSO₄, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography (10percent EtOAc/hexanes) to provide compound 13c (20.0 g, 97percent) as a yellow solid.
94%	With pyrrolidine In methanol for 11 h; Reflux	Intermediate 1: (E)-3-14-Oxo-spiro[chromane-2,4'-piperidine]-6-yl}-acrylic acid methyl ester [Show Image] STEP A A mixture of 2-hydroxy-5-bromoacetophenone (10.75 g, 50 mmol), N-BOC-4-piperidone (9.96 g, 50 mmol) and pyrrolidine (2.09 ml, 25 mmol) in MeOH (80 ml) was heated to reflux for 11 h. The solvent was removed under vacuum and the crude mixture was purified by column chromatography (eluent: hexane/AcOEt 90:10 to 80:20) to give 6-bromo-4-oxo-spiro[chromane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (18.55 g) as a yellow solid. Y=94percent LC-MS: Method A, rt=6.4 min; (ES+) MNa⁺: 419.8 ¹H-NMR (CDCl₃) δ (ppm): 7.96 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 3.84 (m, 2H), 3.18 (t, J=11.6 Hz, 2H), 2.70 (s, 2H), 2.00 (m, 2H), 1.60 (m, 2H), 1.44 (s, 9H).

93%	With pyrrolidine In methanol for 4 h; Reflux	5-bromo-2-hydroxyacetophenone(2.15 g, 10 mmol), N-Boc-4-piperidone (1.99 g, 10 mmol) was dissolved in methanol (15 mL), pyrrolidine (1 mL, 13 mmol) was added and the mixture was heated at reflux for 4 hours until the starting material disappeared. The solvent was distilled off, and the residue was dissolved in dichloromethane (100 mL), washed with 1N hydrochloric acid (50 mL) and saturated brine (50 mL) successively, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution Agent: petroleum ether/ethyl acetate = 10:1 to 4:1) Compound 1-e (3.69 g, 93percent) was obtained.
92%	With pyrrolidine In methanol for 12 h; Reflux	j00228J 1 -(5 -Bromo-2-hydroxyphenyl)ethan- 1-one (10.0 g, 45.5 mmol), tert-butyl 4- oxopiperidine-1-carboxylate (9.27 g, 46.5 mmol) and pyrrolidine (1.91 mL, 23.3 mmol) were combined in 75 mL of MeOH and refluxed for 12 h. After cooling down to room temperature the reaction mixture was concentrated to dryness and purified by normal phase silica gel (EtOAc/hexanes gradient). After purification 17.1 g (92percent yield) of the title compound was obtained. ‘H NIVIR (300 MHz, CDC13) (ppm): 7.96 (d, J= 2.5 Hz, 1H), 7.55 (dd, Jj = 8.8 Hz, J2 = 2.5 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 3.86 (br s, 2H), 3.20-3.10 (m, 2H), 2.71 (s, 2H), 2.05-1.90 (m, 2H), 1.70-1.55 (m, 2H), 1.45 (s, 9H). MS: (ES, m/z): 296/298 [M-Boc].chromatography on
87%	With pyrrolidine In methanol at 60 - 65℃; for 3 h; Heating / reflux	Example 1 :Reaction between 5-Bromo-2-hydroxy acetophenone with N-Boc-4-piperidone; In a 500 ml 3-necked flask, fitted with a reflux condenser, a CaCI₂ gaurd tube and a magnetic needle, 0.1 mol N-Boc-4-piperidone (19.5 g) and 0.1 16 mol pyrrolidine (8.95 g), dissolved in 100 ml of anhydrous MeOH at ambient temperature were added to 0.0837 mol 5-Bromo-2-hydroxyacetophenone (18 g). The reaction mixture was stirred under reflux at 60-65⁰C for about 3 hrs. The reaction mixture was transferred to a rotary flask and MeOH was distilled off to obtain an orange viscous liquid. 75 ml of water was added and the product was extracted with ethyl acetate (4 timesl OO ml). The aqueous layer was discarded and the organic layer was dried over anhydrous Na₂SO₄. Ethyl acetate was distilled off and an orange viscous oil was obtained that was thoroughly dried in vacuo. Further purification by column chromatography with ethyl acetate/petrolether 10/90 yielded 28,7 g (87percent) of a pale yellow crystalline solid. Melting Point: 140 -143⁰C
84%	With pyrrolidine In methanol at 20℃;	To a solution 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol) in methanol (20 mL) was added pyrrolidine (0.8 mL, 9.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (1.91 g, 9.6 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by Biotage chromatography (4OM column, 8percent - 20percent ethyl acetate/heptane gradient) to provide tert-butyl 6-bromo-4-oxo-3,4-dihydro-1 H-spiro[chromene-2,4 -piperidine]-1 -carboxylate as a yellow solid (3.09 g, 84percent). ¹H NMR (CDCI₃) δ 7.96 (d, J=2.5, 1H), 7.56 (dd, J=8.7, 2.5, 1H), 6.89 (d, J=8.7, 1H), 2.70 (s, 2H), 1.44 (s, 9H).
79%	With pyrrolidine In methanol for 17 h; Heating / reflux	Step 1 :; Intermediate 1; Spiro[2H-1 -benzopyran-2,4'-piperidine]-1 '-carboxylic acid, 6-bromo-3,4- dihydro-4-oxo-, 1,1-dimethylethyl ester.; A mixture of 5'-bromo-2'-hydroxyacetophenone (50.0 g, 232.5 mmol), t-butyl 4-oxo-1- piperidinecaboxylate (46.3 g, 232.4 mmol) and pyrrolidine (50 ml_, 599.0 mmol) in methanol (500 mL) was refluxed for 17h, then cooled and concentrated. The red colored residue was dissolved in EtOAc (600 mL) and washed with water (2 x 200 mL), aqueous ~3M citric acid (2x 150 mL), water and brine. The organics were dried (Mg SO₄) and concentrated to a thick, light orange foamy tar. Hexanes (~ 100 mL) was added and the vessel walls were scratched to induce crystallization. Another 150 mL hexanes was added and the mixture was stirred for 66 hrs, then filtered, rinsed with hexanes and air dried to afford 73.2 g (79percent) of the title compound as a dull yellow solid: NMR (CDCI₃) δ 7.94 (d, J = 2.5 Hz, 1 H), 7.54 (dd, J = 8.7, 2.5 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 1 H), 3.85 (br s, 2H), 3.16 (br t, J = 11.6 Hz, 2H), 2.69 (s, 2H), 1.98 (br d, J= 13.3 Hz, 2H), 1.62-1.54 (m, 2H), 1.43 (s, 9H).
42.2 g	With pyrrolidine In methanol for 4 h; Reflux	A solution of tert-butyl 4-oxopiperidine-1-carboxylate (21.5 g, 100 mmol), 1-(5-bromo- 2-hydroxyphenyl) ethan-1-one (20.0 g, 100 mmol), and pyrrolidine (20 mL, 270 mmol) in methanol (200 mL) was heated at reflux for 4 h until completion was confirmed by LC/MS. The methanol was concentrated, the residue was dissolved in TBME (250 mL) and washed with washed with iN HC1 (200mL), saturated NaHCO3 solution (200 mL) and brine (200 mL). The organic phase was dried (Mg504), filtered and concentrated to yield a gum. The cmde product was dissolved in hexanes (500 mL) and stirred at RT overnight to give a yellow solid, which was collected by filtration and further washed with hexanes. After drying, tert-butyl 6-bromo-4- oxospiro[chromane-2,4’-piperidinej-l’-carboxylate was obtained as a yellow solid (42.2 g).

Reference： [1] Patent: WO2009/97567, 2009, A1, . Location in patent: Page/Page column 62
[2] Patent: US2011/166124, 2011, A1, . Location in patent: Page/Page column 36
[3] Patent: EP2110377, 2009, A1, . Location in patent: Page/Page column 14
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3051 - 3064
[5] Patent: CN103304571, 2018, B, . Location in patent: Paragraph 0116-0118
[6] Patent: WO2016/168660, 2016, A1, . Location in patent: Paragraph 00228
[7] Patent: WO2007/54580, 2007, A1, . Location in patent: Page/Page column 30
[8] Patent: WO2008/65508, 2008, A1, . Location in patent: Page/Page column 17
[9] Patent: WO2007/88462, 2007, A1, . Location in patent: Page/Page column 17
[10] Patent: WO2007/11809, 2007, A1, . Location in patent: Page/Page column 92; 105
[11] Patent: US2008/171761, 2008, A1, . Location in patent: Page/Page column 42; 45
[12] Patent: WO2008/88692, 2008, A2, . Location in patent: Page/Page column 104
[13] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 949 - 953
[14] Patent: WO2010/2010, 2010, A1, . Location in patent: Page/Page column 77
[15] Patent: WO2018/112204, 2018, A1, . Location in patent: Paragraph 00313

21
[ 1450-75-5 ]
[ 79099-07-3 ]
[ 921760-46-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: With pyrrolidine In methanol at 80℃; for 16 h; Stage #2: With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 16 h;	A mixture of 5-bromo-2-hydroxyacetophenone (6.0 g, 0.027 mol) and pyrrolidine (2.7 mL, 0.033 mol) in MeOH (48 mL) was stirred at 25°C for 20 min in a sealed flask. The mixture was then treated with 1 -Boc-4-piperidone (5.55 g, 0.027 mol) and heated to 80 °C for 16 h.The reaction mixture was then concentrated in vacuo and the residue dissolved in DCM (50 mL), cooled to 15°C,treated with 4M HC1 -dioxane (30 mL) and stirred for 16 h at rt. The solid was filtered and washed with DCM to the title compound as a cream color HC1 salt (8.92 g, 96percent). Ή NMR (400 MHz, CD₃OD) δ 7.93 (d, .7=2.5 Hz, 1 H), 7.71 (dd, J=8.9, 2.6 Hz, 1 H), 7.1 1 (d, .7=9.0 Hz, 1 H), 3.32 - 3.41 (m, 4 H), 2.90 (s, 2 H), 2.23 - 2.36 (m, 2 H), 1.87 - 2.05 (m, 2 H), MS ESI 297 [M + H]⁺, calcd for [C₁₃H₁₄BrN0₂+H]⁺ 297.02.

Reference： [1] Patent: WO2013/53051, 2013, A1, . Location in patent: Page/Page column 93
[2] Patent: WO2007/11809, 2007, A1, . Location in patent: Page/Page column 92

[ 1450-75-5 ] Synthesis Path-Downstream 1~88

1
[ 1927-95-3 ]
[ 1450-75-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With aluminium trichloride at 100℃; for 2h;
76%	With hydrogenchloride	1 1H 5-Bromo-2-hydroxyacetophenone 1H 5-Bromo-2-hydroxyacetophenone A mixture of 4-bromophenyl acetate (31.3 g, 0.145 mol) and AlCl3 (47.3 g) was heated at 120° C. for 2 h. Afterwards the mixture was left to cool at a temperature of about 50° C. and added carefully with a mixture of ice (70 g) and concentrated hydrochloric acid (15 ml). The resulting mixture was heated at 100° C. to prepare a homogeneous solution. After that was cooled at room temperature and extracted with ethyl acetate (4*100 ml). The organic phase was dried and the solvent was evaporated off under reduced pressure, to obtain a crude which was purified by chromatography through a silica gel column, eluding with hexane:chloroform, 9:1, thereby recovering 23.7 g of the title compound (76% yield). 1 H N.M.R. (300 MHz, CDCl3) δ ppm: 2.56 (s, 3H); 6.78 (d, 1H); 7.43 (dd, 1H); 7.72 (d, 1H); 12.10 (s, 1H).
75%	With aluminium trichloride at 180℃;

75%	With aluminum (III) chloride
72%	With aluminium trichloride at 150℃; for 0.5h;
72%	With aluminum (III) chloride at 150℃; for 3.5h;	4.2.2 Synthesis of 2 A suspension of 1 (46 mmol) and aluminum chloride (69 mmol) was stirred at 150 °C. After 3.5h the mixture was cooled to room temperature and the diluted hydrochloric acid was added to it slowly for quenching aluminum chloride until all solid disappeared. Then the solution was extracted with ethyl acetate (20mL×3), and the combined organic layer was washed by saturated sodium chloride solution for three times, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The decolorized solid was recrystallized with n-hexane. 2: yield 72%. 1H NMR (400MHz, CDCl3): δ 7.38 (d, J=8.0Hz, 1H), 7.32 (s, 1H), 7.23 (d, J=7.9Hz, 1H), 7.06 (d, J=8.2Hz, 1H), 2.28 (s, 3H) ppm.
70%	With aluminum (III) chloride at 150℃; for 3.5h;	Synthesis of 2a-2c General procedure: A suspension of 1a-1c (46 mmol) and aluminum chloride (69 mmol, 9 g) was stirred at 150 ℃. After 3.5 h the mixture was cooled to room temperature and the diluted hydrochloric acid was added to it slowly for quenching aluminum chloride until all solid disappeared. Then the solution was extracted with ethyl acetate (20 mL×3), and the combined organic layer was washed by saturated sodium chloride solution for three times, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The decolorized solid was recrystallized with n-hexane.2a: yield 70%. HPLC purity: 97.7%. 2b: yield 75%. HPLC purity: 98.1%. 2c: yield 75%. HPLC purity: 98.3%.
66%	With aluminium trichloride
62%	With aluminium trichloride at 150℃; for 3h;
50%	With aluminium trichloride at 140℃; for 2h;
	With aluminium trichloride at 150 - 160℃;
	With aluminium trichloride at 120℃;
	With aluminium trichloride
	With aluminium trichloride
	With aluminium trichloride at 160℃;
	With aluminium trichloride Heating;
	at 150℃;
	With aluminum (III) chloride at 120 - 140℃; for 0.333333h; Neat (no solvent);	9.2 (Step 2) 1-(5-Bromo-2-hydroxyphenyl)-1-ethanone A mixture of 4-bromophenyl acetate (23.9 g) and anhydrous aluminum chloride (30 g) was stirred at 120-140°C for 20 minutes. The reaction mixture was cooled to 60-80°C, ice water was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (21 g) as an oil.1H-NMR (CDCl3) δ: 2.61(3H, s), 6.89(1H, d, J=8Hz), 7.55(1H, dd, J=8, 2Hz), 7.83(1H, d, J=2Hz), 12.32(1H, s).
	With aluminum (III) chloride at 150℃;
	With aluminum (III) chloride at 120℃;
	With aluminum (III) chloride
	Stage #1: 4-bromophenyl acetate With aluminum (III) chloride at 120℃; for 6h; Stage #2: With water Cooling;	2 Synthesis of substituted o-hydroxyacetophenone General procedure: Powdered anhydrous AlCl3 (186 g, 1.4 mol) was added little by little to acetic acid phenyl ester b1 (95.3 g, 0.7 mol) in a round-bottomed flask in an ice-water bath. The resultant mixture was heated to 120 °C for 6 h in an oil bath. Then the reaction mixture was added a lot of crushed ice for hydrolysis. The new formed organic layer in the reaction mixture was extracted by EtOAc, dried over anhydrous Na2SO4, and filtered off by suction filtration. The solvent was removed under reduced pressure to give the crude product, which was then purified by chromatography on silica using petroleum ether/ethyl acetate as the eluent. o-hydroxyacetophenone c1 (20.1 g, 21%) was obtained
	With aluminum (III) chloride at 120℃;
	With aluminum (III) chloride at 120 - 130℃; Dean-Stark;
	With aluminum (III) chloride at 120 - 130℃;
	With aluminum (III) chloride
	With aluminum (III) chloride at 0 - 120℃; for 5h;
	With aluminum (III) chloride at 120℃;

Reference： [1]Sangwan, Naresh K.; Rastogi, Shri Nivas [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1981, vol. 20, # 6, p. 480 - 483]
[2]Current Patent Assignee: A. MENARINI - INDUSTRIE FARMACEUTICHE RIUNITE - S.R.L. - US5990142, 1999, A
[3]Shim, Yi Sup; Kim, Ki Chul; Chi, Dae Yoon; Lee, Keun-Hyeung; Cho, Hyeongjin [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2561 - 2563]
[4]Huebscher, Joerg; Guenthel, Michael; Rosin, Robert; Seichter, Wilhelm; Mertens, Florian; Weber, Edwin [Zeitschrift fur Naturforschung, B: Chemical Sciences, 2013, vol. 68, # 3, p. 214 - 222]
[5]Johnson, Alan T.; Wang, Liming; Standeven, Andrew M.; Escobar, Maria; Chandraratna, Roshantha A.S. [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 7, p. 1321 - 1338]
[6]Han, Xuan; Luo, Jiang; Wu, Feng; Hou, XueYan; Yan, Guoyi; Zhou, Meng; Zhang, Mengqi; Pu, Chunlan; Li, Rui [European Journal of Medicinal Chemistry, 2016, vol. 114, p. 232 - 243]
[7]Zhang, Wenjuan; Li, Zhi; Zhou, Meng; Wu, Feng; Hou, Xueyan; Luo, Hao; Liu, Hao; Han, Xuan; Yan, Guoyi; Ding, Zhenyu; Li, Rui [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 799 - 807]
[8]Lauk, Urs H.; Skrabal, Peter; Zollinger, Heinrich [Helvetica Chimica Acta, 1985, vol. 68, p. 1406 - 1426]
[9]Davies, Stephen G.; Mobbs, Bryan E.; Goodwin, Christopher J. [Journal of the Chemical Society. Perkin transactions I, 1987, p. 2597 - 2604]
[10]Akamanchi; Padmawar; Thatte; Rege; Dahanukar [Pharmacy and Pharmacology Communications, 1999, vol. 5, # 5, p. 323 - 329]
[11]Klarmann et al. [Journal of the American Chemical Society, 1933, vol. 55, p. 4657,4660]
[12]Dandegaonker,S.H.; Revankar,G.R. [Monatshefte fur Chemie, 1965, vol. 96, p. 450 - 460]
[13]Begue,J.-P.; Fetizon,M. [Bulletin de la Societe Chimique de France, 1969, p. 781 - 787]
[14]Khelili; Nguyen; Lebrun; Delarge; Pirotte [Pharmacy and Pharmacology Communications, 1999, vol. 5, # 3, p. 189 - 193]
[15]Sebille, Sophie; De Tullio, Pascal; Becker, Bénédicte; Antoine, Marie-Hélène; Boverie, Stéphane; Pirotte, Bernard; Lebrun, Philippe [Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 614 - 621]
[16]Doble, Mukesh; Karthikeyan; Padmaswar; Akamanchi [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 21, p. 5996 - 6001]
[17]Current Patent Assignee: ABBVIE INC - US2005/148590, 2005, A1 Location in patent: Page/Page column 29
[18]Current Patent Assignee: EISAI CO LTD - EP1391451, 2004, A1 Location in patent: Page 112-113
[19]Current Patent Assignee: ABBVIE INC - US2005/4213, 2005, A1 Location in patent: Page 15
[20]Location in patent: scheme or table China Raju; Nageswara Rao; Suman; Yogeeswari; Sriram; Shaik, Thokhir Basha; Kalivendi, Shasi Vardhan [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2855 - 2859]
[21]Location in patent: scheme or table Kelode; Mandlik; Aswar [Oriental Journal of Chemistry, 2011, vol. 27, # 3, p. 1053 - 1062]
[22]Tu, Qi-Dong; Li, Ding; Sun, Yao; Han, Xin-Ya; Yi, Fan; Sha, Yibamu; Ren, Yan-Liang; Ding, Ming-Wu; Feng, Ling-Ling; Wan, Jian [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 2826 - 2831]
[23]Zhu, Wufu; Chen, Chen; Sun, Chengyu; Xu, Shan; Wu, Chunjiang; Lei, Fei; Xia, Hui; Tu, Qidong; Zheng, Pengwu [European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73]
[24]Bano, Mohsina; Barot, Kuldipsinh P.; Jain, Shailesh V.; Ghate, Manjunath D. [Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 3008 - 3020]
[25]Dalal, Aarti; Khanna, Radhika; Berar, Urmila; Kamboj, Ramesh C. [Journal of Photochemistry and Photobiology A: Chemistry, 2016, vol. 329, p. 238 - 245]
[26]Pirotte, Bernard; Florence, Xavier; Goffin, Eric; Lebrun, Philippe [ChemMedChem, 2017, vol. 12, # 21, p. 1810 - 1817]
[27]Bhimapaka, China Raju; Karri, Shailaja; Kuncha, Madhusudana; Kurma, Siva Hariprasad; Sistla, Ramakrishna [Bioorganic and medicinal chemistry letters, 2020, vol. 30, # 16]
[28]Current Patent Assignee: JIANGXI SCIENCE & TECHNOLOGY NORMAL UNIVERSITY - CN113563321, 2021, A Location in patent: Paragraph 0021-0023

2
[ 1450-75-5 ]
[ 18980-21-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydroxide; hydrazine In 2,2'-[1,2-ethanediylbis(oxy)]bisethanol at 170℃; for 24h;	A.22.1 Step 1: 4-Bromo-2-ethyl-phenol Sodium hydroxide (1.4g, 35MMOL) and hydrazine monohydrate (2.04mL, 42MMOL) were added to a solution of 5'-bromo-2'-hydroxyacetophenone (3g, 14MMOL) dissolved in triethylene glycol (17mL). The reaction mixture was heated to 170 C for 24 h and then partitioned between 1 N HCI and EtOAc. The organic layer was washed with saturated NAHC03, brine, dried over NA2SO4AND concentrated. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound (2.52 g, 90%). 'H NMR (CDCl3) : 6 1.22 (t, 3H, J= 7.5 Hz), 2.60 (q, 2H, J= 7. 5 Hz), 6.64 (d, 1H, J= 8.5 Hz), 7.17 (dd, 1H, J= 8.5, 2.5 Hz), 7.24 (d, 1H, J= 2.5 Hz).
90%	With sodium hydroxide; hydrazine In 2,2'-[1,2-ethanediylbis(oxy)]bisethanol at 170℃; for 24h;	A.22.1 Sodium hydroxide (1.4 g, 35 mmol) and hydrazine monohydrate (2.04 mL, 42 mmol) were added to a solution of 5'-bromo-2'-hydroxyacetophenone (3 g, 14 mmol) dissolved in triethylene glycol (17 mL). The reaction mixture was heated to 170° C. for 24 h and then partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound (2.52 g, 90%). 1H NMR (CDCl3): δ 1.22 (t, 3H, J=7.5 Hz), 2.60 (q, 2H, J=7.5 Hz), 6.64 (d, 1H, J=8.5 Hz), 7.17 (dd, 1H, J=8.5, 2.5 Hz), 7.24 (d, 1H, J=2.5 Hz).
50%	With hydrogenchloride; zinc In ethanol for 54h; Heating;

	With alkali hydroxide; hydrazine hydrate; diethylene glycol
	With hydrogenchloride; amalgamated zinc
	(i) N₂H₄, (ii) KOH; Multistep reaction;

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/74270, 2004, A2 Location in patent: Page 57
[2]Current Patent Assignee: PFIZER INC - US2005/176701, 2005, A1 Location in patent: Page/Page column 26
[3]Thakar; Joshi [Journal of the Indian Chemical Society, 1982, vol. 59, # 1, p. 77 - 79]
[4]McCoubrey [Journal of Pharmacy and Pharmacology, 1956, vol. 8, p. 648,649]
[5]Klarmann et al. [Journal of the American Chemical Society, 1933, vol. 55, p. 4657,4660]
[6]Begue,J.-P.; Fetizon,M. [Bulletin de la Societe Chimique de France, 1969, p. 781 - 787]

3
[ 588-96-5 ]
[ 75-36-5 ]
[ 1450-75-5 ]

Reference： [1]Patent: DE96659,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 5,p. 913

4
[ 1450-75-5 ]
[ 106-95-6 ]
[ 444809-89-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In acetone at 50℃;	Step 2: 2-(Allyloxy)-4,6-dimethoxybenzaldehyde (3b) General procedure: To a solution of the product from step 1 (1.00 g, 5.5 mmol) and allyl bromide (0.71 mL, 8.2 mmol) in acetone (10 mL) was added K2CO3 (1.51 g, 11.0 mmol). The mixture was heated to 50°C until the starting material was completely consumed, cooled to ambient temperature and hydrolysed by addition of a semisaturated aqueous solution of NaCl (20 mL). Ethyl acetate (10 mL) was added, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (20 mL each). The combined organic extracts were dried with MgSO4, filtered and evaporated. The residue was purified by chromatography on silica, using hexane-MTBE mixtures of increasing polarity as eluent, to furnish the title compound 3b (0.93 g, 4.2 mmol, 76%).
87%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;
86%	Stage #1: 5-Bromo-2-hydroxyacetophenone With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 20℃; Further stages.;

	With potassium carbonate; acetone
	With potassium hydroxide
	With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide for 20h;
	With potassium carbonate In acetone Reflux;
	With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 20h;	1,3 Diketone Procedure 1 General procedure: To a solution of the required 2-hydroxyacetophenone (1 equiv) in DMF at rt, was added allyl bromide (1.1 equiv), K2CO3 (3 equiv) and TBAI (0.1 equiv), and the suspension was stirred for 20 h. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with water (×3) and brine (×1), dried over Na2SO4, and reduced in vacuo to provide the allyl ether in sufficient purity to be used in the next step. To a solution of the 2-(2-propen-1-yloxy)acetophenone derivative (1 equiv) in THF at 0 °C was added NaH (2.5 equiv) with stirring for 15 min. After this time the reaction was warmed to rt, and a solution of the desired ester (1-2 equiv) in anhydrous THF was added. The resulting solution was heated at reflux for a further 20 h. The reaction was quenched with 2 M HCl and extracted with EtOAc (×2). The combined organic extracts were washed with water (×1) and brine (×1), dried, and reduced in vacuo. The residue was of sufficient purity to be used in the next step, but an analytically pure sample could be obtained by subjecting the crude residue to silica gel chromatography.

Reference： [1]Schmidt, Bernd; Riemer, Martin [Synthesis, 2016, vol. 48, # 1, p. 141 - 149]
[2]Juhasz, Laszlo; Docsa, Tibor; Brunyaszki, Attila; Gergely, Pal; Antus, Sandor [Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 12, p. 4048 - 4056]
[3]Hamilton, Chris J.; Fairlamb, Alan H.; Eggleston, Ian M. [Journal of the Chemical Society. Perkin Transactions 1 (2001), 2002, # 8, p. 1115 - 1123]
[4]Sen; Parmar [Journal of the Indian Chemical Society, 1953, vol. 30, p. 61]
[5]Dalal, Shailendara; Rao, Y. Jayaprakash; Krupadanam, G. L. David [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 6, p. 805 - 810]
[6]Smith, Robert J.; Nhu, Duong; Clark, Mitchell R.; Gai, Sinan; Lucas, Nigel T.; Hawkins, Bill C. [Journal of Organic Chemistry, 2017, vol. 82, # 10, p. 5317 - 5327]
[7]Xiang, Haoyue; Zhao, Qing-Lan; Xia, Peng-Ju; Xiao, Jun-An; Ye, Zhi-Peng; Xie, Xiong; Sheng, Huan; Chen, Xiao-Qing; Yang, Hua [Organic Letters, 2018, vol. 20, # 5, p. 1363 - 1366]
[8]French, Sarah A.; Clark, Mitchell R.; Smith, Robert J.; Brind, Thomasin; Hawkins, Bill C. [Tetrahedron, 2018, vol. 74, # 38, p. 5340 - 5350]

5
[ 5629-98-1 ]
[ 1450-75-5 ]
[ 1836-09-5 ]

Reference： [1]Monatshefte fur Chemie,1965,vol. 96,p. 450 - 460

6
[ 89-91-8 ]
[ 1450-75-5 ]
[ 86344-51-6 ]

Reference： [1]Synthesis,1983,p. 311 - 312

7
[ 1450-75-5 ]
[ 67-64-1 ]
[ 99853-21-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With pyrrolidine In toluene for 24h; Heating;
72%	Stage #1: 5-Bromo-2-hydroxyacetophenone With pyrrolidine In toluene at 25℃; for 0.166667h; Stage #2: acetone In toluene at 25℃; for 16h;
70.9%	With pyrrolidine In toluene for 18h; Reflux;	1.A Example 1 2'-amino-6-(5-chloropyridin-3-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 )- oneStep A: 5'-Bromo-2'-hydroxyacetophenone (21.4 g, 99.5 mmol) was diluted with toluene (400 mL), followed by the addition of propan-2-one (40.2 mL, 498 mmol) and pyrrolidine (8.31 mL, 99.5 mmol). The reaction was heated at reflux for 18 hours. The reaction was allowed to cool, diluted with ethyl acetate and washed with 2N HCl, dried over MgS04, filtered and concentrated. The material was purified on silica gel eluting with 5-30% ethyl acetate/hexanes to yield 6-bromo-2,2-dimethylchroman-4-one (18 g, 70.6 mmol, 70.9% yield) as an oil.

62%	With piperidine; trifluoroacetic acid In benzene for 43h; Heating;
60%	With pyrrolidine In benzene for 16h; Heating;
	With pyrrolidine
	With pyrrolidine In methanol at 25℃;
	With piperidine; trifluoroacetic acid
	With pyrrolidine at 20℃; for 25h; Heating / reflux;	25.1 Example 25Synthesis of 6-bromo-2,2-dimethyl-N-(4-(2-methylpyridin-4-yl)phenyl)-3,4-dihydro-2H- chromene-4-carboxamideStep 1To a solution of 5"-bromo-2"-hydroxyacetophenone (10.0 g, 47 mmol) in toluene (30 mL) was added propan-2-one (7.0 ml, 70 mmol) and pyrrolidine (1.0 ml, 15 mmol). The reaction mixture was stirred at RT for Ih, and then refluxed for 24 h. The solvent was removed under reduced pressure and the residue diluted with EtOAc and washed with 6N HCl, 2N NaOH and water, and dried over MgSO4. After filtration and concentration, the residue was dried on vacumm overnight to give 6-bromo-2,2-dimethyl-2,3-dihydrochromen-4-one as a white solid. The product was used for next reaction without further purification.
	With piperidine; trifluoroacetic acid
	With pyrrolidine In ethanol Reflux;
	Stage #1: 5-Bromo-2-hydroxyacetophenone With pyrrolidine In methanol at 0 - 5℃; for 0.333333h; Stage #2: acetone for 4h; Reflux;	1.1 Step-1 :- Preparation of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one:-To a solution of l-(5-bromo-2-hydroxyphenyl)ethanone (1.0 g, 0.0046 mmol) in methanol (4 mL) was added pyrrolidine (1 mL). The reaction mixture was cooled at 0-5°C and stirred for 20 mins and acetone (0.5 mL, 0.006 mmol) was added. The reaction mixtue was refluxed for 4 hours. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to afford 0.700 g of product. .HNMR (DMSO): δ 1.45 (s, 6H), 2.71 (s, 2H), 6.82 -6.84 (d, J= 8.7 Hz, 1H), 7.52-7.55 (dd, J = 2.4 Hz, J = 2.4 Hz, 1H), 7.96 (s,lH).
	With pyrrolidine In toluene at 20℃; for 4h; Dean-Stark;
	With pyrrolidine In methanol
	With pyrrolidine In ethanol at 75℃; for 4h; Inert atmosphere; Schlenk technique;
	With pyrrolidine In acetonitrile

Reference： [1]Breschi, Maria C.; Calderone, Vincenzo; Martelli, Alma; Minutolo, Filippo; Rapposelli, Simona; Testai, Lara; Tonelli, Federica; Balsamo, Aldo [Journal of Medicinal Chemistry, 2006, vol. 49, # 26, p. 7600 - 7602]
[2]Current Patent Assignee: ROCHE HOLDING AG; RQX PHARMACEUTICALS INC - WO2018/149419, 2018, A1 Location in patent: Paragraph 00677
[3]Current Patent Assignee: PFIZER INC - WO2011/72064, 2011, A1 Location in patent: Page/Page column 56
[4]Johnson, Alan T.; Wang, Liming; Standeven, Andrew M.; Escobar, Maria; Chandraratna, Roshantha A.S. [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 7, p. 1321 - 1338]
[5]Buckle, Derek R.; Arch, Jonathon R. S.; Fenwick, Ashley E.; Houge-Frydrych, Catherine S. V.; Pinto, Ivan L.; et al. [Journal of Medicinal Chemistry, 1990, vol. 33, # 11, p. 3028 - 3034]
[6]Khelili; Nguyen; Lebrun; Delarge; Pirotte [Pharmacy and Pharmacology Communications, 1999, vol. 5, # 3, p. 189 - 193]
[7]Sebille, Sophie; De Tullio, Pascal; Becker, Bénédicte; Antoine, Marie-Hélène; Boverie, Stéphane; Pirotte, Bernard; Lebrun, Philippe [Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 614 - 621]
[8]Current Patent Assignee: ABBVIE INC - US2005/148590, 2005, A1 Location in patent: Page/Page column 29
[9]Current Patent Assignee: AMGEN INC - WO2009/75874, 2009, A1 Location in patent: Page/Page column 127
[10]Current Patent Assignee: ABBVIE INC - US2005/4213, 2005, A1 Location in patent: Page 15
[11]Location in patent: scheme or table Zhu, Mingyan; Lim, Byung Joon; Koh, Minseob; Park, Seung Bum [ACS Combinatorial Science, 2012, vol. 14, # 2, p. 124 - 134]
[12]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/110860, 2012, A1 Location in patent: Page/Page column 33
[13]Bano, Mohsina; Barot, Kuldipsinh P.; Jain, Shailesh V.; Ghate, Manjunath D. [Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 3008 - 3020]
[14]Pirotte, Bernard; Florence, Xavier; Goffin, Eric; Lebrun, Philippe [ChemMedChem, 2017, vol. 12, # 21, p. 1810 - 1817]
[15]Xiao, Meiling; Zhang, Fuming; Du, Zhe; Ma, Baochun [Advanced Synthesis and Catalysis, 2018, vol. 360, # 5, p. 911 - 916]
[16]Ng, Raymond A.; Sun, Minghua; Bowers, Simeon; Hom, Roy K.; Probst, Gary D.; John, Varghese; Fang, Lawrence Y.; Maillard, Michel; Gailunas, Andrea; Brogley, Louis; Neitz, R. Jeffrey; Tung, Jay S.; Pleiss, Michael A.; Konradi, Andrei W.; Sham, Hing L.; Dappen, Michael S.; Adler, Marc; Yao, Nanhua; Zmolek, Wes; Nakamura, David; Quinn, Kevin P.; Sauer, John-Michael; Bova, Michael P.; Ruslim, Lany; Artis, Dean R.; Yednock, Ted A. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 16, p. 4674 - 4679]

8
[ 1450-75-5 ]
[ 106-89-8 ]
[ 73933-64-9 ]

Yield	Reaction Conditions	Operation in experiment
79%
59.49%	With potassium carbonate In acetonitrile at 8℃;	10.1 Step 1: TDI01314-1-a (8.00 g, 37.20 mmol) and 2-(chloromethyl)oxirane (6.88 g, 74.40 mmol) were dissolved in acetonitrile(200 mL), potassium carbonate (15.42 g, 111.60 mmol) was added, and the reaction was performed at 80°Covernight. Thin layer chromatography indicated the reaction was complete. The reaction solution was concentratedunder reduced pressure, and the crude product was separated and purified by flash column chromatography to affordTDI01314-1-b (6 g, white solid, yield: 59.49%). MS m/z (ESI): 271.1; 273.1 [M+H].
59.49%	With potassium carbonate In acetonitrile at 80℃;	10.1 Step 1: TDI01314-1-a (8.00 g, 37.20 mmol) and 2-(chloromethyl)oxirane (6.88 g, 74.40 mmol) were dissolved in acetonitrile (200 mL), potassium carbonate (15.42 g, 111.60 mmol) was added, and the reaction was performed at 80°C overnight. Thin layer chromatography indicated the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by flash column chromatography to afford TDI01314-1-b (6 g, white solid, yield: 59.49%). MS m/z (ESI): 271.1; 273.1 [M+H].

48%	With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 64h;	3-(2-Acetyl-4-bromophenoxy)-1,2-epoxypropane (35). Potassiumcarbonate (1.41 g, 10,2 mmol) and epichlorohydrin (1.46 mL,18.6 mmol) were added to a solution of 2-acetyl-4-bromophenol(2 g, 9.3 mmol) in DMF (22 mL). After stirring at 40 °C for 64 h,the mixture was poured into water (60 mL) and extracted withethyl acetate (3 30 mL). The combined organic extracts werewashed with 1 M NaOH (30 mL) and brine (30 mL), dried overNa2SO4, and concentrated to give a brownish oil, which was purifiedby flash chromatography. Elution with 70/30 cyclohexane/ethylacetate gave 1.21 g (48.0%) of 35 as a white wax: 1H NMR (CDCl3)δ 7.84 (d, 1 H, J 2.6 Hz), 7.53 (dd, 1 H, J 8.8, 2.6 Hz), 6.85 (d, 1 H,J 8.8 Hz), 4.37 (dd, 1 H, J 10.9, 2.7 Hz), 3.97 (dd, 1 H, J 10.9,6.0 Hz), 3.39 (m, 1 H), 2.95 (t, 1 H, J 4.5 Hz), 2.76 (dd, 1 H, J 4.7,2.6 Hz), 2.64 (s, 3 H).
	With potassium hydroxide In ethanol; water Reflux;

Reference： [1]Sangwan, Naresh K.; Rastogi, Shri Nivas [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1981, vol. 20, # 6, p. 480 - 483]
[2]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - EP3421465, 2019, A1 Location in patent: Paragraph 0140; 0141
[3]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - EP3421464, 2019, A1 Location in patent: Paragraph 0138; 0139
[4]Straniero, Valentina; Pallavicini, Marco; Chiodini, Giuseppe; Zanotto, Carlo; Volontè, Luca; Radaelli, Antonia; Bolchi, Cristiano; Fumagalli, Laura; Sanguinetti, Maurizio; Menchinelli, Giulia; Delogu, Giovanni; Battah, Basem; De Giuli Morghen, Carlo; Valoti, Ermanno [European Journal of Medicinal Chemistry, 2016, vol. 120, p. 227 - 243]
[5]Yin, Xuguang; Huang, Yi; Chen, Ziyi; Hu, Yang; Tao, Lin; Zhao, Qingyang; Dong, Xiu-Qin; Zhang, Xumu [Organic Letters, 2018, vol. 20, # 14, p. 4173 - 4177]

9
[ 18664-32-9 ]
[ 1450-75-5 ]
[ 168819-25-8 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 3797 - 3805

10
[ 1450-75-5 ]
[ 107-30-2 ]
[ 148872-85-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 5-Bromo-2-hydroxyacetophenone With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Stage #3: With ammonium chloride In water; N,N-dimethyl-formamide	334.1; 11 [00603] To a slurry of sodium hydride (60% oily dispersion; 1.125 g, 28 mmol) in anhydrous DMF (80 mL), l -(5-bromo-2-hydroxyphenyl)ethanone (4.67 g, 21.7 mmol) was added at 0 0C under a nitrogen atmosphere. After stirring for 1 h at the same temperature, methyl chloromethyl ether (tech, 90%; 2.35 g, 26 mmol) was added dropwise. The reaction mixture was allowed to gradually warm to room temperature and was stirred for 4 h. The reaction mixture was then quenched by pouring it onto saturated NH4Cl (aq) (100 mL). The reaction mixture was then extracted with 8: 1 Et2OZEtOAc (2x 150 mL). The combined organic layers were washed with water (4x 80 mL), brine (60 mL), and dried over MgSO4. After purification by flash chromatography (9: 1 hexane/EtOAc), the title compound (15) was obtained as colorless oil (4.44 g, 79% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (d, IH), 7.50 (dd, IH), 7.09 (d, IH), 5.27 (s, 2H), 3.51 (s, 3H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.5, 155.6, 136.2, 133.0, 130.6, 1 17.0, 1 14.5, 94.8, 56.7, 31.9. MS (GC-MS) for C8H7BrO2: 214, 216 (MH+).
	With sodium hydride In tetrahydrofuran for 0.5h;
	With tetra-(n-butyl)ammonium iodide; N-ethyl-N,N-diisopropylamine In hexane; dichloromethane; ethyl acetate	5-Bromo-2-methoxymethoxyacetophenone (Compound P) 5-Bromo-2-methoxymethoxyacetophenone (Compound P) To a cold solution (0° C.) of 4.5 g (21.0 mmol) of 5-bromo-2-hydroxyacetophenone (Compound F) in 160 mL of dichloromethane (under a blanket of argon) was added 22 mL (16.3 g, 126.3 mmol) of N,N-diisopropylethylamine followed by 2.6 mL (2.8 g, 34.2 mmol) of chloromethyl methyl ether and 52 mg of tetrabutylammonium iodide. The resultant yellow solution was heated to reflux in an oil bath (45° C.) overnight (14.75 hours), cooled to ambient temperature, concentrated in vacuo and then extracted and partitioned between ethyl acetate and sat. NaHCO3 (aq.) solution. The layers were separated and the organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a yellow oil. PMR (CDCl3): δ 2.62 (3H, s), 3.51 (3H, s), 5.26 (2H, s), 7.10 (1H, d, J=8.7 Hz), 7.51 (1H, dd, J=2.6, 8.7 Hz), 7.81 (1H, d, J=2.6 Hz).

With N-ethyl-N,N-diisopropylamine In dichloromethane

46 EXAMPLE 46 To a solution of 2-acetyl-4-bromophenol (3.63 g, 16.9 mmol) in methylene chloride (20 ml) on ice bath were added diisopropylethylamine (5.88 ml, 33.8 mmol) and chloromethyl methyl ether (1.92 ml, 25.3 mmol) with stirring. The mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give 4-(methoxymethyl) oxy-3-acetylbromobenzene (4.35 g, quantitatively).

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2008/133955, 2008, A1 Location in patent: Page/Page column 182; 183
[2]Lim, Soon Sung; Jung, Sang Hoon; Ji, Jun; Shin, Kuk Hyun; Keum, Sam Rok [Journal of Pharmacy and Pharmacology, 2001, vol. 53, # 5, p. 653 - 668]
[3]Current Patent Assignee: ABBVIE INC - US6037488, 2000, A
[4]Current Patent Assignee: Mitsubishi Chemical Corp (in: MCHC Group); MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US5514711, 1996, A

11
[ 1450-75-5 ]
[ 74-88-4 ]
[ 16740-73-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In acetone;	1-(5-Bromo-2-methoxy-phenyl)-ethanone A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 47 mmol), methyl iodide (3.5 mL, 56 mmol), and potassium carbonate (10 g, 73 mmol) in acetone (80 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and the resulting white solid filtered and washed thoroughly with ethyl acetate. The filtrate was washed with water, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to provide the title compound (10 g, 94%) as a white solid.
91%		Potassium carbonate (9.6 g) was added to a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et2O and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91% yield). LC-MS (Method 1): m/z [M+H]+=229.1 (MW calc.=229.07); Rt=3.30 min.
91%		Intermediate 7a) Potassium carbonate (9.6 g) was added to a solution of 1 -(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et20 and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91 % yield). LC-MS (Method 1): m/z [M+H]+ = 229.1 (MW calc. = 229.07); R, = 3.30 min.

89%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	A mixture of 5-Bromo-2-hydroxyacetophenone 2a (10g, 46.5mmol, 1 eq), potassium carbonate (9.62g, 69.75mmol, 1.5 eq) and iodomethane (5.8mL, 93mmol, 2 eq) in DMF (120mL) were stirred overnight in a sealed round bottom flask at room temperature. DMF was removed under reduced pression and the residue was partitioned between water and EtOAc. The combined EtOAc extracts were washed with brine, 0.5M NaOH and then three times with water. The organic layer was dried over MgSO4 and the solvent evaporated. The product was obtained as an off-white solid (9.5g, 89%). m.p. 31-32C. SM (ESI): m/z 251-253 [M+Na]+. 1H NMR (delta ppm): 2.54 (s, 3H, COCH3), 3.90 (s, 3H, OCH3), 7.18 (d, Jortho=8.9Hz, 1H, CHar), 7.66 (d, Jmeta=2.6Hz, 1H, CHar), 7.72 (dd, Jortho=8.9Hz, Jmeta=2.6Hz, 1H, CHar).
75%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere;	To a stirred solution of 1 -(5-bromo-2-hydroxyphenyl)ethan- 1-one 1 (10 g, 46.51 mmol) in DMF (100 mL) were added K2C03 (9.63 g, 69.77 mmol) and Mel (5.8 mL, 93.02 mmol) at 0C under Ar. The mixture was stirred at RT for 12 h then quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure to afford compound 2 (8.8 g, 75%) as pale yellow liquid. ?H NIVIR (500MHz, DMSO-d6): 7.70 (dd, J 9.0, 2.6 Hz, 1H), 7.64 (d, J= 2.6 Hz, 1H), 7.16 (d, J= 9.0 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H); LC-MS (ESI):m/z 228.8 (M + Hf).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2561 - 2563
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 4142 - 4157
[3]Tetrahedron,2001,vol. 57,p. 5027 - 5038
[4]Chemistry - A European Journal,2016,vol. 22,p. 10415 - 10419
[5]Patent: US2003/187007,2003,A1
[6]Patent: US2014/194443,2014,A1 .Location in patent: Paragraph 0427-0429
[7]Patent: WO2014/108337,2014,A1 .Location in patent: Page/Page column 56; 57
[8]European Journal of Medicinal Chemistry,2018,vol. 144,p. 774 - 796
[9]Journal of the Chemical Society. Perkin Transactions 1 (2001),2002,p. 1115 - 1123
[10]Patent: WO2017/15221,2017,A1 .Location in patent: Paragraph 00255
[11]Organic and Biomolecular Chemistry,2005,vol. 3,p. 4432 - 4443
[12]Advanced Synthesis and Catalysis,2018,vol. 360,p. 1634 - 1638

12
[ 1450-75-5 ]
[ 33513-42-7 ]
[ 52817-12-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: N,N-dimethyl-formamide With bis(trichloromethyl) carbonate In 1,2-dichloro-ethane at 0 - 20℃; Stage #2: 5-Bromo-2-hydroxyacetophenone In 1,2-dichloro-ethane at 0 - 20℃; for 4.5h; Further stages.;
81%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate Cooling; Stage #2: 5-Bromo-2-hydroxyacetophenone at 20℃; Cooling;	Synthesis of 4-oxo-4H-chromene-3-carbaldehydes(2a-2d). General procedure: The Vilsmeier-Haack adduct was synthesizedfrom POCl3 (10 mmol) and N,N-dimethylformamide(25 mmol) at 0°C. A substituted-2-hydroxy acetophenone1a-1d, (1.0 mmol) was added to theVilsmeier-Haack adduct and the mixture was stirred atroom temperature for 16-18 h. Progress of the reactionwas monitored by TLC. Upon completion of theprocess, the reaction mixture was poured into ice coldwater and the white product was filtered off and dried.The products 2a-2d were purified by recrystallizationfrom petroleum ether : ethyl acetate mixture.
76.9%	With trichlorophosphate In water at 0 - 25℃; for 12h;	Synthesis of 4-oxo-4H-chromene-3-carbaldehyde analogues General procedure: 2-hydroxyacetophenones 1a-f (40 mmol) in DMF (23 mL) were cooled to 0 °C, then POCl3 (150 mmol) was added gradually to the solution with constant stirring. The solution was then stirred at room temperature for 12 h, quenched with ice water (50 mL). The solid formed was filtered, dried and recrystallized from ethanol to afford the corresponding 4-oxo-4H-chromene-3-carbaldehyde analogues 2a-f.

72%	Stage #1: 5-Bromo-2-hydroxyacetophenone; N,N-dimethyl-formamide at -10℃; for 0.5h; Stage #2: With trichlorophosphate at -10 - 20℃; for 16h;	2 4.3.2 Synthesis of 6-bromo-4-oxo-4H-chromene-3-carbaldehyde (15) A solution of 5'-bromo-2'-hydroxyacetophenone (14) (6 mmol) and anhydrous N,N-dimethylformamide (12 mL) was stirred at a temperature of -10 °C for 30 min. Phosphoryl chloride (POCl3) (12 mmol) was added dropwise during 1 h. The mixture was stirred at room temperature for 15 h and poured into water (40 mL) [42]. The product was filtered and washed with ethyl ether (2 x10 mL). Yield: 72%. 1H NMR (400 MHz, DMSO-d6) δ: 10.10 (1H, s, COH), 8.96 (1H, s, H(2)), 8.20 (1H, d, J = 2.5 Hz, H(5)), 8.05 (1H, dd, J = 8.9, 2.5 Hz, H(7)), 7.76 (1H, d, J = 8.9 Hz, H(8)). 13C NMR (101 MHz, DMSO-d6) δ: 189.4 (COH), 175.1 (C4), 165.2 (C2), 156.0 (C8a), 139.1 (C7), 128.7 (C5), 127.6 (C4a), 122.9 (C6), 121.4 (C8), 120.6 (C3).
53%	With trichlorophosphate at 0 - 20℃; for 1.5h;
24%	With trichlorophosphate at 0 - 20℃;	3 Synthesis of 6-substituted 4-oxo-4H-chromene-3-carbaldehydes General procedure: POCl3 (112.6 g, 0.72 mol) was added slowly to a well stirred and cooled (0-5 °C) mixture of N,N-dimethylformamide (53.6 g, 0.72 mol), o-hydroxyacetophenone c1 (20.1 g, 0.14 mol) for 30 min. The ice bath was removed and the mixture was further stirred for 8-12 h at room temperature. The orange-yellow colored organic mass was poured into crushed ice (400 g) with stirring, extracted with EtOAc (8 * 50 mL) and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. Thus obtained residue was subjected to column chromatography purification on silica gel .
	With trichlorophosphate at 60℃;
	With trichlorophosphate at 20℃; for 12h;
	Stage #1: 5-Bromo-2-hydroxyacetophenone; N,N-dimethyl-formamide With trichlorophosphate Stage #2: With water
	Stage #1: 5-Bromo-2-hydroxyacetophenone; N,N-dimethyl-formamide With trichlorophosphate Stage #2: With water
	With oxalyl dichloride at 0 - 20℃;	General procedure for the synthesis of 4-oxo-4H-chromene-3-carbaldehydes using oxalyl chloride (4a-j): Oxalyl chloride (4.7 g, 35 mmol) was added slowly to a well stirred and cooled (0-5 0C) mixture of N,N-Dimethylformamide (2.5 g, 35 mmol), 1-(2-hydroxyphenyl)ethanone (1 g, 7 mmol) for 30 min. The ice bath was removed and the mixture was further stirred for 8-12 h at room temperature. The orange-yellow colored organic mass was poured into crushed ice (20 g) with stirring, extracted with chloroform (2 x 30 mL) and the layers were separated. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. Thus obtained residue was subjected to column chromatography purification on silica gel to give 4-oxo-4H-chromene-3-carbaldehyde (4a) in 86% yield. The similar procedure was adopted in making other chromene carbaldehydes (4b-j).
	With trichlorophosphate at -5 - 0℃;
	With trichlorophosphate at 20℃;
	With trichlorophosphate	General Procedure for the preparation of 3-vinyl chromones 1a-e and 1l-v General procedure: The substituted 4-oxo-4H-chromene-3-carbaldehydes were prepared by Vilsmeier-Haack synthesis of 2′-hydroxyacetophenones following literature produces. [3]
	With trichlorophosphate at 0 - 65℃;
	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 5-Bromo-2-hydroxyacetophenone In chloroform at 20℃; for 16h; Inert atmosphere; Reflux;
	With trichlorophosphate at 0 - 64℃; for 4h;	1. General procedure for the synthesis of compounds 1a-1t General procedure: To a cooled (0°C)solution of 2'-hydroxyacetophenone (1 g, 1 eq) in DMF (30 mL) was added phosphorusoxychloride (5 eq). The mixture stirred at 64 °C for 4 h until the 2'-hydroxyacetophenone consumed completely (TLC). The reaction was quenched withglacial water (100 mL), and the mixture stirred for an additional 30 mins. Then themixture was extracted three times with dichloromethane (100 mL). And then the solventwas evaporated in vacuo and the crude product was purified by column chromatographyon silica gel.
	With trichlorophosphate at 0℃; for 2h;
	With trichlorophosphate at 20℃;
	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; Stage #2: 5-Bromo-2-hydroxyacetophenone at 20℃;

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[13]Zhu, Wufu; Chen, Chen; Sun, Chengyu; Xu, Shan; Wu, Chunjiang; Lei, Fei; Xia, Hui; Tu, Qidong; Zheng, Pengwu [European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73]
[14]Huang, Xu-Jiao; Tao, Yuan; Li, Yue-Kun; Wu, Xin-Yan; Sha, Feng [Tetrahedron, 2016, vol. 72, # 52, p. 8565 - 8577]
[15]Koh, Dongsoo; Jung, Yearam; Ahn, Seunghyun; Mok, Kenneth Hun; Shin, Soon Young; Lim, Yoongho [Magnetic Resonance in Chemistry, 2017, vol. 55, # 9, p. 864 - 876]
[16]Giardinetti, Maxime; Jessen, Nicolaj Inunnguaq; Christensen, Mette Louise; Jørgensen, Karl Anker [Chemical Communications, 2019, vol. 55, # 2, p. 202 - 205]
[17]Yuan, Jiaqi; He, Qian; Song, Shanshan; Zhang, Xiaofei; Miao, Zehong; Yang, Chunhao [Molecules, 2019, vol. 24, # 16]
[18]Huang, Ming; Jiang, Neng; Kong, Ling-Yi; Lan, Jin-Shuai; Wang, Xiao-Bing; Yin, Fu-Cheng [2020, vol. 11, # 2, p. 225 - 233]
[19]Current Patent Assignee: JIANGXI SCIENCE & TECHNOLOGY NORMAL UNIVERSITY - CN113563321, 2021, A Location in patent: Paragraph 0021-0023
[20]Wang, Taimin; Zhang, Biwei; Hu, Lin; Sun, Haiyan; Wang, Yan; Zhai, Hongbin; Cheng, Bin [Journal of Organic Chemistry, 2022, vol. 87, # 2, p. 1348 - 1356]

13
[ 1450-75-5 ]
[ 98-80-6 ]
[ 14031-80-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate In water monomer; isopropanol at 20℃; Inert atmosphere; Reflux;	General procedure for the synthesis of 6-substituted 1-(4-hydroxybiphenyl-3-yl)ethanone: PdCl2(PPh3)2 (0.07 g, 10 mol%) was added to a stirred solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (2b, 0.26 g, 1 mmol), phenylboronic acid (0.121 g, 1 mmol), K2CO3 (0.276 g, 2 mmol) in water (0.7 mL) and isopropanol (3 mL) at room temperature under N2 atmosphere and the contents were stirred at the same temperature for 20 min. The reaction mixture slowly heated to reflux for 12 h. After completion of the reaction (TLC), the solvents were removed under reduced pressure, the reaction mixture was extracted with ethyl acetate (2 x 30 mL) and washed with water, the organic layer was separated, dried over sodium sulfate, solvent removed under reduced pressure and the obtained crude product was purified by flash chromatography using silica gel (60-120) with hexane: ethyl acetate (98:2) as eluent to give 1-(4-hydroxybiphenyl-3-yl)ethanone (3g) in 94% yield as light greenish solid, mp 57-59 0C.
92%	With tripotassium phosphate tribasic; dichloro{bis[1-(dicyclohexylphosphanyl)(II) In toluene at 80℃; for 2h; Air;
91%	With C₂₀H₂₀N₂O₂Pd; Sodium hydrogenocarbonate In water monomer at 80℃; for 6h;

80%	With C₂₅H₁₆O₆C₄H₁₁NH₂O; palladium diacetate; potassium carbonate In water monomer at 80℃; for 1 - 2h;	Suzuki cross-coupling reactions General procedure: A mixture of aryl halide (1.0 mmol), phenylboronic acid (1.2 mmol), K2CO3 (2.0 mmol), novel ligand (0.1 mol %, 0.5 mg), and Pd(OAc)2 (0.1 mol%, 0.23 mg) was heated in water (5 ml) at 80 °C temperature. The progress of the reaction is monitor by TLC. After the completion of the reaction, ethyl acetate (10 ml) was added to the reaction mixture and extracted with ethyl acetate (3 x 10 ml). The combined organic layer was dried with anhyd. Na2SO4 and the solvent were concentrated in vacuum to obtain a light yellow-white solid. The residue was purified by silica gel column chromatography (5-10% EtOAc in hexane) to afford the corresponding pure products.
80%	With 2-hydroxy-3-(p-tolyl)-2,3-dihydroindan-1-one; palladium diacetate; potassium carbonate In ethanol at 20℃;	General Procedure for Suzuki-Miyaura Cross-Coupling Reactions (14-24) General procedure: A mixture of aryl halide/tosylate (1.0 mmol), phenylboronic acid (1.2 mmol), K2CO3 (2.0 mmol), ligand (0.1 mol%) and Pd(OAc)2 (0.1 mol%) in EtOH (5 mL) was stirred at r.t. The progress of the reaction was monitored by TLC. Upon completion of the reaction, solvent was removed under reduced pressure. Water (10 mL) was added to the reaction mixture and extracted with EtOAc (3 × 10 mL). The combined organic layer was dried with anhydrous Na2SO4 and the solvent was concentrated in vacuum to obtain a light yellow-white solid. The residue was purified by silica gel column chromatography (EtOAc-hexane,5-10%) to afford the corresponding pure products.
74%	With tetrabutylammonium bromide; palladium diacetate; potassium carbonate In water monomer at 150℃; for 0.25h; Microwave irradiation;	General procedure: General procedure: To a suspension of 5'-bromo-2'-hidroxyacetophenone(2.3 mmol) in water (7-10 mL), TBAB (2.3 mmol), K2CO3 (6.9 mmol), the appropriate boronic acid (2.3 mmol) and Pd(OAc)2 (0.4 mol %) were added. The system was heated to 150 °C for 15 min in a microwave apparatus. After cooling, the reaction mixture was filtered through a celite pad and washed with dichloromethane. The filtrated was collected dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography using gradient elution (hexane/EtOAc).
72%	With phenone oxime-derived palladacycle; potassium carbonate In water monomer for 1.66667h; Heating;
71%	With potassium carbonate In toluene at 110℃; for 0.25h;
	With dicyclohexyl({2’,6’-dimethoxy-[1,1‘-biphenyl]-2-yl})phosphane; tripotassium phosphate tribasic; palladium diacetate In water monomer; toluene at 100℃;	104.a a) 1-(4-Hydroxy-biphenyl-3-yl)-ethanone A solution was prepared of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (Combi-blocks, 6.2 g, 0.028 mol), 2% Pd(OAc)2(126 mg, 0.56 mmol), S-Phos (575 mg, 1.4 mmol), phenylboronic acid (5.1 g, 0.042 mol), and K3PO4(11.92 g, 0.056 mol) in toluene (140 mL) and water (1 mL). The reaction mixture was stirred at 100 C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc (500 mL) and washed with 0.1 N HCl and water. The dried extract (MgSO4) was concentrated in vacuo and purified by ISCO over silica gel, eluting with 2-50% EtOAc / hexanes, to give product. MS (m/z) 213.0 (M+1)+.

Reference： [1]China Raju; Nageswara Rao; Suman; Yogeeswari; Sriram; Shaik, Thokhir Basha; Kalivendi, Shasi Vardhan [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2855 - 2859]
[2]Location in patent: experimental part Bolliger, Jeanne L.; Frech, Christian M. [Chemistry - A European Journal, 2010, vol. 16, # 13, p. 4075 - 4081]
[3]Fu, Leiqing; Cao, Xiaoji; Wan, Jie-Ping; Liu, Yunyun [Chinese Journal of Chemistry, 2020, vol. 38, # 3, p. 254 - 258]
[4]Waheed, Mohammed; Ahmed, Naseem [Tetrahedron Letters, 2016, vol. 57, # 33, p. 3785 - 3789]
[5]Waheed, Mohammed; Ahmed, Naseem [Synthesis, 2017, vol. 49, # 18, p. 4372 - 4382]
[6]Fernandes, Carlos; Soares, Pedro; Gaspar, Alexandra; Martins, Daniel; Gomes, Ligia R.; Low, John N.; Borges, Fernanda [Tetrahedron Letters, 2016, vol. 57, # 27-28, p. 3006 - 3010]
[7]Botella, Luis; Nájera, Carmen [Journal of Organometallic Chemistry, 2002, vol. 663, # 1-2, p. 46 - 57]
[8]Alonso, Diego A.; Najera, Carmen; Pacheco, Ma Carmen [Journal of Organic Chemistry, 2002, vol. 67, # 16, p. 5588 - 5594]
[9]Current Patent Assignee: FIBROGEN, INC. - WO2022/47230, 2022, A1 Location in patent: Paragraph 0547

14
[ 1450-75-5 ]
[ 139755-99-0 ]
[ 778639-46-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,2004,vol. 41,p. 541 - 548

15
[ 1450-75-5 ]
[ 99-61-6 ]
[ 1021684-65-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 5-Bromo-2-hydroxyacetophenone With sodium hydride In tetrahydrofuran at 20℃; for 0.333333h; Stage #2: 3-nitro-benzaldehyde In tetrahydrofuran at 20℃;
69%	With sodium hydroxide In methanol; water at 70℃;	2.1.2. Synthesis of 2′ -hydroxychalcone derivatives General procedure: Chalcones were synthesised following (Kachadourian et al., 2012),with some modifications (Scheme 2). One mL of a 50% aqueous solutionof NaOH was added to a stirred solution of each acetophenone (1 mmol)and benzaldehyde (1 mmol) in MeOH (10 mL). The reaction mixture washeated for 3-5 h at 70 C (Scheme 2) and the reaction was monitored byHPLC.Upon reaction completion, the solution was neutralized with 10%HCl(aq) and extracted twice with an equal volume of CH2Cl2. Theorganic layer was dried under reduced pressure and recrystallized fromMeOH/H2O (70/30, v/v). Compounds purity was confirmed by HPLC as>98%. These recrystallized compounds were used for chemical identificationand assays
	With sodium hydroxide In ethanol; water at 20℃;

Reference： [1]Barros, Ana I. R. N. A.; Silva, Artur M. S. [Monatshefte fur Chemie, 2006, vol. 137, # 12, p. 1505 - 1528]
[2]Žakelj, Simon; Abin-Carriquiry, Juan Andrés; Carvalho, Diego; Colettis, Natalia; Gobec, Stanislav; Higgs, Josefina; Kamecki, Fabiola; Knez, Damijan; Marcos, Alejandra; Marcucci, Carolina; Marder, Mariel; Rademacher, Marina; de Tezanos Pinto, Felicitas [Neuropharmacology, 2021, vol. 201]
[3]Location in patent: experimental part Lorenz, Michael; Shahjahan Kabir; Cook, James M. [Tetrahedron Letters, 2010, vol. 51, # 7, p. 1095 - 1098]

16
[ 1450-75-5 ]
[ 33839-11-1 ]

Reference： [1]Bulletin de la Societe Chimique de France,1969,p. 781 - 787

17
[ 1450-75-5 ]
[ 70978-54-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With nitric acid; In tetrachloromethane;	1I 5-Bromo-2-hydroxy-3-nitroacetophenone A solution of 5-bromo-2-hydroxyacetophenone (23.7 g, 0.110 mol) in carbon tetrachloride (90 ml) was added with concentrated nitric acid (17.2 ml). The mixture was left under stirring at 75 C. for 50 minutes, then left to cool at room temperature. The precipitated solid was recovered by filtration washing with cold carbon tetrachloride. After drying under vacuum, 20.9 g of the title product were obtained as a light yellow solid (73% yield). 1 H N.M.R. (300 MHz, CDCl3) delta ppm: 2.73 (s, 3H); 8.14 (d, 1H); 8.31 (d, 1H); 12.92 (s, 1H).
	With sulfuric acid; nitric acid; at -5 - 0℃; for 1h;	A mixture of 12 mL of concentrated nitric acid and 12 mL of concentrated sulfuric acid was added to a solution of the 1-(5-bromo-2-hydroxy-3-nitrophenyl)-1-ethanone in 80 mL of concentrated sulfuric acid while stirring at -5 to 0C over a period of 1 hour. Ice water was added to the mixture and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (17.4 g) as yellow crystals.1H-NMR (CDCl3) delta: 2.75(3H, s), 8.13(1H, d, J=2Hz), 8.32(1H, d, J=2Hz), 12.90(1H, s).
	With nitric acid; In tetrachloromethane; at 70℃; for 1h;	To a solution of 1 -(5-bromo-2-hydroxyphenyl)ethan-1-one (1 g, 4.65 mmol) in CCI4 (6 mL) was added HNO3 (0.52 mL). The mixture was stirred at 70C for 1 h and then cooled to 25C and the precipitate was collected. The precipitate was washed with water (20 mL) and then petroluem ether (10 mL) to obtain a yellow solid.

Reference： [1]Patent: US5990142,1999,A
[2]Patent: EP1391451,2004,A1 .Location in patent: Page 113
[3]Patent: WO2017/221002,2017,A1 .Location in patent: Page/Page column 92

18
[ 1450-75-5 ]
[ 105-36-2 ]
[ 34849-50-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	1 Step-1: Ethyl 2-(2-acetyl-4-bromophenoxy)acetate To a mixture of l-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol) and K2CO3 (2.6 g, 18.6 mmol) in DMF (20 mL) was added, ethyl 2-bromoacetate (1.3 mL, 11.6 mmol) under nitrogen and the reaction mixture was stirred at room temperature (RT) overnight. After completion, the mixture was poured into ice cold water, filtered and dried to furnish the titled compound (2.75 g, 98%) as pale brown solid.
97%	With potassium carbonate In DMF (N,N-dimethyl-formamide) for 12h;	45.1 To a mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (2.1 g, 9.8 mmol, 1 eq) and K2CO3 (2.4 g, 17.4 mmol, 1.8 eq) in 15 mL of DMF was added 1.3 mL of bromo-acetic acid ethyl ester (11.7 mmol, 1.2 eq) under nitrogen. After 12 h, the mixture was worked up and crude compound recrystallized to give (2-acetyl-4-bromo-phenoxy)-acetic acid ethyl ester in 97% yield (2.87 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.7 (s, 3 H) 4.3 (q, J=7.1 Hz, 2 H) 4.7 (s, 2 H) 6.7 (d, J=8.8 Hz, 1 H) 7.5 (dd, J=8.8, 2.8 Hz, 1 H) 7.9 (d, J=2.8 Hz, 1 H).
64%	Stage #1: 5-Bromo-2-hydroxyacetophenone With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide at 20℃;	85.1 Step 1. Ethyl 2-(2-acetyl-4-bromophenoxy)acetateTo a solution of l-(5-bromo-2-hydroxyphenyl)ethan-l-one (10 g, 46.50 mmol) in N,N- dimethylformamide (80 mL) was added sodium hydroxide (2.23 g, 92.92 mmol) and then stirred for 1 hour at room temperature. Ethyl 2-bromoacetate (8.24 g, 49.34 mmol) was added dropwise and stirred overnight at room temperature. The reaction mixture was quenched by the addition of water (200 mL), adjusted to pH 5 with HCl (3N), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue which was purified by silica gel chromatography (5% ethyl acetate in petroleum ether) to afford ethyl 2-(2-acetyl-4-bromophenoxy)acetate as a light yellow oil (8.9 g, 64%). 'H-NMR (300 MHz, CDC13) δ 7.87 (d, J = 2.7 Hz, 1H), 7.52 - 7.55 (m, 1H), 6.74 (d, J = 8.7 Hz, 1H), 4.72 (s, 2H), 4.24 - 4.30 (m, 2H), 2.71 (s, 3H), 1.28 - 1.36 (m, 3H)

	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃;	20 (2-Acetyl-4-bromophenoxy)acetic acid Reference Example 20; (2-Acetyl-4-bromophenoxy)acetic acid; Ethyl bromoacetate (0.62mL) was added to a mixture of 5-bromo-2-hydroxyacetophenone (1.0g) and potassium carbonate (0.96g) inN,N-dimethylformamide (10mL) at room temperature with stirring, and the mixture was stirred at that temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl (2-acetyl-4-bromophenoxy)acetate as a crude product. The crude ethyl (2-acetyl-4-bromophenoxy)acetate was dissolved in ethanol (5mL). A 2mol/L aqueous solution of sodium hydroxide (5mL) was added to the solution, and the mixture was stirred at room temperature for 1hr. The reaction mixture was made acidic with the addition of 2mol/L hydrochloric acid (7mL), and then ethyl acetate and brine were added. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate and n-hexane to afford the title compound (0.85g).1H-NMR(CDCl3)δ ppm: 2.67 (3H, s), 4.75 (2H, s), 6.85 (1H, d, J=8.9Hz), 7.62 (1H, dd, J=2.5, 8.9Hz), 7.89 (1H, d, J=2.5Hz)
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	26 Reference Example 26; (2-Acetyl-4-bromophenoxy)acetic acid; Ethyl bromoacetate (0.619mL) was added to a mixture of 5-bromo-2-hydroxyacetophenone (1.0g) and potassium carbonate (0.964g) in N,N-dimethylformamide (10mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl (2-acetyl-4-bromophenoxy)acetate as a crude product. The crude ethyl (2-acetyl-4-bromophenoxy)-acetate was dissolved in ethanol (5mL). A 2mol/L aqueous solution of sodium hydroxide (5mL) was added to the solution, and the mixture was stirred for 1hr. The reaction mixture was made acidic with an addition of 2mol/L hydrochloric acid (7mL), and then ethyl acetate and brine were added. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate and n-hexane to afford the title compound (0.851g).
	With potassium carbonate In chloroform; acetone	R.1.a Preparation of (5-Cyano-3-methyl-2-benzofuranyl)methyltriphenylphosphonium Chloride a) 13.31 g of 2-acetyl-4-bromophenol, 11.0 g of ethyl bromoacetate and 9.7 g of anhydrous potassium carbonate were refluxed under heating in 70 ml of acetone for 2 hours. Insoluble materials were removed by filtration, and the resulting filtrate was concentrated and dried. The residue thus obtained was dissolved in chloroform, washed with water, and then dried to remove the solvent. The thus treated residue was washed with a mixed solvent system of ethanol and n-hexane to isolate insoluble crystals by filtration. In this way, 16.82 g of ethyl (2-acetyl-4-bromophenyl)oxyacetate was obtained in the form of colorless plate crystals. mp: 66°-68° C.
	With potassium carbonate In acetonitrile

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2015/162538, 2015, A1 Location in patent: Page/Page column 33; 36; 37
[2]Current Patent Assignee: PFIZER INC - US2005/143422, 2005, A1 Location in patent: Page/Page column 41
[3]Current Patent Assignee: SYNERGENICS LCC - WO2012/119046, 2012, A2 Location in patent: Page/Page column 180
[4]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - EP1593666, 2005, A1 Location in patent: Page/Page column 29-30
[5]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - EP1679304, 2006, A1 Location in patent: Page/Page column 37
[6]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US5576343, 1996, A
[7]Ando, Kumiko; Kawamura, Yoko; Akai, Yukiko; Kunitomo, Jun-Ichi; Yokomizo, Takehiko; Yamashita, Masayuki; Ohta, Shunsaku; Ohishi, Takahiro; Ohishi, Yoshitaka [Organic and Biomolecular Chemistry, 2008, vol. 6, # 2, p. 296 - 307]

19
[ 72287-26-4 ]
[ 477251-79-9 ]
[1,1'-bis(diphenylphosphino)ferrocene]dichloronickel [ No CAS ]
[ 1450-75-5 ]
[ 497-19-8 ]
[ 73183-34-3 ]
[ 477252-06-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate; In hexane; N,N-dimethyl-formamide;	Example 23 N-Isopropyl-1-[3-(3-Acetyl-4-Hydroxyphenyl)Phenyl]-1,4-Dihydro[1,8]Naphthyridin-4-One-3-Carboxamide A mixture of 5'-bromo-2'-hydroxyacetophenone, diboron pinacol ester (1.25 eq), potassium acetate (3 eq) and [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) in N,N-dimethylformamide (10 ml/mmol) was stirred at 80° C. for 3 hours and cooled down. A solution of N-Isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 1, Step 4 (0.75 eq) in N,N-dimethylformamide (7 ml/mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) and 2M aqueous sodium carbonate (8.5 eq) were added and the resulting mixture was stirred at 80° C. for 2.5 hours. The cooled mixture was partitioned between ethyl acetate and water and the product from the organic phase was chromatographed on silica gel eluding with 60percent ethyl acetate in hexane to afford the title compound as a light yellow solid. 1H NMR (Acetone-d6) delta 1.24 (d, 6H), 2.75 (s, 3H), 4.19 (m, 1H), 7.06 (d, 1H), 7.59-7.63 (m, 2H), 7.72 (t, 1H), 7.92 (d, 1H), 7.97 (d, 1H), 8.02 (s, 1H), 8.33 (s, 1H), 8.73 (m, 1H), 8.78 (dd, 1H), 8.90 (s, 1H), 9.65 (br, NH).

Reference： [1]Patent: US2003/96829,2003,A1

20
[ 1450-75-5 ]
[ 35794-84-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	In hexane; ethyl acetate; N,N-dimethyl-formamide;	Step-(i): 3-Acetyl-4-hydroxy-benzonitrile 12 A solution of 5-bromo-2-hydroxyacetophenone (11, 10.00 g, 46.5 mmoles) in anhydrous DMF (25 mL) was mixed with copper cyanide (6.25 g, 69.75 mmoles) and the resulting reaction mixture was heated for about 8 to 16 hours at a temperature of about 160 C. The reaction mixture was cooled to room temperature and mixed with ether, the ether mixture was filtered through celite and the filtrate concentrated to afford a solid which was purified by flash column chromatography through silica using Hexane/EtOAc (4:1) as eluant to yield compound 12 as a clear colorless oil (5.25 g, 70%). 1H-NMR (DMSO-66) d: 8.31 (s, 1H), 7.92 (d, 1H, J=8.4 Hz), 7.12 (d, 1H, J=8.7 Hz), 2.65 (s, 3H).

Reference： [1]Patent: US2002/45650,2002,A1

21
[ 110-89-4 ]
[ 1450-75-5 ]
[ 99853-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid In acetone; benzene	2,2-Dimethyl-6-bromo-chroman-4-one (Compound 260) 2,2-Dimethyl-6-bromo-chroman-4-one (Compound 260) To a solution of piperidine (2,83 g, 33.25 mmol) in 45 mL benzene was added trifluoroacetic acid (344.6 mg, 3.02 mmol) as a solution in 4.0 mL of benzene. Acetone (8.78 g, 151.3 mmol) was added followed by 2-hydroxy-5-bromoacetophenone (Compound 259, 6.50 g, 30.23 mmol). The resulting solution was heated to reflux in a flask fitted with a Dean-Stark trap. After 24 hours, an additional 2.5 equivalents of acetone and 0.1 equivalents of trifluoroacetic acid were added. After a total of 43 hours the reaction was cooled to room temperature and diluted with EtOAc. The solution was washed with 1M aqueous HCl, H2 O, and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Distillation of the residual oil (bulb-to-bulb) afforded 4.80 g (62%) of the title compound as a clear yellow oil, bp 105-115° C./5 mm. The reaction conditions here are a moderate modification of the synthesis of the title compound described by Buckle et al. in J. Med. Chem. 1990 3028-3034. 1 H NMR (300 MHz, CDCl3) δ: 7.97 (1H, d, J=2.6 Hz), 7.54 (1H, dd, J=2.6, 8.7 Hz), 6.84 (1H, d, J=8.8 Hz), 2.72 (2H, s), 1.46 (6H, s).

Reference： [1]Current Patent Assignee: IO THERAPEUTICS - US5958954, 1999, A

22
[ 620-72-4 ]
[ 1450-75-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	aluminium trichloride;	Anhydrous aluminum chloride (11.03 g, 82.8 mmol) was added bit by bit to <strong>[620-72-4]4-bromoacetoxybenzene</strong> (8.90 g, 41.4 mmol) heated at 80° C. with stirring. The mixture was stirred at 100° C. for 2.5 hours, allowed to cool, mixed bit by bit with ice water and extracted with ethyl acetate (80 ml1; 20 ml1). The extract was dried over anhydrous magnesium sulfate and concentrated to give 2-acetyl-4-bromophenol (7.92 g, 89percent).

Reference： [1]Patent: US5514711,1996,A

23
[ 123-75-1 ]
[ 1450-75-5 ]
[ 99853-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In acetone; toluene	R.73 Reference Example 73 Reference Example 73 A solution of 5-bromo-2-hydroxyacetophenone 10.0 g (46.5 milli mole), acetone (17 ml) and pyrrolidine (3.9 ml) in toluene (100 ml) was refluxed for 4 hours. To the mixture was added acetone (17 ml), and the mixture was refluxed for 15 hours. To the mixture was added 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brined, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:7) to give yellow oil of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-1-benzopyran-4-one (7.57 g). 1H-NMR (200 MHz, CDCl3) δ 1.46 (6H, s), 2.72 (2H, s), 6.83 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J=8.8, 2.6 Hz), 7.97 (1H, d, J=2.6 Hz). IR (neat) 1689, 1597, 1464, 1414, 1373, 1319, 1282, 1225, 1167, 1132, 1066, 926, 827 cm-1.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US6235771, 2001, B1

24
[ 1450-75-5 ]
[ 79099-07-3 ]
[ 690632-38-3 ]

Yield	Reaction Conditions	Operation in experiment
99%		To a stirred solution of pyrrolidine (1.07g, 15 mmol) in MeOH (150 mL) was added 5-bromo-2-hydroxy acetophenone (6.45g, 30 mmol) (solution turned yellow). Then 4-t- butoxycarbonyl-piperidone (5.98g, 30 mmol) was added (solution turned brown). The reaction was heated at 80 0C overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (300 mL). The mixture was washed with 1 N HCl (150 mL), IN NaOH (150 mL x 2), water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to give compound 8A (11.7g, 99%). 1H-NMR (CDCl3) delta 7.95 (d, J = 2.7 Hz, IH), 7.55 (dd, J = 8.7, 2.7 Hz, IH), 6.88 (d, J = 8.7 Hz, IH), 3.84 (br s, 2H), 3.21-3.13 (m, 2H), 2.03-1.95 (m, 2H), 1.64-1.55 (m, 2H), 1.44 (s, 9H).
97%		Example 13Preparation of Compound 17 Step 1A mixture of compound 13a (11.1 g, 52 mmol) and pyrrolidine (5.6 mL, 67 mmol) in toluene (200 mL) was stirred at 20 C. for 20 minutes. The mixture was then treated with 1-BOC-4-piperidone 13b (13.4 g, 67 mmol) and refluxed for about 15 hours. The reaction mixture was then cooled to room temperature, washed sequentially with 10% aqueous NaOH and H2O, dried over MgSO4, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography (10% EtOAc/hexanes) to provide compound 13c (20.0 g, 97%) as a yellow solid.
94%	With pyrrolidine; In methanol; for 11h;Reflux;	Intermediate 1: (E)-3-14-Oxo-spiro[chromane-2,4'-piperidine]-6-yl}-acrylic acid methyl ester [Show Image] STEP A A mixture of 2-hydroxy-5-bromoacetophenone (10.75 g, 50 mmol), N-BOC-4-piperidone (9.96 g, 50 mmol) and pyrrolidine (2.09 ml, 25 mmol) in MeOH (80 ml) was heated to reflux for 11 h. The solvent was removed under vacuum and the crude mixture was purified by column chromatography (eluent: hexane/AcOEt 90:10 to 80:20) to give 6-bromo-4-oxo-spiro[chromane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (18.55 g) as a yellow solid. Y=94% LC-MS: Method A, rt=6.4 min; (ES+) MNa+: 419.8 1H-NMR (CDCl3) delta (ppm): 7.96 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 3.84 (m, 2H), 3.18 (t, J=11.6 Hz, 2H), 2.70 (s, 2H), 2.00 (m, 2H), 1.60 (m, 2H), 1.44 (s, 9H).

93%	With pyrrolidine; In methanol; for 4h;Reflux;	5-bromo-2-hydroxyacetophenone(2.15 g, 10 mmol), N-Boc-4-piperidone (1.99 g, 10 mmol) was dissolved in methanol (15 mL), pyrrolidine (1 mL, 13 mmol) was added and the mixture was heated at reflux for 4 hours until the starting material disappeared. The solvent was distilled off, and the residue was dissolved in dichloromethane (100 mL), washed with 1N hydrochloric acid (50 mL) and saturated brine (50 mL) successively, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution Agent: petroleum ether/ethyl acetate = 10:1 to 4:1) Compound 1-e (3.69 g, 93%) was obtained.
92%	With pyrrolidine; In methanol; for 12h;Reflux;	j00228J 1 -(5 -Bromo-2-hydroxyphenyl)ethan- 1-one (10.0 g, 45.5 mmol), tert-butyl 4- oxopiperidine-1-carboxylate (9.27 g, 46.5 mmol) and pyrrolidine (1.91 mL, 23.3 mmol) were combined in 75 mL of MeOH and refluxed for 12 h. After cooling down to room temperature the reaction mixture was concentrated to dryness and purified by normal phase silica gel (EtOAc/hexanes gradient). After purification 17.1 g (92% yield) of the title compound was obtained. ?H NIVIR (300 MHz, CDC13) (ppm): 7.96 (d, J= 2.5 Hz, 1H), 7.55 (dd, Jj = 8.8 Hz, J2 = 2.5 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 3.86 (br s, 2H), 3.20-3.10 (m, 2H), 2.71 (s, 2H), 2.05-1.90 (m, 2H), 1.70-1.55 (m, 2H), 1.45 (s, 9H). MS: (ES, m/z): 296/298 [M-Boc].chromatography on
88%		To a stirred solution of 1 -(5-bromo-2-hydroxyphenyl)ethan-1 -one (10.0 g, 46.5 mmol) in MeOH (80 mL) in a screw capped pressure vessel was added pyrrolidine (1 .92 mL, 23.3 mmol). The resulting yellow-orange solution was stirred at RT for 30 minutes, and then treated with tert-butyl 4-oxopiperidine-1 -carboxylate (9.27 g, 46.5 mmol). The reaction vessel was sealed and heated to 80 C. After 18 hours LCMS indicated complete reaction. The solution was cooled to RT and concentrated to a syrup at reduced pressure. The residue was partitioned between EtOAc and 10% aqueous citric acid and the phases separated. The aqueous phase was extracted with EtOAc (1 x). The combined EtOAc solutions were washed with 10% aqueous citric acid (1 x), saturated aqueous NaHC03 (2x), dried over Na2S04, and concentrated at reduced pressure. The residue was subjected to flash chromatography (silica gel, 0-60% EtOAc/hexanes, gradient elution) followed by crystallization from hexanes to afford the title compound as a white solid (16.1 g, 88% yield). NMR (400 MHz, CDCI3) delta 7.96 (d, J = 2.3 Hz, 1 H), 7.56 (dd, J = 9.0, 2.3 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 3.86 (br s, 2H), 3.1 1 - 3.23 (m, 2H), 2.70 (s, 2H), 1 .94 - 2.04 (m, 2H), 1 .54 - 1 .67 (m, 2H), 1 .44 (s, 9H).
87%	With pyrrolidine; In methanol; at 60 - 65℃; for 3h;Heating / reflux;	Example 1 :Reaction between 5-Bromo-2-hydroxy acetophenone with N-Boc-4-piperidone; In a 500 ml 3-necked flask, fitted with a reflux condenser, a CaCI2 gaurd tube and a magnetic needle, 0.1 mol N-Boc-4-piperidone (19.5 g) and 0.1 16 mol pyrrolidine (8.95 g), dissolved in 100 ml of anhydrous MeOH at ambient temperature were added to 0.0837 mol 5-Bromo-2-hydroxyacetophenone (18 g). The reaction mixture was stirred under reflux at 60-650C for about 3 hrs. The reaction mixture was transferred to a rotary flask and MeOH was distilled off to obtain an orange viscous liquid. 75 ml of water was added and the product was extracted with ethyl acetate (4 timesl OO ml). The aqueous layer was discarded and the organic layer was dried over anhydrous Na2SO4. Ethyl acetate was distilled off and an orange viscous oil was obtained that was thoroughly dried in vacuo. Further purification by column chromatography with ethyl acetate/petrolether 10/90 yielded 28,7 g (87%) of a pale yellow crystalline solid. Melting Point: 140 -1430C
84%	With pyrrolidine; In methanol; at 20℃;	To a solution 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol) in methanol (20 mL) was added pyrrolidine (0.8 mL, 9.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (1.91 g, 9.6 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by Biotage chromatography (4OM column, 8% - 20% ethyl acetate/heptane gradient) to provide tert-butyl 6-bromo-4-oxo-3,4-dihydro-1 H-spiro[chromene-2,4 -piperidine]-1 -carboxylate as a yellow solid (3.09 g, 84%). 1H NMR (CDCI3) delta 7.96 (d, J=2.5, 1H), 7.56 (dd, J=8.7, 2.5, 1H), 6.89 (d, J=8.7, 1H), 2.70 (s, 2H), 1.44 (s, 9H).
83%	With pyrrolidine; In isopropyl alcohol; for 24h;Reflux;	General procedure: To a stirred solution of 2-hydroxyacetophenone derivative (1 eq)and Boc-4-piperidone (1.5 eq) in Isopropanol (10 mL for 1 mmol ofsubstrate), pyrrolidine (2 eq) was added drop wise at RT and stirred for15 min. Reaction mass heated to reflux for 24 h. TLC showed completionof starting material. The reaction mixture was cooled to RT andconcentrated under reduced pressure. The crude compound was dilutedwith water, pH adjusted to ~6 using 1 N HCl and extracted with ethylacetate. Combined organic layer washed with brine, dried over Na2SO4,filtered and concentrated to get crude compound. The crude compoundwas purified by flash column chromatography using 10-30% (v/v)ethyl acetate in pet ether as eluent to get desired compound 2.
79%	With pyrrolidine; In methanol; for 17h;Heating / reflux;	Step 1 :; Intermediate 1; Spiro[2H-1 -benzopyran-2,4'-piperidine]-1 '-carboxylic acid, 6-bromo-3,4- dihydro-4-oxo-, 1,1-dimethylethyl ester.; A mixture of 5'-bromo-2'-hydroxyacetophenone (50.0 g, 232.5 mmol), t-butyl 4-oxo-1- piperidinecaboxylate (46.3 g, 232.4 mmol) and pyrrolidine (50 ml_, 599.0 mmol) in methanol (500 mL) was refluxed for 17h, then cooled and concentrated. The red colored residue was dissolved in EtOAc (600 mL) and washed with water (2 x 200 mL), aqueous ~3M citric acid (2x 150 mL), water and brine. The organics were dried (Mg SO4) and concentrated to a thick, light orange foamy tar. Hexanes (~ 100 mL) was added and the vessel walls were scratched to induce crystallization. Another 150 mL hexanes was added and the mixture was stirred for 66 hrs, then filtered, rinsed with hexanes and air dried to afford 73.2 g (79%) of the title compound as a dull yellow solid: NMR (CDCI3) delta 7.94 (d, J = 2.5 Hz, 1 H), 7.54 (dd, J = 8.7, 2.5 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 1 H), 3.85 (br s, 2H), 3.16 (br t, J = 11.6 Hz, 2H), 2.69 (s, 2H), 1.98 (br d, J= 13.3 Hz, 2H), 1.62-1.54 (m, 2H), 1.43 (s, 9H).
	With pyrrolidine; In methanol;Heating / reflux;	Reference Example 3: beta-bromo-r-ftert-butoxycarbonvDspirofchroman^Lambda'-piperidini^-one. 6O mL of MeOH, 7.97 g of N-Boc-piperidin-4-one, and 3.34 mL of pyrrolidine were added to 8.60 g of 5-bromo-2- hydroxyacetophenone put in a 200- mL flask equipped with a condenser, and the mixture was overnight heated under reflux. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified through silica gel column chromatography (eluted with n-hexane/EtOAc=6/l) to obtain the intended compound as a pale yellow solid.; Reference Example 59: 6-(lH-tetrazol-5-yl)spiro[chroman-2,4'-piperidme"l-4-one hydrochloride salt. A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of Eta2O were added, and the mixture was filtered and dried to give tot-butyl 6-bromo-4-oxospiro-[chroman-2,4'-piperidine]-l'- carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tot-butyl 6-bromo-4-oxospiro[chroman-2,4'-piperidine]-r-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CNu)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, .17 mol). The slurry was heated to 900C for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5C, stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-buty 6-cyano-4-oxospiro[chroman-2,4'- piperidinej-l'-carboxylate. A solution of 23 g of tot-butyl 6-cyano-4-oxospiro[chroman-2,4'-piperidine]- l'-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100 0C for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of IM HCl (322 mmol). Alternatively, 0.5M HCl maybe added until pH = 3. The resulting layers were separated, the organic layer was washed with water/methanol (115 mL/46 mL), and then concentrated to give tot-butyl 4-oxo-6-(lH-tetrazol-5-yl)spiro[chroman-2,4'-piperidine]-r-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(lH-tetrazol-5-yl)spiro[chroman-2,4'-piperidine]-r-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 500C until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(lH-tetrazol-5-yl)spiro[chroman-2,4'-piperidine]-4-one hydrochloride salt.
	With pyrrolidine; In methanol;Heating / reflux;Product distribution / selectivity;	REFERENCE EXAMPLE 14 6-bromo-1'-(tert-butoxycarbonyl)spiro[chroman-2,4'-piperidin]-4-one 60 mL of MeOH, 7.97 g of N-Boc-piperidin-4-one, and 3.34 mL of pyrrolidine were added to 8.60 g of 5-bromo-2-hydroxyacetophenone put in a 200-mL flask equipped with a condenser, and the mixture was overnight heated under reflux. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified through silica gel column chromatography (eluted with n-hexane/EtOAc=6/1) to obtain the intended compound as a pale yellow solid. REFERENCE EXAMPLE 15 6-bromospiro[chroman-2,4'-piperidin]-4-one hydrochloride A mixture of 25.0 g of 5-bromo-2-hydroxyacetophenone, 25.0 g of N-Boc-piperidin-4-one, 9.68 mL of pyrrolidine and 250 mL of MeOH was heated under reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was put into 300 mL of 1,4-dioxane, and 100 mL of concentrated hydrochloric acid was added thereto and stirred at room temperature for 4 hour. The reaction solution was poured into water, and stirred overnight. The resulting precipitate was taken out through filtration, washed with water and n-hexane, and dried under reduced pressure to obtain the intended compound as a yellow solid. REFERENCE EXAMPLE 36 6-(1H-tetrazol-5-yl)spiro[chroman-2,4'-piperidine]-4-one hydrochloride salt A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate.
	With pyrrolidine; In methanol;Heating / reflux;	A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro-[chroman-2,4'-piperidine]-r-carboxylate. Alternatively, lO mL of pyrrolidine (121.31 mmol) may be used in this procedure.
	With pyrrolidine; In methanol;Reflux;	Reference Example 1-1: fert-Butyl 6-bromo-4-oxospirorchroman-2,4'-piperidinel-r-carboxylateA mixture of 5-bromo-2-hydroxyacetophenone (104 g, 485 mmol), N-Boc- piperidin-4-one (98.6 g, 494 mmol), 20 mL of pyrrolidine (17.3 g, 243 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give intended compound as a colorless solid.
42.2 g	With pyrrolidine; In methanol; for 4h;Reflux;	A solution of tert-butyl 4-oxopiperidine-1-carboxylate (21.5 g, 100 mmol), 1-(5-bromo- 2-hydroxyphenyl) ethan-1-one (20.0 g, 100 mmol), and pyrrolidine (20 mL, 270 mmol) in methanol (200 mL) was heated at reflux for 4 h until completion was confirmed by LC/MS. The methanol was concentrated, the residue was dissolved in TBME (250 mL) and washed with washed with iN HC1 (200mL), saturated NaHCO3 solution (200 mL) and brine (200 mL). The organic phase was dried (Mg504), filtered and concentrated to yield a gum. The cmde product was dissolved in hexanes (500 mL) and stirred at RT overnight to give a yellow solid, which was collected by filtration and further washed with hexanes. After drying, tert-butyl 6-bromo-4- oxospiro[chromane-2,4?-piperidinej-l?-carboxylate was obtained as a yellow solid (42.2 g).

Reference： [1]Patent: WO2009/97567,2009,A1 .Location in patent: Page/Page column 62
[2]Patent: US2011/166124,2011,A1 .Location in patent: Page/Page column 36
[3]Patent: EP2110377,2009,A1 .Location in patent: Page/Page column 14
[4]Journal of Medicinal Chemistry,2011,vol. 54,p. 3051 - 3064
[5]Patent: CN103304571,2018,B .Location in patent: Paragraph 0116-0118
[6]Patent: WO2016/168660,2016,A1 .Location in patent: Paragraph 00228
[7]Patent: WO2019/3148,2019,A1 .Location in patent: Page/Page column 27-28
[8]Patent: WO2007/54580,2007,A1 .Location in patent: Page/Page column 30
[9]Patent: WO2008/65508,2008,A1 .Location in patent: Page/Page column 17
[10]Bioorganic Chemistry,2019,vol. 92
[11]Patent: WO2007/88462,2007,A1 .Location in patent: Page/Page column 17
[12]Patent: WO2007/11809,2007,A1 .Location in patent: Page/Page column 92; 105
[13]Patent: US2008/171761,2008,A1 .Location in patent: Page/Page column 42; 45
[14]Patent: WO2008/88692,2008,A2 .Location in patent: Page/Page column 104
[15]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 949 - 953
[16]Patent: WO2010/2010,2010,A1 .Location in patent: Page/Page column 77
[17]Patent: WO2018/112204,2018,A1 .Location in patent: Paragraph 00313
[18]Journal of Medicinal Chemistry,2020,vol. 63,p. 3552 - 3562

25
[ 1450-75-5 ]
[ 79099-07-3 ]
[ 921760-46-5 ]

Yield	Reaction Conditions	Operation in experiment
96%		A mixture of 5-bromo-2-hydroxyacetophenone (6.0 g, 0.027 mol) and pyrrolidine (2.7 mL, 0.033 mol) in MeOH (48 mL) was stirred at 25C for 20 min in a sealed flask. The mixture was then treated with 1 -Boc-4-piperidone (5.55 g, 0.027 mol) and heated to 80 C for 16 h.The reaction mixture was then concentrated in vacuo and the residue dissolved in DCM (50 mL), cooled to 15C,treated with 4M HC1 -dioxane (30 mL) and stirred for 16 h at rt. The solid was filtered and washed with DCM to the title compound as a cream color HC1 salt (8.92 g, 96%). ? NMR (400 MHz, CD3OD) delta 7.93 (d, .7=2.5 Hz, 1 H), 7.71 (dd, J=8.9, 2.6 Hz, 1 H), 7.1 1 (d, .7=9.0 Hz, 1 H), 3.32 - 3.41 (m, 4 H), 2.90 (s, 2 H), 2.23 - 2.36 (m, 2 H), 1.87 - 2.05 (m, 2 H), MS ESI 297 [M + H]+, calcd for [C13H14BrN02+H]+ 297.02.
		Reference Example 4: 6-bromospiro[chroman-2,4'-piperidin1-4-one hydrochloride. A mixture of 25.0 g of 5-bromo-2-hydroxyacetophenone, 25.0 g of Nu-Boc-piperidin-4-one, 9.68 mL of pyrrolidine and 250 mL of MeOH was heated under reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was put into 300 mL of 1,4-dioxane, and 100 mL of concentrated hydrochloric acid was added thereto and stirred at room temperature for 4 hour. The reaction solution was poured into water, and stirred overnight. The resulting precipitate was taken out through filtration, washed with water and n-hexane, and dried under reduced pressure to obtain the intended compound as an yellow solid.

Reference： [1]Patent: WO2013/53051,2013,A1 .Location in patent: Page/Page column 93
[2]Patent: WO2007/11809,2007,A1 .Location in patent: Page/Page column 92

26
[ 1450-75-5 ]
[ 16420-13-6 ]
[ 1051383-78-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 20℃;	228.a a) O-(2-Acetyl-4-bromophenyl) dimethylcarbamothioate mx ure o -(- romo- - y roxyp eny)e an- -one (. g,. mmol) and 1,4-diazabicyclo[2.2.2]octane (8.60 g, 69.6 mmol) in N,N-dimethylformamide (120 mL) was stirred at room temperature for 10 min. Dimethylthiocarbamoyl chloride (10.5 g, 93.2 mmol) was then added in one portion and stirred overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude material was concentrated and purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a pale green oil (14.1 g, 100%). H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 2.4 Hz, 1 H), 7.63 (dd, J = 2.5, 8.7 Hz, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 3.45 (s, 3 H), 3.39 (s, 3 H), 2.53 (s, 3 H).
100%	With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 20℃;	228.a a) O-(2-Acetyl-4-bromophenyl) dimethylcarbamothioate mx ure o -(- romo- - y roxyp eny)e an- -one (. g,. mmol) and 1,4-diazabicyclo[2.2.2]octane (8.60 g, 69.6 mmol) in N,N-dimethylformamide (120 mL) was stirred at room temperature for 10 min. Dimethylthiocarbamoyl chloride (10.5 g, 93.2 mmol) was then added in one portion and stirred overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude material was concentrated and purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a pale green oil (14.1 g, 100%). H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 2.4 Hz, 1 H), 7.63 (dd, J = 2.5, 8.7 Hz, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 3.45 (s, 3 H), 3.39 (s, 3 H), 2.53 (s, 3 H).
67%	With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 20℃; for 16h;	97 Reference Example 97 O-(2-acetyl-4-bromophenyl)dimethylthiocarbamate [Show Image] To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (2.00 g, 9.30 mmol) and DABCO (2.09 g, 18.6 mmol) in DMF (23 mL) was added dimethylcarbamothioyl chloride (1.72 g, 14.0 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1N hydrochloric acid, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1) to give the title compound (61.3 mg, yield 67%) as an oil. 1H NMR (CDCl3) δ2.53 (3H, s), 3.39 (3H, s), 3.45 (3H, s), 6.98 (1H, d, J = 9.0 Hz), 6.62 (1H, dd, J = 9.0, 2.7 Hz), 7.88 (1H, d, J = 2.7 Hz).

Reference： [1]Current Patent Assignee: SCHROEDINGER LLC - WO2022/15624, 2022, A1 Location in patent: Page/Page column 279
[2]Current Patent Assignee: SCHROEDINGER LLC - WO2022/15624, 2022, A1 Location in patent: Page/Page column 279
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2123652, 2009, A1 Location in patent: Page/Page column 78

27
[ 1450-75-5 ]
[ 587-04-2 ]
[ 1212017-01-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydroxide In methanol; water at 70℃;	2.1.2. Synthesis of 2′ -hydroxychalcone derivatives General procedure: Chalcones were synthesised following (Kachadourian et al., 2012),with some modifications (Scheme 2). One mL of a 50% aqueous solutionof NaOH was added to a stirred solution of each acetophenone (1 mmol)and benzaldehyde (1 mmol) in MeOH (10 mL). The reaction mixture washeated for 3-5 h at 70 C (Scheme 2) and the reaction was monitored byHPLC.Upon reaction completion, the solution was neutralized with 10%HCl(aq) and extracted twice with an equal volume of CH2Cl2. Theorganic layer was dried under reduced pressure and recrystallized fromMeOH/H2O (70/30, v/v). Compounds purity was confirmed by HPLC as>98%. These recrystallized compounds were used for chemical identificationand assays
	With sodium hydroxide In ethanol; water at 20℃;

Reference： [1]Žakelj, Simon; Abin-Carriquiry, Juan Andrés; Carvalho, Diego; Colettis, Natalia; Gobec, Stanislav; Higgs, Josefina; Kamecki, Fabiola; Knez, Damijan; Marcos, Alejandra; Marcucci, Carolina; Marder, Mariel; Rademacher, Marina; de Tezanos Pinto, Felicitas [Neuropharmacology, 2021, vol. 201]
[2]Location in patent: experimental part Lorenz, Michael; Shahjahan Kabir; Cook, James M. [Tetrahedron Letters, 2010, vol. 51, # 7, p. 1095 - 1098]

28
[ 16740-73-1 ]
[ 1450-75-5 ]

Reference： [1]Journal of Chemical Research,2010,p. 222 - 227

29
[ 1450-75-5 ]
[ 105-58-8 ]
[ 4139-61-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium hydride; In toluene; at 100℃; for 4.5h;Cooling with ice;	2 (74 mmol) and diethyl carbonate (111 mmol) in toluene (160 mL) were added dropwise to sodium hydride (369 mmol) in toluene (50 mL) in ice-water bath. The mixture was stirred at ice bath for 30 min and at 100C for 4 h. The sodium hydride was quenched with water, acidized with hydrochloric acid and then the suspension was filtered separately, and the solid collected from this filtration was washed with toluene and water for three times. The solid dried at room temperature with phosphorus pentoxide. 3: yield 71%. 1H NMR (400MHz, CDCl3): delta 12.17 (s, 1H), 7.83 (d, J=2.45, 1H), 7.55 (dd, J=2.4Hz, 8.8Hz, 1H), 6.90 (d, J=9.2Hz, 1H), 2.63 (s, 3H) ppm.
70%	With sodium hydride; In toluene; at 100℃; for 4.5h;Cooling with ice;	General procedure: 2a-2c (23.1 mmol) and diethyl carbonate (34.7 mmol, 4.14 g) in toluene (10 mL) were added dropwise to sodium hydride (115 mmol, 4.7 g) in toluene (50 mL) in ice-water bath. The mixture was stirred at ice bath for 30 min and at 100 ? for 4 h. The sodium hydride was quenched with water, acidized with hydrochloric acid and then the suspension was filtered separately, and the solid collected from this filtration was washed with toluene and water for three times. The solid dried at room temperature with phosphorus pentoxide. 3a: yield 70%. HPLC purity: 96.9%.1H NMR (400 MHz, d6-DMSO): delta 5.62 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.81 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 12.51 (br s, 1H). 3b: yield 67%. HPLC purity: 96.9%. 3c: yield 86%. HPLC purity: 98.2%.1H NMR (400 MHz, d6-DMSO): delta 3.83 (s, 3H), 5.51 (s, 1H), 6.92-6.96 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 12.51 (br s, 1H).
69%	With sodium hydride; In toluene; at 0℃; for 4.5h;Reflux;	General procedure: To a stirred mixture of 5a-f (1.15 mmol) and sodium hydride (138 mg, 5.75 mmol) in 5 ml dry toluene, a solution of the diethyl carbonate (1.15 mmol) in dry toluene was dropped. The mixture was reacted at 0C for 30 min, then heated to reflux and reacted for another 4 h. The reaction mixture was quenched with water (20 mL) at ice bath and neutralized to pH 7 with 2 N HCl. The precipitate was filtered, washed with cold water and dried to get 6a-f.

		General procedure: Preparation of 4-hydroxycoumarin (step 1)9aA solution of 2-hydroxy-5-methoxyacetophenone (9 mmol,1.5 g) in toluene (15 mL) was added dropwise to a dry three-neckround-bottom flask containing sodium hydride (60% w/w suspension,45 mmol, 1.8 g) in toluene (10 mL). This was done under N2atmosphere at ice bath temperature. The mixturewas stirred at thesame temperature for 15 min and followed by the dropwise additionof diethylcarbonate (13.5 mmol, 1.6 g) in toluene (10 mL). Aftercomplete addition, the reaction mixturewas stirred at rt for 30 minand refluxed for five more hours. The reaction mixture wasquenched at ice bath temperature by slow addition of water(20 mL) and acidified with 2 N HCl. The product obtained as a solidprecipitate was filtered, washed with water, and dried under vacuumto get 4-hydroxy-6-methoxy-2H-chromen-2-one as a whitesolid (1.4 g, 82%). This product was directly used in step 2.
	With sodium hydride; In mineral oil; at 100℃; for 4h;	A mixture of 2-hydroxy-5-bromoacetophenone (5g, 23.1mmol) and diethyl carbonate (4.14g, 34.7mmol) were combined then added toluene (10ml) was dissolved. Sodium hydride (4.7g, mass fraction of 60%, 115mmol) and toluene (50ml) After mixing, the toluene was dissolved 2-hydroxy-5-bromoacetophenone and diethyl carbonate mixed solution was slowly added dropwise under ice bath among them. After dropping about 20min,The reaction temperature was raised to 100 deg.] C for 4 hours. After completion of the reaction, insolubles were filtered off the solid, the filter cake washed with toluene, repeating the first layer, followed by two to three times a small amount of water. With phosphorus pentoxide at room temperature under reduced pressure and dried to give a yellow solid (3.9g, 70% crude yield).
		In a 250 mL two-neck round-bottom flask, 9 mmol of ohydroxyacetophenonein 15 mL toluene was slowly added to sodiumhydride (60% w/w suspension, 5 equiv, 45 mmol, 1.8 g) intoluene (10 mL) under N2 atmosphere at 0 C. After 15 min,13.5 mmol of diethyl carbonate in 10 mL toluene was added dropwise,and the mixture was stirred at room temperature for 30 minand refluxed until the reaction finished (monitored by TLC (ThinLayer Chromatography)). After the mixture cooled to room temperature,the reaction was quenched by slowly addition of 2 N hydrochloricacid. The resulting precipitate was further purified by ashort silica gel column chromatography to give a white solid.

Reference： [1]New Journal of Chemistry,2018,vol. 42,p. 13985 - 13997
[2]European Journal of Medicinal Chemistry,2016,vol. 114,p. 232 - 243
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 799 - 807
[4]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2129 - 2135
[5]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3649 - 3653
[6]Advanced Synthesis and Catalysis,2013,vol. 355,p. 2550 - 2557
[7]Tetrahedron,2014,vol. 70,p. 6995 - 7005
[8]Journal of Heterocyclic Chemistry,2015,vol. 52,p. 1014 - 1018
[9]Patent: CN103254203,2016,B .Location in patent: Paragraph 0062; 0072; 0073
[10]Tetrahedron,2018,vol. 74,p. 970 - 974
[11]Bioorganic and medicinal chemistry letters,2020

30
[ 1450-75-5 ]
[ 98977-36-7 ]
[ 1212022-15-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With pyrrolidine; In methanol; at 70℃; for 3h;Microwave irradiation;	A mixture of 2-hydroxy-5-bromoacetophenone (4.36 g, 20.3 mmol), 1-BOC-piperidin-3-one (3.93 g, 20.3 mmol) and pyrrolidine (3.38 ml, 40.6 mmol) in MeOH (15 ml) was heated in the microwave apparatus at 70 C for 3 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography (eluent: petroleum ether/EtOAc 9:1 to 8:2) to give (+/-)-6-bromo-4-oxo-spiro[chromane-2,3'-piperidine-6-yl]-1'-carboxylic acid tert-butyl ester (6.3 g) as a red oil. Y = 78% LC-MS: (ES+) MNa+: 418 1H NMR (CDCl3) delta (ppm): 7.98 (d, J=2.35 Hz, 1 H), 7.58 (dd, J=8.80, 2.05 Hz, 1 H), 6.86 (d, J=8.51 Hz, 1 H), 3.89-4.06 (m, 1 H), 3.72-3.89 (m, 1 H), 3.12 (d, J=14.09 Hz, 1 H), 3.10 (ddd, J=13.50, 9.98, 3.52 Hz, 1 H), 2.75 (d, J=16.73 Hz, 1 H), 2.68 (d, J=17.61 Hz, 1 H), 2.02-2.17 (m, 2 H), 1.05-1.99 (m, 11 H).
78%	With pyrrolidine; In methanol; at 70℃; for 3h;Microwave irradiation;	Intermediate 2: (+/-)-(E)-3-[4-Oxo-spiro(chromane-2,3'-piperidine)-6-yl]-acrylic acid methyl ester STEP AA mixture of 2-hydroxy-5-bromoacetophenone (4.36 g, 20.3 mmol), 1 -BOC-piperidin- 3-one (3.93 g, 20.3 mmol) and pyrrolidine (3.38 ml, 40.6 mmol) in MeOH (15 ml) was heated in the microwave apparatus at 70 C for 3 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography (eluent: petroleum ether/EtOAc 9:1 to 8:2) to give (+/-)-6-bromo-4- oxo-spiro[chromane-2,3'-piperidine-6-yl]-1 '-carboxylic acid fe/t-butyl ester (6.3 g) as a red oil.Y = 78%LC-MS: (ES+) MNa+: 4181 H NMR (CDCIs) delta (ppm): 7.98 (d, J=2.35 Hz, 1 H), 7.58 (dd, J=8.80, 2.05 Hz, 1 H), 6.86 (d, J=8.51 Hz, 1 H), 3.89-4.06 (m, 1 H), 3.72-3.89 (m, 1 H), 3.12 (d, J=14.09 Hz, 1 H), 3.10 (ddd, J=13.50, 9.98, 3.52 Hz, 1 H), 2.75 (d, J=16.73 Hz, 1 H), 2.68 (d, J=17.61 Hz, 1 H), 2.02-2.17 (m, 2 H), 1 .05-1 .99 (m, 1 1 H).
78%	With pyrrolidine; In methanol; at 70℃; for 4h;Microwave irradiation;	General procedure: A mixture of 2-hydroxy-5-bromoacetophenone (2, 5.00 g, 23.3 mmol), N-BOC pyrrolidin-3-one (4.30 g, 23.3 mmol) and pyrrolidine (3.87 mL, 46.5 mmol) in MeOH (20 mL) was heated under microwave irradiation for 4 h at 70 C. The solution was concentrated and the crude mixture was purified by column chromatography (eluent: petroleum ether/EtOAc 95:5 to 7:3) to give the tert-butyl ester 4 (6.00 g, 68%) as a yellow solid.

37%

With pyrrolidine; In methanol; for 2h;Reflux;

5-Bromo-2-hydroxyacetophenone (3.0 g, 13.95 mmol),N-Boc-3-piperidone (2.8 g, 14.07 mmol) was dissolved in methanol (15 mL),Pyrrolidine (1.28 g, 18.14 mmol) was added and the mixture was heated at reflux for 2 hours until the starting material disappeared.The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate (100 mL).The mixture was washed successively with 1N hydrochloric acid (50 mL) and saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate.Concentrate, column chromatography (eluent: petroleum ether/ethyl acetate = 9:1 to 4:1)Compound 7-e (2.07 g, 37%) was obtained

Reference： [1]Patent: EP2311840,2011,A1 .Location in patent: Page/Page column 14-15
[2]Patent: WO2011/45265,2011,A2 .Location in patent: Page/Page column 27-28
[3]European Journal of Medicinal Chemistry,2016,vol. 108,p. 53 - 67
[4]Patent: CN103304571,2018,B .Location in patent: Paragraph 0178-0180

31
[ 188975-88-4 ]
[ 1450-75-5 ]
[ 1291076-33-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With pyrrolidine In methanol for 6h; Reflux;	3.A A mixture of 2-hydroxy-5-bromoacetophenone (5.04 g, 23.4 mmol), 1-BOC-azepan-4-one (5.00 g, 23.4 mmol) and pyrrolidine (3.90 ml, 46.8 mmol) in MeOH (100 ml) was heated under reflux for 6 h. The solution was then concentrated under vacuum and water was added to the mixture. The solution was neutralized with HCl 20% and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude mixture was purified by column chromatography (eluent: petroleum ether/EtOAc 9:1 to 8:2) to give (+/-)-6-bromo-4-oxo-spiro[chromane-2,4'-azepane-6-yl]-1'-carboxylic acid tert-butyl ester (7.5 g). Y = 78% LC-MS: (ES+) MNa+: 432 1H NMR (CDCl3) δ (ppm): 7.96 (d, J=2.35 Hz, 1 H), 7.56 (dd, J=8.80, 2.35 Hz, 1 H), 6.89 (d, J=8.80 Hz, 1 H), 3.45-3.78 (m, 2 H), 3.31-3.40 (m, 1 H), 3.31 (ddd, J=12.62, 10.27, 2.35 Hz, 1 H), 2.78 (d, J=16.73 Hz, 1 H), 2.68 (d, J=16.73 Hz, 1 H), 2.09-2.27 (m, 2 H), 1.72-2.03 (m, 2 H), 1.55-1.72 (m, 2 H), 1.48 (s, 9 H).
78%	With pyrrolidine In methanol at 70℃; for 6h; Reflux;	3.A Intermediate 3: (+/-)-(E)-3-[4-Oxo-spiro(chromane-2,4'-azepane)-6-yl]-acrylic acid methyl esterSTEP AA mixture of 2-hydroxy-5-bromoacetophenone (5.04 g, 23.4 mmol), 1 -BOC-azepan-4- one (5.00 g, 23.4 mmol) and pyrrolidine (3.90 ml, 46.8 mmol) in MeOH (100 ml) was heated under reflux for 6 h. The solution was then concentrated under vacuum and water was added to the mixture. The solution was neutralized with HCI 20% and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude mixture was purified by column chromatography (eluent: petroleum ether/EtOAc 9:1 to 8:2) to give (+/-)-6-bromo-4-oxo-spiro[chromane-2,4'- azepane-6-yl]-1 '-carboxylic acid fe/t-butyl ester (7.5 g).Y = 78%LC-MS: (ES+) MNa+: 4321 H NMR (CDCI3) δ (ppm): 7.96 (d, J=2.35 Hz, 1 H), 7.56 (dd, J=8.80, 2.35 Hz, 1 H), 6.89 (d, J=8.80 Hz, 1 H), 3.45-3.78 (m, 2 H), 3.31 -3.40 (m, 1 H), 3.31 (ddd, J=12.62, 10.27, 2.35 Hz, 1 H), 2.78 (d, J=16.73 Hz, 1 H), 2.68 (d, J=16.73 Hz, 1 H), 2.09-2.27 (m, 2 H), 1 .72-2.03 (m, 2 H), 1 .55-1 .72 (m, 2 H), 1 .48 (s, 9 H).
78%	With pyrrolidine In methanol at 70℃; for 4h; Microwave irradiation;	4.1.1 (+-)-6-bromo-4-oxo-spiro(chromane-2,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (4) General procedure: A mixture of 2-hydroxy-5-bromoacetophenone (2, 5.00 g, 23.3 mmol), N-BOC pyrrolidin-3-one (4.30 g, 23.3 mmol) and pyrrolidine (3.87 mL, 46.5 mmol) in MeOH (20 mL) was heated under microwave irradiation for 4 h at 70 °C. The solution was concentrated and the crude mixture was purified by column chromatography (eluent: petroleum ether/EtOAc 95:5 to 7:3) to give the tert-butyl ester 4 (6.00 g, 68%) as a yellow solid.

Reference： [1]Current Patent Assignee: GENEXTRA SPA; DAC S R I - EP2311840, 2011, A1 Location in patent: Page/Page column 15
[2]Current Patent Assignee: GENEXTRA SPA; DAC S R I - WO2011/45265, 2011, A2 Location in patent: Page/Page column 29-30
[3]Thaler, Florian; Moretti, Loris; Amici, Raffaella; Abate, Agnese; Colombo, Andrea; Carenzi, Giacomo; Fulco, Maria Carmela; Boggio, Roberto; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Sartori, Luca; Varasi, Mario; Mercurio, Ciro [European Journal of Medicinal Chemistry, 2016, vol. 108, p. 53 - 67]

32
[ 398489-26-4 ]
[ 1450-75-5 ]
[ 1291076-37-3 ]

Yield	Reaction Conditions	Operation in experiment
58%	With pyrrolidine In methanol at 70℃; for 5h; Microwave irradiation;	4.A 1-BOC-azetidin-3-one (2.00 g, 11.7 mmol) was added to a mixture of 2-hydroxy-5-bromoacetophenone (2.50 g, 11.7 mmol) and pyrrolidine (0.97 ml, 11.7 mmol) in MeOH (8 ml), and the reaction mixture was heated to 70 °C by MW (closed vessel) for 5 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc form 9:1 to 8:2) to give 6-bromo-4-oxo-spiro(chromane-2,3'-azetidine-6-yl)-1'-carboxylic acid tert-butyl ester (2.50 g) as a yellow solid. Y = 58% LC-MS: (ES+) MH+-56:312 1H NMR (300 MHz, DMSO-d6) δ (ppm): 7.81 (dd, J=2.64, 0.59 Hz, 1 H), 7.78 (dd, J=8.51, 2.64 Hz, 1 H), 7.16 (dd, J=8.51, 0.59 Hz, 1 H), 3.99 (d, J=9.39 Hz, 2 H), 3.89 (d, J=9.68 Hz, 2 H), 3.20 (s, 2 H), 1.38 (s, 9 H).
58%	With pyrrolidine In methanol at 70℃; for 5h;	4.A Intermediate 4: (£)-3-[4-Oxo-spiro(chromane-2,3'-azetidine)-6-yl]-acrylic acid methyl esterSTEP A1 -BOC-azetidin-3-one (2.00 g, 1 1 .7 mmol) was added to a mixture of 2-hydroxy-5- bromoacetophenone (2.50 g, 1 1 .7 mmol) and pyrrolidine (0.97 ml, 1 1 .7 mmol) in MeOH (8 ml), and the reaction mixture was heated to 70 °C by MW (closed vessel) for 5 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc form 9:1 to 8:2) to give 6-bromo-4-oxo-spiro(chromane-2,3'-azetidine-6-yl)-1 '-carboxylic acid fe/t-butyl ester (2.50 g) as a yellow solid.Y = 58%LC-MS: (ES+) MH+-56: 3121 H NMR (300 MHz, DMSO-d6) δ (ppm): 7.81 (dd, J=2.64, 0.59 Hz, 1 H), 7.78 (dd, J=8.51 , 2.64 Hz, 1 H), 7.16 (dd, J=8.51 , 0.59 Hz, 1 H), 3.99 (d, J=9.39 Hz, 2 H), 3.89 (d, J=9.68 Hz, 2 H), 3.20 (s, 2 H), 1 .38 (s, 9 H).
58%	With pyrrolidine In methanol at 70℃; for 4h; Microwave irradiation;	4.1.1 (+-)-6-bromo-4-oxo-spiro(chromane-2,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (4) General procedure: A mixture of 2-hydroxy-5-bromoacetophenone (2, 5.00 g, 23.3 mmol), N-BOC pyrrolidin-3-one (4.30 g, 23.3 mmol) and pyrrolidine (3.87 mL, 46.5 mmol) in MeOH (20 mL) was heated under microwave irradiation for 4 h at 70 °C. The solution was concentrated and the crude mixture was purified by column chromatography (eluent: petroleum ether/EtOAc 95:5 to 7:3) to give the tert-butyl ester 4 (6.00 g, 68%) as a yellow solid.

58%

With pyrrolidine In methanol Reflux;

Synthesis of Compound 13-e 5-bromo-2-hydroxyacetophenone (2.62 g, 10 mmol), 1-Boc-3-azetidinone (2.5 g, 14.6 mmol) was dissolved in methanol (50 mL) and pyrrolidine (0.95) was added. g, 13.4 mmol), and the mixture was heated at reflux overnight. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (350 mL), washed successively with 1N hydrochloric acid (50 mL) and saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography ( Eluent: petroleum ether/ethyl acetate = 10:1) Compound 13-e (2.6 g, 58%) was obtained.

Reference： [1]Current Patent Assignee: GENEXTRA SPA; DAC S R I - EP2311840, 2011, A1 Location in patent: Page/Page column 16
[2]Current Patent Assignee: GENEXTRA SPA; DAC S R I - WO2011/45265, 2011, A2 Location in patent: Page/Page column 31
[3]Thaler, Florian; Moretti, Loris; Amici, Raffaella; Abate, Agnese; Colombo, Andrea; Carenzi, Giacomo; Fulco, Maria Carmela; Boggio, Roberto; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Sartori, Luca; Varasi, Mario; Mercurio, Ciro [European Journal of Medicinal Chemistry, 2016, vol. 108, p. 53 - 67]
[4]Current Patent Assignee: SHANGHAI YUNYI HEALTH ADMINISTRATION CONSULTING - CN103304571, 2018, B Location in patent: Paragraph 0242-0244

33
[ 1445-73-4 ]
[ 1450-75-5 ]
[ 1192127-79-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With pyrrolidine In methanol at 80℃; for 16h;	A Synthesis of 6-bromo- -methylspiro[chroman-2.4'-piperidinl-4-one A mixture of 5-bromo-2-hydroxyacetophenone (2.0 g, 9.3 mmol), pyrrolidine (0.99 mL, 12.1 mmol), l-methyl-4-piperidone (1.41 mL, 12.1 mmol) and MeOH (40 mL) heated to 80 °C for 16 h. The reaction mixture was then concentrated in vacuo and the residue purified by flash chromatography (Biotage Isolera, 50 g HP-SIL, 0-25% EtOAc in hexanes) to give the title compound as a brown solid (2.52 g, 87%). Ή NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=2.3 Hz, 1 H), 7.57 (dd, ^8.8, 2.5 Hz, 1 H), 6.91 (d, J=8.8 Hz, 1 H), 2.71 (s, 2 H), 2.60 (d, J= 1.5 Hz, 2 H),2.45-2.35 (m, 2 H), 2.33 (s, 3 H), 2.05 (d, J=12.0 Hz, 2 H), 1.69 - 1.83 (m, 2 H); MS ESI 298.1 [M + H]+, calcd for [C,4H16BrN02+H]+ 31 1.0.
74%	With pyrrolidine In methanol for 11h; Reflux;
70%	With pyrrolidine In methanol for 16h; Reflux;	48 A mixture of 1-(5-bromo-2-hydroxyphenyl) ethanone (3.0 g, 13.9 mmol), 1-methylpiperidin- 4-one (2.27 mL, 19.5 mmol) and pyrrolidine (2.30 mL, 27.9 mmol) in methanol (100 mL) was refluxed for 16 h. The reaction mass was cooled to room temperature and the solvent was evaporated under vacuum. Ethyl acetate (100 mL) was added to the residue followed byHC1 (20 mL, 10%). The layers were separated and aqueous layer was extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL),dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 3% EtOAc in hexane as eluent) to afford 3.0 g (70%) of the title compound as colorlessliquid. ‘HNMR (400 MHz, CDC13) ö 7.96 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 2.71 (s, 2H), 2.61-2.56 (m, 2H), 2.42- 2.36 (m, 2H), 2.32 (s, 3H), 2.08-2.00 (m, 2H), 1.79-1.72 (m, 2H); ESI-MS (mlz) 310, 312 [(MH), Br79’81]

Reference： [1]Current Patent Assignee: UNIVERSITY HEALTH NETWORK - WO2013/53051, 2013, A1 Location in patent: Page/Page column 91
[2]Varasi, Mario; Thaler, Florian; Abate, Agnese; Bigogno, Chiara; Boggio, Roberto; Carenzi, Giacomo; Cataudella, Tiziana; Dal Zuffo, Roberto; Fulco, Maria Carmela; Rozio, Marco Giulio; Mai, Antonello; Dondio, Giulio; Minucci, Saverio; Mercurio, Ciro [Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3051 - 3064]
[3]Current Patent Assignee: LUPIN LIMITED - WO2014/207648, 2014, A1 Location in patent: Page/Page column 71; 72

34
[ 1450-75-5 ]
[ 29976-53-2 ]
[ 1192127-84-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: 5-Bromo-2-hydroxyacetophenone With pyrrolidine In methanol at 20℃; for 0.5h; Stage #2: N-ethoxycarbonyl-4-piperidone In methanol at 80℃; for 4h; Sealed tube;	1.1 Step 1 : Preparation of ethyl 6-bromo-4-oxospiro[chroman-2,4'-piperidine]-1 '-carboxylate To a stirred solution of 1 -(5-bromo-2-hydroxyphenyl)ethan-1 -one (2.00 g, 9.30 mmol) in MeOH (15 mL) in a screw capped pressure vessel was added pyrrolidine (0.385 mL, 4.65 mmol). The resulting yellow-orange solution was stirred at RT for 30 minutes, and then treated with a solution of ethyl 4-oxopiperidine-1 -carboxylate (1 .59 g, 9.30 mmol) in MeOH (3 mL). The reaction vessel was sealed and heated to 80 °C. After 4 hours LCMS indicated complete reaction. The vessel was cooled to RT during which time a solid crystallized. The suspension was cooled in an ice water bath for 30 minutes, and the solid collected by vacuum filtration, washing with two portions of ice cold MeOH. Drying in vacuo afforded the title compound as a light tan solid (3.02 g, 88%). LCMS (ESI) m/z calcd for Ci6Hi8BrN04: 367.04. Found: 368.12 (M+1)+. NMR (400 MHz, DMSO-c/6) δ 7.68 - 7.81 (m, 2H), 7.07 (d, J = 9.0 Hz, 1 H), 4.01 (q, J = 7.0 Hz, 2H), 3.67 - 3.81 (m, 2H), 3.15 (br s, 2H), 2.86 (s, 2H), 1 .87 (m, 2H), 1 .54 - 1 .70 (m, 2H), 1 .15 (t, J = 7.0 Hz, 3H).
88%	With pyrrolidine In methanol at 80℃; for 4h;
83%	With pyrrolidine In methanol for 11h; Reflux;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2019/3148, 2019, A1 Location in patent: Page/Page column 20; 21
[2]Kazmierski, Wieslaw M.; Xia, Bing; Miller, John; De La Rosa, Martha; Favre, David; Dunham, Richard M.; Washio, Yoshiaki; Zhu, Zhengrong; Wang, Feng; Mebrahtu, Makda; Deng, Hongfeng; Basilla, Jonathan; Wang, Liping; Evindar, Ghotas; Fan, Lijun; Olszewski, Alison; Prabhu, Ninad; Davie, Christopher; Messer, Jeffrey A.; Samano, Vicente [Journal of Medicinal Chemistry, 2020, vol. 63, # 7, p. 3552 - 3562]
[3]Varasi, Mario; Thaler, Florian; Abate, Agnese; Bigogno, Chiara; Boggio, Roberto; Carenzi, Giacomo; Cataudella, Tiziana; Dal Zuffo, Roberto; Fulco, Maria Carmela; Rozio, Marco Giulio; Mai, Antonello; Dondio, Giulio; Minucci, Saverio; Mercurio, Ciro [Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3051 - 3064]

35
[ 3027-13-2 ]
[ 1450-75-5 ]
[ 1311265-28-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With pyrrolidine; acetic acid; In toluene; at 80℃; for 18h;	Example 297 (2S',4R')-2'-amino-6-(5-chloropyridin-3-yl)-2-(3-methoxybenzyl)- 1 ',2- dimethylspiro[chroman-4 4'-imidazol]-5'( H)-oneStep A: A thick wall glass pressure tube with a stir bar was charged with l-(3-methoxyphenyl)propan-2- one (10.7 g, 65.0 mmol), l-(5-bromo-2-hydroxyphenyl)ethanone (10.8 g, 50.0 mmol), and toluene (15 mL). Pyrrolidine (4.1 1 mL, 50.0 mmol) was then added, followed by acetic acid (2.86 mL, 50.0 mmol). The mixture was heated to 80C for 18 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and aqueous IN HC1 (100 mL). The phases were separated, and then carefully the organic phase was shaken with aqueous saturated NaHCC>3 (100 mL; gas evolution, vent sep funnel cautiously). The organic phase was washed with brine (100 mL), dried (NaHC03), filtered, and concentrated. The crude was purified by Biotage Flash 65 chromatography system, eluting with 10%- 20% EtOAc/hexanes. Yield: 12.1 g (64%) of 6-bromo-2-(3-methoxybenzyl)-2-methylchroman-4-one.

Reference： [1]Patent: WO2011/72064,2011,A1 .Location in patent: Page/Page column 133-134

36
[ 1450-75-5 ]
[ 5676-56-2 ]
[ 42524-21-0 ]

Yield	Reaction Conditions	Operation in experiment
65%; 7%	With acetylhydroxamic acid; sulfuric acid; In acetonitrile; at 80℃; under 1292.9 Torr; for 0.166667h;Microwave irradiation;	General procedure: 2-Hydroxy acetophenone 4a (1.0 g, 7.4 mmol), acetohydroxamic acid (0.83 g, 11.0 mmol), acetonitrile (3 ml), and conc. H2SO4 (0.2 ml) were taken into a 10 ml pressure tube and subjected to microwave heating (CEM discover, 360 W, 80 C, 25 psi) for 8 min. Next, the reaction mixture was diluted with ethyl acetate (3 ml) and to this; saturated sodium bicarbonate solution (5 ml) was added drop-wise. The mixture was extracted with ethyl acetate (2 × 10 ml) and the combined organic layer was washed with saturated NaCl solution, dried over anhy. Na2SO4, and concentrated under reduced pressure. Purification of the mixture by normal column chromatography (silica gel 60-120 mesh, ethyl acetate/hexane: 1:9) gave benzoxazole 5a (0.67 g, 70%) in the form of a yellow oil and 2-hydroxy acetophenone oxime 6a (68 mg, 6%, mp 104-107 C) in the form of a white powder.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6103 - 6107
[2]Catalysis Letters,2015,vol. 145,p. 939 - 946

37
[ 1450-75-5 ]
[ 104-88-1 ]
(2E)-1-(5-bromo-2-hydroxyphenyl)-3-(4-chlorophenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium hydroxide In ethanol; water at 20℃;
37%	With sodium hydroxide In methanol; water at 70℃;	2.1.2. Synthesis of 2′ -hydroxychalcone derivatives General procedure: Chalcones were synthesised following (Kachadourian et al., 2012),with some modifications (Scheme 2). One mL of a 50% aqueous solutionof NaOH was added to a stirred solution of each acetophenone (1 mmol)and benzaldehyde (1 mmol) in MeOH (10 mL). The reaction mixture washeated for 3-5 h at 70 C (Scheme 2) and the reaction was monitored byHPLC.Upon reaction completion, the solution was neutralized with 10%HCl(aq) and extracted twice with an equal volume of CH2Cl2. Theorganic layer was dried under reduced pressure and recrystallized fromMeOH/H2O (70/30, v/v). Compounds purity was confirmed by HPLC as>98%. These recrystallized compounds were used for chemical identificationand assays
	Stage #1: 5-Bromo-2-hydroxyacetophenone; 4-chlorobenzaldehyde In ethanol for 0.0833333h; Stage #2: With sodium hydroxide In ethanol at 20℃; for 5h;

Reference： [1]Sawant; Gill; Nirwan [Indian Journal of Heterocyclic Chemistry, 2012, vol. 22, # 1, p. 61 - 66]
[2]Žakelj, Simon; Abin-Carriquiry, Juan Andrés; Carvalho, Diego; Colettis, Natalia; Gobec, Stanislav; Higgs, Josefina; Kamecki, Fabiola; Knez, Damijan; Marcos, Alejandra; Marcucci, Carolina; Marder, Mariel; Rademacher, Marina; de Tezanos Pinto, Felicitas [Neuropharmacology, 2021, vol. 201]
[3]Location in patent: experimental part Rapposelli, Simona; Da Settimo, Federico; Digiacomo, Maria; La Motta, Concettina; Lapucci, Annalina; Sartini, Stefania; Vanni, Michael [Archiv der Pharmazie, 2011, vol. 344, # 6, p. 372 - 385]

38
[ 118-93-4 ]
[ 1836-05-1 ]
[ 1450-75-5 ]

Yield	Reaction Conditions	Operation in experiment
26%; 61%	With Oxone; ammonium bromide; In methanol; at 20℃; for 4.5h;	General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3×25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 191 - 195
[2]European Journal of Organic Chemistry,2019,vol. 2019,p. 4593 - 4596

39
[ 1450-75-5 ]
[ 1423-27-4 ]
[ 893739-66-7 ]

Yield	Reaction Conditions	Operation in experiment
95%		A mixture of 5-bromo-2-hydroxy acetophenone (3.00 g, 13.9 mmol), 2-(trifluoromethyl)benzeneboronic acid (3.97 g, 20.9 mmol), potassium carbonate (3.86 g, 27.9 mmol) and tetrakistriphenylphosphinepalladium (0) (1.61 g, 1.39 mmol) in 1,4-dioxane (90 mL) and water (18.0 mL) was heated to 50 C. over 2 days under an atmosphere of nitrogen. The reaction was allowed to cool to room temperature and poured into a 1M aqueous solution of hydrogen chloride (50 mL). The aqueous layer was then extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown oil. The oil was purified by silica gel column chromatography (10% ethyl acetate in heptane) to afford the title compound as a colourless oil (3.70 g, 95%).1HNMR (CDCl3): delta 2.62 (s, 3H), 7.02 (d, 1H), 7.35 (d, 1H), 7.45 (dd, 1H), 7.49 (t, 1H), 7.59 (t, 1H), 7.72 (d, 1H), 7.77 (d, 1H)LCMS Rt=3.67 minutes MS m/z 279 [M-H]-.

Reference： [1]Patent: US2012/10182,2012,A1 .Location in patent: Page/Page column 42

40
[ 1071-73-4 ]
[ 1450-75-5 ]
[ 1369628-38-5 ]

Yield	Reaction Conditions	Operation in experiment
50%	With pyrrolidine; acetic acid; In toluene; at 80℃; for 18h;	A thick walled glass pressure tube plus stir bar was charged with 5- hydroxypentan-2-one (15.3 g, 150 mmol), l-(5-bromo-2-hydroxyphenyl)ethanone (21.5 g, 100 mmol), and toluene (100 mL). Then, pyrrolidine (8.21 mL, 100 mmol) was added, followed by acetic acid (5.72 mL, 100 mmol). The mixture was heated to 80C for 18 hours with stirring. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and aqueous IN HC1 (100 mL). The phases were separated. The aqueous phase was re-extracted with EtOAc (50 mL), and then carefully shook organic phases with aqueous saturated NaHC03 (100 mL; gas evolution, vent separatory funnel cautiously). The organic phases were washed with brine (100 mL), dried (MgS04), filtered, and concentrated. The crude was purified by Biotage Flash 65 silica gel chromatography, eluting with 25%-2:l EtOAc/hexanes to yield 6-bromo-2-(3-hydroxypropyl)-2-methylchroman-4-one (15.8 g, 50%).

Reference： [1]Patent: WO2012/40641,2012,A2 .Location in patent: Page/Page column 97; 98
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 10112 - 10129

41
[ 1450-75-5 ]
[ 42524-21-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydroxylamine hydrochloride In ethanol; water at 70℃; for 2h;
90%	With hydroxylamine hydrochloride; sodium acetate In methanol at 0 - 20℃; for 2h; Reflux;	75; 77.2 Step 2: synthesis of 1- (5-bromo-2-hydroxyphenyl) ethanone oxime 1- (5-Bromo-2-hydroxyphenyl) ethanone (106 g, 495 mmol) , hydroxylamine hydrochloride (64 g, 989 mmol) and anhydrous sodium acetate (93 g, 1.14 mol) were added into a reaction flask, then methanol (100 mL) was added to dissolved the solid. The mixture was refluxed for 2 h. After the reaction was completed, the mixture was poured into water, and there was a large amount of white solid precipitated out. The mixture was filtered by suction to give a white solid (102 g) , yield: 90%.[0945]MS-ESI: m/z 230.1 [M+H]+.
	With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water

With hydroxylamine hydrochloride

Reference： [1]Haym, Isabell; Huynh, Tri H. V.; Hansen, Stinne W.; Pedersen, Martin H. F.; Ruiz, Josep A.; Erichsen, Mette N.; Gynther, Mikko; Bjørn-Yoshimoto, Walden E.; Abrahamsen, Bjarke; Bastlund, Jesper F.; Bundgaard, Christoffer; Eriksen, Anette L.; Jensen, Anders A.; Bunch, Lennart [ChemMedChem, 2016, vol. 11, # 4, p. 403 - 419]
[2]Current Patent Assignee: GUANGDONG HEC TECHNOLOGY HOLDING CO., LTD. - WO2019/62802, 2019, A1 Location in patent: Paragraph 00331
[3]Location in patent: body text Kociolek, Martin G.; Hoermann, Olivia [Synthetic Communications, 2012, vol. 42, # 17, p. 2632 - 2638]
[4]Kociolek, Martin George; Casbohm, Jerry S. [Journal of Physical Organic Chemistry, 2013, vol. 26, # 10, p. 863 - 867]

42
[ 118-93-4 ]
[ 22362-66-9 ]
[ 1836-05-1 ]
[ 1450-75-5 ]

Yield	Reaction Conditions	Operation in experiment
52%Chromat.; 6%Chromat.; 19%Chromat.	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 2h;	General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 5823 - 5828
[2]Tetrahedron,2017,vol. 73,p. 6564 - 6572

43
[ 1450-75-5 ]
[ 120-14-9 ]
[ 56492-66-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydroxide In methanol; water at 20℃;	3.1.2. General Procedure for the Synthesis of 3a-c General procedure: To the stirred solution of the acetophenone (1a,b, 1.29 g, 6 mmol) in MeOH (10 mL) 50% aq.NaOH (1.26 mL, 24 mmol) was added. Benzaldehyde (2a,b, 6.3 mmol) suspension in MeOH (5 mL)was added to the solution of the acetophenone and the mixture was stirred for 1 h, and then it wasallowed to stand at room temperature for one day. HCl solution (10%, w/v) was added to reach pH1; the precipitate was filtered off and washed with water (3 × 30 mL) to give 3a-c (88-97%).(E)-1-(5-Bromo-2-hydroxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (3a). 1H NMR (300 MHz, 298K, CDCl3): δ (ppm) = 3.95-3.98 (m, 6H, OMe), 6.89-6.93 (m, 2H, 5-H, 3’-H), 7.17 (s, 1H, 2-H), 7.27-7.29 (d, J = 7.35 Hz, 1H, 6-H), 7.37-7.41 (d, J= 15.25 Hz, 1H, α-H), 7.53-7.56 (dd, 1H, 4’-H), 7.87-7.92(d, J= 15.34 Hz, 1H, β-H), 8.00-8.00 (d, J= 1.62 Hz, 6’-H), 12.89 (s, 1H, OH).
	With potassium hydroxide In ethanol at 20℃;	1.A Step A: To a mixture of l-(5-bromo-2-hydroxyphenyl)ethanone (2.15 g, 10 mmol) and 3,4-dimethoxybenzaldehyde (1.83 g, 11 mol) in ethanol (13 mL) was added KOH (2.24 g, 40 mmol). After stirring at room temperature overnight, the reaction mixture was acidified to pH~5 with IN HCl at 0 °C. The resulting precipitate was filtered and dried to provide (E)-l-(5-bromo- 2-hydroxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-l-one. MS m/z 363.1, 365.1 [M+H]+. The crude product was used directly in the next step without further purification.

Reference： [1]Szabados-Furjesi, Peter; Pajtas, David; Barta, Aliz; Csepanyi, Evelin; Kiss-Szikszai, Attila; Tosaki, Arpad; Bak, Istvan [Molecules, 2018, vol. 23, # 12]
[2]Current Patent Assignee: PTC THERAPEUTICS INC - WO2013/142236, 2013, A1 Location in patent: Paragraph 001206

44
[ 1136-45-4 ]
[ 1450-75-5 ]
C₁₉H₁₄BrNO₄ [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2013,vol. 50,p. 999 - 1004

45
[ 3484-35-3 ]
[ 1450-75-5 ]
[ 1487412-24-7 ]

Reference： [1]Heterocycles,2013,vol. 87,p. 2053 - 2069

46
[ 1450-75-5 ]
[ 199328-10-4 ]
[ 1487412-43-0 ]

Reference： [1]Heterocycles,2013,vol. 87,p. 2053 - 2069

47
[ 1450-75-5 ]
[ 14733-73-4 ]

Reference： [1]Advanced Synthesis and Catalysis,2013,vol. 355,p. 3591 - 3596

48
[ 67-56-1 ]
[ 201230-82-2 ]
[ 1450-75-5 ]
[ 57009-12-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; triethylamine; at 100℃;	A solution of l-(5-bromo-2-hydroxyphenyl)ethanone (20.0 g, 93.0 mmol, 1.00 equiv) in methanol (500 mL), Pd(dppf)2Cl2 (4 g, 4.7 mmol, 0.05 equiv) and triethylamine (20 g, 200.00 mmol, 2.00 equiv) were stirred overnight at 100C under an atmosphere of CO (g). The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was diluted with 200 mL of H20 and the resulting solution was extracted with 5x50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solids were filtered off. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 15 g (83%) of methyl 3-acetyl-4-hydroxybenzoate as a light yellow solid. H NMR (300 MHz, CDC13): 12.68 (s, 1 H), 8.49 (d, 1H), 8.14 (dd, / = 2.1 Hz, l H), 7.02 (d, / = 9.6 Hz,l H), 3.93 (s, 3 H), 2.71 (s,3 H)

Reference： [1]Patent: WO2014/66795,2014,A1 .Location in patent: Paragraph 0175

49
[ 3752-25-8 ]
[ 1450-75-5 ]
C₁₇H₁₂BrClO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; trichlorophosphate; at 20℃;Cooling with ice;	General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography.

Reference： [1]Molecules,2014,vol. 19,p. 16058 - 16081

50
[ 2316-26-9 ]
[ 1450-75-5 ]
C₁₉H₁₇BrO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; trichlorophosphate; at 20℃;Cooling with ice;	General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography.

Reference： [1]Molecules,2014,vol. 19,p. 16058 - 16081

51
[ 1450-75-5 ]
[ 17768-41-1 ]
2-(1-((adamantan-1-ylmethyl)amino)ethyl)-4-bromophenol hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		General procedure: To a solution of corresponding amine (1 mmol) and corresponding aldehyde (1.1 mmol) in EtOH (5ml) was added acetic acid (catalytic amount) and stirred under nitrogen for 30 minutes. The reaction mixture was brought to 0C then added sodium borohydride (1 mmol) portionwise and stirred at RT for 1-2 h. Upon completion, the reaction mixture was quenched with water and concentrated under vacuum. The crude product was basified with saturated sodium carbonate solution and extracted with ethylacetate (2 x 20 ml). The solvent was evaporated under reduced pressure, purified by Combiflash eluting with 5-30% (hexane:ethylacetate) solvent system to afford the final product. The obtained product (1 mmol) was dissolved in DCM (2 ml) and cooled to 0C and then 2M HCl in diethylether (2 mmol) was added dropwise and stirred for 15 minutes. The obtained solid was filtered, washed with diethylether and dried under vacuum to get product as HCl salt. (All the compounds were converted to hydrochloride salt except for compounds 11 & 18).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 952 - 955

52
[ 1450-75-5 ]
[ 175883-62-2 ]
1-(6-hydroxy-3-(3-methyl-4-methoxyphenyl)phenyl)ethanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1184 - 1194

53
[ 1450-75-5 ]
[ 175883-60-0 ]
1-(6-hydroxy-3-(3-chloro-4-methoxyphenyl)phenyl)ethanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1184 - 1194

54
[ 1450-75-5 ]
[ 613-33-2 ]

Reference： [1]Tetrahedron,2014,vol. 70,p. 6995 - 7005
[2]Tetrahedron,2014,vol. 70,p. 6995 - 7005

55
[ 1450-75-5 ]
[ 5676-56-2 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 8657 - 8667
[2]Catalysis Letters,2015,vol. 145,p. 939 - 946

56
[ 1450-75-5 ]
[ 5676-56-2 ]
5-bromo-N-methylbenzo[d]oxazol-2-amine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 8657 - 8667

57
[ 1450-75-5 ]
[ 5676-56-2 ]
[ 42524-21-0 ]
[ 6329-74-4 ]

Reference： [1]Catalysis Letters,2015,vol. 145,p. 939 - 946

58
[ 1450-75-5 ]
[ 5676-56-2 ]
[ 6329-74-4 ]

Reference： [1]Catalysis Letters,2015,vol. 145,p. 939 - 946

59
[ 1450-75-5 ]
[ 32870-98-7 ]
1-(2-hydroxy-5-(2-(phenanthren-9-yl)ethynyl)phenyl)ethanone [ No CAS ]

Reference： [1]Photochemical and Photobiological Sciences,2015,vol. 14,p. 1864 - 1871

60
[ 1450-75-5 ]
[ 292638-85-8 ]
(E)-4-hydroxyl-3-(3-acetylphenyl)acrylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With C₂₅H₁₆O₆C₄H₁₁NH₂O; tetrabutylammomium bromide; palladium diacetate; potassium carbonate In water at 90℃;	Mizoroki-Heckcross-coupling reactions General procedure: A mixture of aryl halide (1.0 mmol), alkenes (1.5 mmol), K2CO3 (2.0 mmol), novel ligand (0.3 mol %), Pd(OAc)2 (0.3 mol %) and TBAB (0.6 mmol) was heated in water (5 ml) at 90 °C temperature. The progress of the reaction is monitor by TLC. After the completion of the reaction, ethyl acetate (10 ml) was added to the reaction mixture and extracted with ethyl acetate (3 x 10 ml). The combined organic layer was dried with anhyd. Na2SO4 and the solvent were concentrated in vacuum to obtain a solid. The residue was purified by silicagel column chromatography (5-10% EtOAc in hexane) to afford the corresponding pure products.
88%	With potassium phosphate; 2-hydroxy-3-(p-tolyl)-2,3-dihydroindan-1-one; palladium diacetate In 1,4-dioxane at 80℃;	General Procedure for Mizoroki-Heck Cross-Coupling Reactions (25-33) General procedure: A mixture of aryl halides/tosylates (1.0 mmol), alkenes (1.5 mmol), K3PO4 (2.0 mmol), ligand (0.3 mol%) and Pd(OAc)2 (0.3 mol%) was heated in dioxane (5 mL) at 80 °C. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was cooled to r.t., and solvent was removed under reduced pressure. Water (10 mL) was added to the mixture, and extracted with EtOAc (3 × 10mL). The combined organic layer was dried with anhydrous Na2SO4 and the solvent was concentrated in vacuum to obtain a solid. The residue was purified by silica gel column chromatography (EtOAc-hexane, 5-10%) to afford the corresponding pure products.

Reference： [1]Waheed, Mohammed; Ahmed, Naseem [Tetrahedron Letters, 2016, vol. 57, # 33, p. 3785 - 3789]
[2]Waheed, Mohammed; Ahmed, Naseem [Synthesis, 2017, vol. 49, # 18, p. 4372 - 4382]

61
[ 1450-75-5 ]
[ 105191-12-6 ]
(2E)-1-(5-bromo-2-hydroxyphenyl)-3-(6-bromo-1H-indol-2-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4%	With piperidine; In ethanol; for 20h;Reflux;	General procedure: To a mixture of 1H-indole-2-carbaldehyde (290 mg, 2.0 mmol, 1.0 eq.) and 1-(5-bromo-2-hydroxyphenyl)ethanone (430 mg, 2.0 mmol, 1.0 eq.) in ethanol (10 mL) was added piperidine (1 mL). The mixture was refluxed during 16 hours and then diluted with ethyl acetate after cooling to room temperature. The organic layer was washed with a 1M aqueous hydrochloric acid solution and water, dried over Na2SO4and then evaporated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 90/10 to 80/20) to afford, after trituration with diethyl ether,7aas a red solid (160 mg, 23 %).

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 1 - 13

62
[ 1450-75-5 ]
[ 120-21-8 ]
6-bromo-2-(4-(diethylamino)phenyl)-3-hydroxy-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: 5-Bromo-2-hydroxyacetophenone; 4-Diethylaminobenzaldehyde With morpholine In 1,2-dichloro-ethane at 100℃; for 0.416667h; Microwave irradiation; Stage #2: With sodium hydroxide In ethanol; dihydrogen peroxide at 20℃; for 48h; Cooling with ice;	6-Bromo-2-(4-diethylamino)phenyl-3-hydroxy-4H-chromen-4-one (1): 1-(5-Bromo-2-hydroxyphenyl)ethanone (1.7 g, 7.75 mmol, 1 eq.) and 4-(diethylamino)benzaldehyde (1.56 g, 8.52mmol, 1.1 eq.) were solubilized in 1,2-dichloroethane (10 mL) and morpholine (10 mL).The reaction solution was irradiated by microwave (25 min, 100 C, 200 W). The volatileswere removed in vacuo to give a reddish brown solid, which was solubilized in ethanol(15 mL). To the stirred mixture cooled in an ice bath, were added sequentially an aq. 5 MNaOH solution (20 mL, 13 eq.) and H2O2 (30% w/w in H2O, 7.65 mL, 10 eq.). After stirringovernight, the mixture was neutralized by an aq. 1 N HCl solution, and the resultingprecipitate was filtered and washed with water and cyclohexane sequentially. Compound1 was obtained as an orange solid. (2.24 g, 77%). Rf = 0.38 (Toluene/Acetone 4:1) or 0.58(DCM/MeOH, 99.5:0.5). 1H-NMR (CDCl3, 200 MHz): d 1.15 (t, 3J = 7.0 Hz, 6H, NCH2-CH3),3.41 (q, 3J = 7.0 Hz, 4H, NCH2-CH3), 6.67 (d, 3J = 9.0 Hz, 2H, Hmeta), 7.35 (d, 3J = 8.8 Hz,1H, H8), 7.62 (dd, 3J = 8.8 Hz, 4J = 2.4 Hz, 1H, H7), 8.05 (d, 3J = 9.0 Hz, 2H, Hortho), 8.26(d, 4J = 2.4 Hz, 1H, H5), 9.37 (s, 1H, OH). 13C-NMR (CDCl3, 50 MHz): d 12.7 (N-CH2-CH3),44.5 (N-CH2-CH3), 110.9 (Cm), 116.7 (Cp), 119.8 (Ci), 122.3 (C8), 127.6 (C6), 129.5 (C7),135.5 (Co), 136.9 (C5), 147.3 (C10), 149.1 (C2), 153.7 (C9), 171.0 (C4). HRMS (ESI+): m/z calcdfor C19H18NO3BrH+: 388.0543, 390.0522 [M + H]+; found: 388.0550, 390.0529 [M + H]+.
41.4%	With pyrrolidine In ethanol at 20℃; for 12h;

Reference： [1]Barnoin, Guillaume; Burger, Alain; Le, Hoang-Ngoan; Mallick, Suman; Michel, Benoît Y.; Vincent, Steve [Molecules, 2022, vol. 27, # 7]
[2]Wu, Qianqian; Wang, Zian; Li, Jiale; Qiu, Shuang; Cao, Duxia; Liu, Zhiqiang; Guan, Ruifang [RSC Advances, 2016, vol. 6, # 76, p. 72698 - 72702]

63
[ 1450-75-5 ]
copper(l) cyanide [ No CAS ]
[ 35794-84-4 ]

Reference： [1]Chemical Communications,2016,vol. 52,p. 12306 - 12309

64
[ 1570-45-2 ]
[ 1450-75-5 ]
[ 60072-81-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium hydride In tetrahydrofuran at 1 - 5℃; for 3h;	1 1-(5-bromo-2-hydroxyphenyl)-3-(4-pyridyl)propane-1,3-dione (M1) In a 100 mL three-necked flask was added 30 mL of tetrahydrofuran (anhydrous treatment)1.2 g (49 mmol) of NaH was added to the reaction solution,The reaction flask was placed in an ice bath,The temperature in the reaction flask was controlled at 1-5 ° C.562 mg (3.72 mmol) of ethyl isonicotinate was added.(12.25 mmol) of 2-hydroxy-5-bromoacetophenone (200 mg, 0.93 mmol) was diluted with 15 mL of THF,The reaction solution was added dropwise using a constant-pressure dropping funnel,The temperature in the reaction flask was controlled at 1-5 ° C.After stirring for 3 h, the reaction was monitored by TLC plate,Raw materials disappear,The reaction was stopped.The reaction solution was poured into ice water,The pH was adjusted to 6-7 with dilute hydrochloric acid,A large number of yellow solid precipitation,Filtration,The crude product was 223 mg, yield: 75%. Directly cast the next step.

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN105315252, 2016, A Location in patent: Paragraph 0044-0046

65
[ 321-37-9 ]
[ 1450-75-5 ]
(S)-1-(5-bromo-2-hydroxyphenyl)-3-(4-chlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 2634 - 2637

66
[ 1736-06-7 ]
[ 1450-75-5 ]
(S)-1-(5-bromo-2-hydroxyphenyl)-4,4,4-trifluoro-3-hydroxy-3-(m-tolyl)butan-1-one [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 2634 - 2637

67
[ 1450-75-5 ]
[ 27104-73-0 ]
[ 1300033-85-5 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 8515 - 8537

68
[ 1450-75-5 ]
[ 107407-80-7 ]
C₁₆H₉BrN₂O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 8515 - 8537

69
[ 2142-63-4 ]
[ 1836-06-2 ]
[ 1450-75-5 ]

Yield	Reaction Conditions	Operation in experiment
15%; 15%	With (difluoroboryl)dimethylglyoximatocobalt(II) bis(acetonitrile); water; 3-cyano-1-methylquinolinium cation; In acetonitrile; at 20℃; for 5h;Inert atmosphere; Irradiation; Green chemistry;	1-methyl-3-cyanoquinoline salt as a photosensitizer, Cobalt oxime complex 2 as a cobalt catalyst, 5mL acetonitrile was added2.69 mg (1 × 10 -2 mmol) photosensitizer and 2.80 mg (6 × 10 -3 mmol) cobalt catalyst, Replacing the atmosphere with Ar atmosphereAnd then0.2 mmol of 3'-bromoacetophenone (R1 is COCH3, R3 is Br, R2, R4 are independently H) and 2 mmol of H2O. Room temperature, high pressureMercury lamp irradiation 5h. After the reaction was completed, the H2 production was detected by GC (TCD) and the conversion of benzene by GC (FID), And then separated by column. 1H NMR and MS identified products were 3'-bromo-2-hydroxyacetophenone, 3'-bromo-4-hydroxyacetophenone and 3'-bromo-6-hydroxyacetophenone. The conversion of 3'-bromoacetophenone was 32%, the yield of coupling products was 2%, 15% and 15%, respectively, and the yield of H2 was 8%.

Reference： [1]Patent: CN107324975,2017,A .Location in patent: Paragraph 0130-0131

70
[ 1450-75-5 ]
[ 1736-67-0 ]
6-bromo-2-(4-fluorobenzyl)chroman-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.68%	Stage #1: 1-(5-bromo-2-hydroxyphenyl)ethan-1-one With tetrahydropyrrole; glacial acetic acid In toluene at 20℃; for 0.166667h; Stage #2: 1-(4-fluoro phenyl)-2-ethanone In toluene at 70℃; for 18h;	33 6-Bromo-2-(4-Jluorobenzyl)chroman-4-one: To a mixture of 1-(5-bromo-2- hydroxyphenyl)ethanone (1.3 g, 6.05 mmol) in toluene (5 mL) was added acetic acid(0.346 mL, 6.05 mmol) and pyrrolidine (0.500 mL, 6.05 mmol). It was then stirred at rt for 10 mm, then 2-(4-fluorophenyl)acetaldehyde (1.002 g, 7.25 mmol) was added. The mixture was heated to 70 °C for 18 hours. The reaction mixture was concentrated in vacuo. The mixture was diluted with diethyl ether and iN aqueous NaOH. The phases were separated, and the organic was washed with more water. The combined organicphases were dried (MgSO4), filtered and concentrated. The concentrate was purified by biotage silica gel chromatography, eluting with 10% EtOAc/hexanes to isolate 6-bromo- 2-(4-fluorobenzyl)chroman-4-one (500 mg, 1.492 mmol, 24.68 % yield). ‘H NMR (400MHz, CDC13) ö 8.00 (d, J2.2 Hz, 1H), 7.57 (dd, J8.7, 2.3 Hz, 1H), 7.24 (dd, J=8.2, 5.5 Hz, 2H), 7.05 (t, J=8.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 1H), 4.71 - 4.60 (m, 1H),3.22-3.13 (m, 1H), 3.10-3.01 (m, 1H), 2.71 -2.66 (m, 2H).
24.7%	Stage #1: 1-(5-bromo-2-hydroxyphenyl)ethan-1-one With tetrahydropyrrole; glacial acetic acid In toluene at 20℃; for 0.166667h; Stage #2: 1-(4-fluoro phenyl)-2-ethanone In toluene at 70℃; for 18h;

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO; GLAXOSMITHKLINE PLC - WO2017/195113, 2017, A1 Location in patent: Page/Page column 81
[2]Belema, Makonen; Bowsher, Michael; Cianci, Christopher; Dicker, Ira B.; Ding, Bo; Eastman, Kyle; Falk, Paul; Frennesson, David; Gillis, Eric; Hanumegowda, Umesh; Jenkins, Susan; Kadow, John F.; Kish, Kevin; Krystal, Mark; Lewis, Hal; McAuliffe, Brian; Meanwell, Nicholas A.; Naidu, B. Narasimhulu; Parcella, Kyle; Parker, Dawn D.; Patel, Manoj; Peese, Kevin; Saulnier, Mark G.; Simmermacher, Jean; Sivaprakasam, Prasanna; Tu, Yong; Walker, Michael A.; Wang, Tao; Yin, Zhiwei; Zhang, Zhongxing; Zheng, Barbara Zhizhen [ACS Medicinal Chemistry Letters, 2022]

71
[ 459-03-0 ]
[ 1450-75-5 ]
6-bromo-2-(4-fluorobenzyl)-2-methylchroman-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.3%	With pyrrolidine; acetic acid; In toluene; at 70℃; for 18h;	To a mixture of 1-(5-bromo-2- hydroxyphenyl)ethanone (1 g, 4.65 mmol) in toluene (5 mL), 1 -(4-fluorophenyl)propan-2-one (0.849 g, 5.58 mmol) was added acetic acid (0.266 mL, 4.65 mmol) and pyrrolidine (0.385 mL, 4.65 mmol). The mixture was heated to 70 C for 18 hours. The reaction mixture was concentrated in vacuo. The mixture was diluted with diethyl ether and iN aqueous NaOH. The phases were separated, and the organic was washed with more water. The combined organic phases were dried (MgSO4), filtered and concentrated. The residuewas purified by biotage silica gel chromatography, eluting with 10% EtOAc/hexane to isolate 6-bromo-2-(4-fluorobenzyl)-2-methylchroman-4-one (0.93 g, 2.66 mmol, 57.3 % yield). LCMS (M+H) = 350.8. ?H NMR (400MHz, CDC13) oe 7.99 (d, J=2.4 Hz, 1H), 7.59 (dd, J=8.8, 2.4 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.08 - 6.96 (m, 2H), 6.89 (d, J=8.8 Hz, 1H), 3.09 - 2.93 (m, 2H), 2.81 -2.57 (m, 2H), 1.40 (s, 3H).

Reference： [1]Patent: WO2017/195113,2017,A1 .Location in patent: Page/Page column 89

72
[ 1450-75-5 ]
[ 92444-99-0 ]
(E)-1-(5-bromo-2-hydroxyphenyl)-3-(2-chloro-5-methylpyridin-3-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium hydroxide In ethanol; water at 0 - 20℃;	General procedure for the preparation ofpyridinylchalcones (3a-q) General procedure: 1-(2-Hydroxyphenyl)ethanone 2a (176 mg, 1.29 mmol) and2-chloronicotinaldehyde 1a (200 mg, 1.29 mmol) weredissolved in ethanol (1 ml). Aqueous sodium hydroxide solution (40%, 0.3 ml) was added gradually to the reactionmixture under stirring and the contents were stirred at roomtemperature till starting materials disappeared (TLC). Aftercompletion of the reaction, the solvent was removed underreduced pressure. Cold water was added to the residue,neutralized with cold acetic acid and the reaction mixturewas extracted with ethyl acetate (2 × 20 ml). The organiclayer was washed with brine (2 × 20 ml) and the layers wereseparated. The organic layer was dried over anhydrousNa2SO4 and solvent was removed under reduced pressure.The crude product was purified by column chromatography(EtOAc/hexane) to give pure yellow solid 3a. Similarly,compounds 3b-q were prepared by the reaction of 2-chloronicotinaldehydes 1b-e with substituted 1-(2-Hydroxyphenyl)ethanones 2b-d under optimized conditions.

Reference： [1]Dayakar, Cherupally; Suman, Pathi; Rajkumar, Kommera; Murthy, Thampunuri Ramalinga; Kalivendi, Shasi Vardhan; Raju, Bhimapaka China [Medicinal Chemistry Research, 2018, vol. 27, # 1, p. 80 - 94]

73
[ 94-08-6 ]
[ 1450-75-5 ]
1-(5-bromo-2-hydroxyphenyl)-3-(p-tolyl)propane-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium hydride In tetrahydrofuran; mineral oil at 65℃; for 2h;

Reference： [1]Wang, Rui; Han, Jie; Li, Chenchen; Zhang, Jie; Liang, Yong; Wang, Tao; Zhang, Zunting [Organic and Biomolecular Chemistry, 2018, vol. 16, # 14, p. 2479 - 2488]

74
[ 613-69-4 ]
[ 1450-75-5 ]
5'-bromo-2'-hydroxy-2-ethoxychalcone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium hydroxide; In ethanol; water; at 20℃;	General procedure: To a solution of 2-methoxybenzaldehyde (25?mg, 0.18?mmol) and 2'-hydroxy-5'-methoxyacetophenone (30?mg, 0.18?mmol) in EtOH (0.2?mL) was added 40% aqueous KOH (0.2?mL), and the mixture was stirred at room temperature. After the reaction was complete, ice-water was added to the reaction mixture, which was then neutralized with 1?N HCl. The mixture was extracted with EtOAc and the resultant organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-EtOAc (15:1) to give 2'-hydroxy-2,5'-dimethoxychalcone (13) (44?mg, 0.15?mmol) in 85% yield as an yellow solid. Chalcones 16, 17, 20, 26-29, and 32 were produced by the same procedure.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1143 - 1152

75
[ 1450-75-5 ]
[ 7091-12-5 ]
5'-bromo-2'-hydroxy-2-propoxychalcone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium hydroxide; In ethanol; water; at 20℃;	General procedure: To a solution of 2-methoxybenzaldehyde (25 mg, 0.18 mmol) and 2'-hydroxy-5'-methoxyacetophenone (30 mg, 0.18 mmol) in EtOH (0.2 mL) was added 40% aqueous KOH (0.2 mL), and the mixture was stirred at room temperature. After the reaction was complete, ice-water was added to the reaction mixture, which was then neutralized with 1 N HCl. The mixture was extracted with EtOAc and the resultant organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-EtOAc (15:1) to give 2'-hydroxy-2,5'-dimethoxychalcone (13) (44 mg, 0.15 mmol) in 85% yield as an yellow solid. Chalcones 16, 17, 20, 26-29, and 32 were produced by the same procedure.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1143 - 1152

76
[ 14527-42-5 ]
[ 1450-75-5 ]
1-(5-bromo-2-hydroxyphenyl)-3-(thiazol-2-yl)propane-1,3-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8468 - 8473

77
[ 1450-75-5 ]
[ 921760-46-5 ]

Reference： [1]Patent: WO2019/3148,2019,A1

78
[ 1450-75-5 ]
[ 5736-88-9 ]
6-bromo-2-(4-butoxyphenyl)-3-hydroxy-4H-chromen-4-one [ No CAS ]

Reference： [1]Bioorganic Chemistry,2019,vol. 89

79
[ 1450-75-5 ]
[ 5736-88-9 ]
C₁₉H₁₉BrO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In methanol; for 3h;Reflux;	General procedure: In a round-bottom flask (25 mL), equipped with magnetic stirrer 2-hydroxyacetophenone (a) (0.2 mL, 1.66 mmol), cumanaldehyde (b) (0.24 g, 1.66 mmol), sodium hydroxide (0.2 g, 5 mmol) and methanol (10 mL) were introduced. The pale yellow mixture was refluxed untilthe color was changed into orange (about 3 h). The reaction mixturewas cooled to room temperature and sodium hydroxide (0.5 N, 10 mL)and then hydrogen peroxide (35%, 0.684 mL) were added. After stirring2-3 h, the mixture was poured into ice-water and the formed precipitatewas filtered to obtain 1 as a yellow solid (75%)

Reference： [1]Bioorganic Chemistry,2019,vol. 89

80
[ 1450-75-5 ]
[ 89763-93-9 ]
6-bromo-2-(2-fluoro-4-(trifluoromethyl)phenyl)-3-hydroxy-4H-chromen-4-one [ No CAS ]

Reference： [1]Bioorganic Chemistry,2019,vol. 89

81
[ 1450-75-5 ]
[ 89763-93-9 ]
C₁₆H₉BrF₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In methanol; for 3h;Reflux;	General procedure: In a round-bottom flask (25 mL), equipped with magnetic stirrer 2-hydroxyacetophenone (a) (0.2 mL, 1.66 mmol), cumanaldehyde (b) (0.24 g, 1.66 mmol), sodium hydroxide (0.2 g, 5 mmol) and methanol (10 mL) were introduced. The pale yellow mixture was refluxed untilthe color was changed into orange (about 3 h). The reaction mixturewas cooled to room temperature and sodium hydroxide (0.5 N, 10 mL)and then hydrogen peroxide (35%, 0.684 mL) were added. After stirring2-3 h, the mixture was poured into ice-water and the formed precipitatewas filtered to obtain 1 as a yellow solid (75%)

Reference： [1]Bioorganic Chemistry,2019,vol. 89

82
[ 5381-20-4 ]
[ 1450-75-5 ]
2-(benzo[b]thiophen-3-yl)-6-bromo-3-hydroxy-4H-chromen-4-one [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 183

83
[ 5381-20-4 ]
[ 1450-75-5 ]
(E)-3-(benzo[b]thiophen-3-yl)-1-(5-bromo-2-hydroxyphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydroxide; In ethanol; water; at 20℃;	General procedure: An aqueous solution of NaOH (3M, 1.6mL) was added to a solution of aromatic ketone (1mmol) and 3-methoxybenzaldehyde (1.2 eq), in EtOH (1-2mL). The reaction was stirred at r.t for 18-24h. The reaction mixture was cooled in an ice-water bath and acidified to pH 2 with concentrated HCl (37%). The solid formed was filtered, washed with ethanol and then further purified by recrystallization from ethanol. When no precipitate occurred, the reaction mixture was extracted with dichloromethane and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Column chromatography was then utilized to purify the desired product.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 183

84
[ 26272-83-3 ]
[ 1450-75-5 ]
1-(5-bromo-2-(oxetan-3-yloxy)phenyl)ethan-1-one [ No CAS ]

Reference： [1]Organic Letters,2020,vol. 22,p. 249 - 252

85
[ 1450-75-5 ]
[ 82386-89-8 ]
[ 105-56-6 ]
6-(5-bromo-2-hydroxyphenyl)-4-(2-chloro-5-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile [ No CAS ]

Reference： [1]Drug Design, Development and Therapy,2019,vol. 13,p. 4247 - 4263

86
[ 29976-54-3 ]
[ 1450-75-5 ]
methyl 6-bromo-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 3552 - 3562

87
[ 1450-75-5 ]
[ 102-32-9 ]
[ 108-24-7 ]
3-(4,5-diacetyloxyphenyl)-6-bromo-4-methylchromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With triethylamine at 120℃; for 3h;	3.2.1. General Procedure for the Synthesis of Acetyloxy Coumarins (3a-3o) General procedure: A mixture of the appropriate phenylacetic acid (2.83 mmol) and the appropriate2-hydroxyacetophenone (2.97 mmol) in acetic anhydride (3.1 mL) in the presence of triethylamine(8.77 mmol) was refluxed for 3 h. Water was then added, and the mixturewas extracted with dichloromethane, dried over anhydrous Na2SO4, filtered, and concentratedin vacuo to afford the crude products, which on recrystallization from methanol anddichloromethane gave the purified products.

Reference： [1]Deligiannidou, Georgia-Eirini; Detsi, Anastasia; Iliou, Triantafylia; Katopodi, Annita; Kontogiorgis, Christos; Pontiki, Eleni; Tsopelas, Fotios; Tsotsou, Evangelia [Molecules, 2021, vol. 26, # 19]

88
[ 1450-75-5 ]
[ 1692-25-7 ]
1-(2-hydroxy-5-(pyridin-3-yl)phenyl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 95℃; for 5h;
76%	With tetrakis-(triphenylphosphine)-palladium	1-(2-Hydroxy-5-(pyridin-3-yl)phenyl)ethan-1-one (A11) 1-(2-Hydroxy-5-(pyridin-3-yl)phenyl)ethan-1-one (A11) A clean, dry 40 mL vial was charged with 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (1.0 g, 4.65 mmol), pyridin-3-ylboronic acid (0.85 g, 6.97 mmol), Pd(PPh3)4 (0.24 g, 0.23 mmol), Na2CO3 (1.48 g, 14.04 mmol), water (6 mL) and DME (18 mL), and the mixture was purged with argon for 2 min. The reaction mixture was stirred at 95° C. for 5 h. Upon completion (monitored by LC/MS), the mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure to afford the crude residue, which was purified by flash column chromatography on silica gel (0-100% n-heptane/ethyl acetate) to afford A11 (0.75 g, 76%). 1H NMR (400 MHz, DMSO-d6): δ 2.75 (s, 3H), 7.09 (d, J=8.0 Hz, 1H), 7.46-7.49 (m, 1H), 7.89 (d, J=4.0 Hz, 1H), 8.08-8.11 (m, 1H), 8.17 (d, J=4.0 Hz, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.93 (d, J=4.0 Hz, 1H), 12.01 (s, 1H). LC/MS (ESI, m/z): 214.22 [M+H]+.
76%	With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 95℃; for 5h; Inert atmosphere;	1 1-(2-Hydroxy-5-(pyridin-3-yl)phenyl)ethan-1-one (A11) A clean, dry 40 mL vial was charged with 82 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (1.0 g, 4.65 mmol), 83 pyridin-3-ylboronic acid (0.85 g, 6.97 mmol), 84 Pd(PPh3)4 (0.24 g, 0.23 mmol), 85 Na2CO3 (1.48 g, 14.04 mmol), 86 water (6 mL) and 87 DME (18 mL), and the mixture was purged with argon for 2 min. The reaction mixture was stirred at 95° C. for 5 h. Upon completion (monitored by LC/MS), the mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure to afford the crude residue, which was purified by flash column chromatography on silica gel (0-100% n-heptane/ethyl acetate) to afford 88 A11 ( 0.75 g , 76% ). 1H NMR (400 MHz, DMSO-d6): δ 2.75 (s, 3H), 7.09 (d, J=8.0 Hz, 1H), 7.46-7.49 (m, 1H), 7.89 (d, J=4.0 Hz, 1H), 8.08-8.11 (m, 1H), 8.17 (d, J=4.0 Hz, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.93 (d, J=4.0 Hz, 1H), 12.01 (s, 1H) . LC/ MS (ESI, m/z): 214.22 [M+H]+ .

76%	With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 95℃; for 5h; Inert atmosphere;	1 1-(2-Hydroxy-5-(pyridin-3-yl)phenyl)ethan-1-one (A11) A clean, dry 40 mL vial was charged with 82 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (1.0 g, 4.65 mmol), 83 pyridin-3-ylboronic acid (0.85 g, 6.97 mmol), 84 Pd(PPh3)4 (0.24 g, 0.23 mmol), 85 Na2CO3 (1.48 g, 14.04 mmol), 86 water (6 mL) and 87 DME (18 mL), and the mixture was purged with argon for 2 min. The reaction mixture was stirred at 95° C. for 5 h. Upon completion (monitored by LC/MS), the mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure to afford the crude residue, which was purified by flash column chromatography on silica gel (0-100% n-heptane/ethyl acetate) to afford 88 A11 ( 0.75 g , 76% ). 1H NMR (400 MHz, DMSO-d6): δ 2.75 (s, 3H), 7.09 (d, J=8.0 Hz, 1H), 7.46-7.49 (m, 1H), 7.89 (d, J=4.0 Hz, 1H), 8.08-8.11 (m, 1H), 8.17 (d, J=4.0 Hz, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.93 (d, J=4.0 Hz, 1H), 12.01 (s, 1H) . LC/ MS (ESI, m/z): 214.22 [M+H]+ .
76%	With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 95℃; for 5h; Inert atmosphere;	1 1-(2-Hydroxy-5-(pyridin-3-yl)phenyl)ethan-1-one (A11) A clean, dry 40 mL vial was charged with 82 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (1.0 g, 4.65 mmol), 83 pyridin-3-ylboronic acid (0.85 g, 6.97 mmol), 84 Pd(PPh3)4 (0.24 g, 0.23 mmol), 85 Na2CO3 (1.48 g, 14.04 mmol), 86 water (6 mL) and 87 DME (18 mL), and the mixture was purged with argon for 2 min. The reaction mixture was stirred at 95° C. for 5 h. Upon completion (monitored by LC/MS), the mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure to afford the crude residue, which was purified by flash column chromatography on silica gel (0-100% n-heptane/ethyl acetate) to afford 88 A11 ( 0.75 g , 76% ). 1H NMR (400 MHz, DMSO-d6): δ 2.75 (s, 3H), 7.09 (d, J=8.0 Hz, 1H), 7.46-7.49 (m, 1H), 7.89 (d, J=4.0 Hz, 1H), 8.08-8.11 (m, 1H), 8.17 (d, J=4.0 Hz, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.93 (d, J=4.0 Hz, 1H), 12.01 (s, 1H) . LC/ MS (ESI, m/z): 214.22 [M+H]+ .

Reference： [1]Bu, Yahao; Lau, Johnson Y. N.; Locher, Kaspar P.; Nasief, Nader N.; Nosol, Kamil; Said, Ahmed M.; Smolinski, Michael P.; Urgaonkar, Sameer [Journal of Medicinal Chemistry, 2022, vol. 65, # 1, p. 191 - 216]
[2]Current Patent Assignee: ATHENEX INC - US2022/106312, 2022, A1
[3]Current Patent Assignee: ATHENEX INC - US2022/106312, 2022, A1 Location in patent: Paragraph 1212; 1264
[4]Current Patent Assignee: ATHENEX INC - US2022/106312, 2022, A1 Location in patent: Paragraph 1212; 1264
[5]Current Patent Assignee: ATHENEX INC - US2022/106312, 2022, A1 Location in patent: Paragraph 1212; 1264

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[ CAS No. 1450-75-5 ] {[proInfo.proName]}

Quality Control of [ 1450-75-5 ]

Related Doc. of [ 1450-75-5 ]

Product Details of [ 1450-75-5 ]

Calculated chemistry of [ 1450-75-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1450-75-5 ]

Application In Synthesis of [ 1450-75-5 ]

[ 1450-75-5 ] Synthesis Path-Upstream 1~21

[ 1450-75-5 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 1450-75-5 ]

Aryls

Bromides

Ketones

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

[ CAS No. 1450-75-5 ] {[proInfo.proName]}

Quality Control of [ 1450-75-5 ]

Related Doc. of [ 1450-75-5 ]

Product Details of [ 1450-75-5 ]

Calculated chemistry of [ 1450-75-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1450-75-5 ]

Application In Synthesis of [ 1450-75-5 ]

[ 1450-75-5 ] Synthesis Path-Upstream 1~21

[ 1450-75-5 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 1450-75-5 ]

Aryls

Bromides

Ketones

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1450-75-5 ]