Name: 1989-33-9|9H-Fluorene-9-carboxylic acid|95%
Brand: Ambeed
SKU: A439526
Price: 5.0 USD
Availability: InStock
Rating: 93 (30 reviews)

1
[ 67-56-1 ]
[ 1989-33-9 ]
[ 3002-30-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane Inert atmosphere; Sealed tube;
	With acetyl chloride
	With hydrogenchloride

	With sulfuric acid
	With perchloric acid
	With sulfuric acid Heating;
	With sulfuric acid for 12h; Heating;
10 g	With thionyl chloride In N,N-dimethyl-formamide at 0℃; for 0.5h;	1 Example 1: Preparation of formula 2a (methyl 9H-fluorene-9-carboxylate) Example 1: Preparation of formula 2a (methyl 9H-fluorene-9-carboxylate)To a stirred solution of 9H-fluorene-9-carboxylic acid (10 g) in MeOH (50 mL), SOCl2 (10 mL) was added drop wise at 0 °C followed by DMF (catalytic amount) and stirred at 0 °C for 30 min. The reaction mixture was concentrated by distilling off MeOH and SOCl2 completely. The obtained crude was diluted with ethyl acetate and washed with 10 % NaHCO3. The organic layer was separated and concentrated under reduced pressure to yield formula 2a as a pale brown solid (10 g).
	With sulfuric acid for 2h; Reflux;	1.B Step B: to a 250 mL three-necked flask were added 2 g (9.5 mmol) 9-fluorene carboxylic acid, methanol (30 mL), concentrated sulfuric acid (0.2 mL); the mixture was heated to reflux for 2 h; cooled to room temperature; poured into saturated sodium bicarbonate solution, and extracted twice with ethyl acetate (30 mL2), the combined organic phase was washed with brine (30 mL1), evaporated under reduced pressure to give a yellow solid, followed by drying with oil pump to give 1.8 g crude products with mp 62-65° C.
	With sulfuric acid for 2h; Reflux;	1.B to a 250 mL three-necked flask were added 2 g (9.5 mmol) 9-fluorene carboxylic acid, methanol (30 mL), concentrated sulfuric acid (0.2 mL); the mixture was heated to reflux for 2 h, cooled to room temperature, and poured into a saturated sodium bicarbonate solution, and extracted twice with ethyl acetate (30 mL2), the combined organic phase was washed with brine (30 mL1), evaporated under reduced pressure to give a yellow solid, followed by drying with oil pump to give 1.8 g crude products with mp 62-65° C.
	With thionyl chloride at 80℃;

Reference： [1]Zhukhovitskiy, Aleksandr V.; Kobylianskii, Ilia J.; Wu, Chung-Yeh; Toste, F. Dean [Journal of the American Chemical Society, 2018, vol. 140, # 1, p. 466 - 474]
[2]Collins [Journal of the American Chemical Society, 1948, vol. 70, p. 2418]
[3]Tucker [Journal of the Chemical Society, 1949, p. 2182,2185]
[4]Jeanes; Adams [Journal of the American Chemical Society, 1937, vol. 59, p. 2608,2619]
[5]Mathieu,A. [Bulletin de la Societe Chimique de France, 1971, p. 1526 - 1533]
[6]Rouzaud,J. et al. [Bulletin de la Societe Chimique de France, 1965, p. 2345 - 2353]
[7]Krogh, Erik; Wan, Peter [Journal of the American Chemical Society, 1992, vol. 114, # 2, p. 705 - 712]
[8]Current Patent Assignee: VIATRIS INC - WO2016/12934, 2016, A1 Location in patent: Page/Page column 14
[9]Current Patent Assignee: BEIJING LIHE TECHNOLOGY; BEIJING LIHE ZHIXIN TECHNOLOGY; BEIJING LIHE TECH - US2017/88642, 2017, A1 Location in patent: Paragraph 0069
[10]Current Patent Assignee: BEIJING LIHE TECH; BEIJING LIHE TECHNOLOGY - US2017/283530, 2017, A1 Location in patent: Paragraph 0097
[11]Deng, Xiao-Jun; Liu, Hui-Xia; Zhang, Lu-Wen; Zhang, Guan-Yu; Yu, Zhi-Xiang; He, Wei [Journal of Organic Chemistry, 2021, vol. 86, # 1, p. 235 - 253]

2
[ 64-17-5 ]
[ 1989-33-9 ]
[ 26878-12-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane Inert atmosphere; Sealed tube;
93%	With sulfuric acid for 8.5h; Heating;
	With sulfuric acid

	With hydrogenchloride
	With hydrogenchloride

Reference： [1]Zhukhovitskiy, Aleksandr V.; Kobylianskii, Ilia J.; Wu, Chung-Yeh; Toste, F. Dean [Journal of the American Chemical Society, 2018, vol. 140, # 1, p. 466 - 474]
[2]Ohwada, Tomohiko [Journal of the American Chemical Society, 1992, vol. 114, # 23, p. 8818 - 8827]
[3]Adickes [Journal fur praktische Chemie (Leipzig 1954), 1936, vol. <2> 145, p. 235,242]
[4]Friedlaender [Chemische Berichte, 1877, vol. 10, p. 534]
[5]Tucker [Journal of the Chemical Society, 1949, p. 2182,2185]

3
[ 1989-33-9 ]
[ 24168-51-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrachloromethane; thionyl chloride
	With phosphorus pentachloride at 70℃;
	With thionyl chloride In tetrachloromethane

	With thionyl chloride for 4h; Heating;
	With oxalyl dichloride; N,N-dimethyl-formamide
	With thionyl chloride
	With thionyl chloride In benzene at 60℃; for 2h;
	With thionyl chloride In toluene for 2h; Heating;
	With thionyl chloride In benzene at 60℃;
	With thionyl chloride for 3h; Heating;
	With thionyl chloride at 50 - 60℃;
	With thionyl chloride In tetrachloromethane Inert atmosphere; Schlenk technique;
	With thionyl chloride In chloroform at 60℃; for 4h;
	With thionyl chloride In benzine for 6h; Inert atmosphere; Reflux;	5.9. General procedure for the synthesis of 9H-fluorene-9-carbonyl chloride (20) A solution of 9H-fluorene-9-carboxylic acid 19 (2.5 g, 23.56 mmol) in benzene (5 mL) was treated by the dropwise addition of SOCl2 (17 g, 0.14 mol, 10.4 mL) under nitrogen atmosphere. Then the reaction mixture was heated at reflux with stirring for 6 h, and subsequently the excess of SOCl2 was removed under reduced pressure to obtained desired acid chloride 20 as a colorless oil, which solidified on standing. The crude 9H-fluorene-9-carbonyl chloride (20) was further used without any purification.
Ca. 0.57 g	In tetrachloromethane at 75℃; for 2h;	6-10 Synthesis of 9-fluorenecarbonyl chloride: Add 0.525g of 9-fluorenic acid, 4mL of dimethylsulfoxide, and 20mL of carbon tetrachloride into a 100mL single-necked flask. After dissolving under stirring at 300r/min, install the condenser, and then place it in a 75 °C oil bath for refluxing for 2h. After the reaction is over, the mixed solution is quickly rotated and evaporated, the solvent and unreacted dimethyl sulfoxide were removed, and the product was dried under vacuum at 40 °C for 24 hours to obtain 9-fluorenyl chloride (about 0.57 g).

Reference： [1]Vorlaender; Pritzsche [Chemische Berichte, 1913, vol. 46, p. 1795] Stolle; Wolf [Chemische Berichte, 1913, vol. 46, p. 2250]
[2]Boyd,G.V.; Harms,M.D. [Journal of the Chemical Society C: Organic, 1970, p. 807 - 810]
[3]Zakharova,N.A. et al. [Journal of Organic Chemistry USSR (English Translation), 1967, vol. 3, p. 1087 - 1094][Zhurnal Organicheskoi Khimii, 1967, vol. 3, p. 1128 - 1136]
[4]Duperrouzel, Paul; Lee-Ruff, Edward [Canadian Journal of Chemistry, 1980, vol. 58, # 1, p. 51 - 54]
[5]Roufos; Hays; Dooley; Schwarz; Campbell; Probert Jr. [Journal of Medicinal Chemistry, 1994, vol. 37, # 2, p. 268 - 274]
[6]Buehler,C.A. et al. [Journal of Medicinal Chemistry, 1963, vol. 6, p. 230 - 233] Sabin; Horwell; McKnight; Broqua [Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 3, p. 291 - 296]
[7]Teodori, Elisabetta; Dei, Silvia; Quidu, Patricia; Budriesi, Roberta; Chiarini, Alberto; Garnier-Suillerot, Arlette; Gualtieri, Fulvio; Manetti, Dina; Romanelli, Maria Novella; Scapecchi, Serena [Journal of Medicinal Chemistry, 1999, vol. 42, # 10, p. 1687 - 1697]
[8]Mitsch, Andreas; Wi, Pia; Sattler, Isabel; Schlitzer, Martin [Archiv der Pharmazie, 2001, vol. 334, # 2, p. 40 - 44]
[9]Teodori, Elisabetta; Dei, Silvia; Garnier-Suillerot, Arlette; Gualtieri, Fulvio; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Sudwan, Paiwan; Salerno, Milena [Journal of Medicinal Chemistry, 2005, vol. 48, # 23, p. 7426 - 7436]
[10]Robarge; Husbands; Kieltyka; Brodbeck; Thurkauf; Newman [Journal of Medicinal Chemistry, 2001, vol. 44, # 19, p. 3175 - 3186]
[11]Singh, Chandan; Chaudhary, Sandeep; Puri, Sunil K. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1436 - 1441]
[12]Arkhypchuk, Anna I.; Svyaschenko, Yurii V.; Orthaber, Andreas; Ott, Sascha [Angewandte Chemie - International Edition, 2013, vol. 52, # 25, p. 6484 - 6487][Angew. Chem., 2013, vol. 125, # 25, p. 6612 - 6615]
[13]Teodori, Elisabetta; Dei, Silvia; Bartolucci, Gianluca; Perrone, Maria Grazia; Manetti, Dina; Romanelli, Maria Novella; Contino, Marialessandra; Colabufo, Nicola Antonio [ChemMedChem, 2017, vol. 12, # 16, p. 1369 - 1379]
[14]Borowiecki, Paweł; Wińska, Patrycja; Bretner, Maria; Gizińska, Małgorzata; Koronkiewicz, Mirosława; Staniszewska, Monika [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 307 - 333]
[15]Current Patent Assignee: INST OF CHEMICAL ENGINEERING GUANGDONG ACADEMY OF SCIENCES - CN112707903, 2021, A Location in patent: Paragraph 0104-0107; 0112-0115; 0118-0121; 0124-0127

4
[ 76-93-7 ]
[ 1989-33-9 ]

Yield	Reaction Conditions	Operation in experiment
65%	In benzene at -45℃; for 1h;
	With aluminium trichloride; benzene zuletzt bei Siedetemperatur;
	With sulfuric acid In acetic acid

Reference： [1]Ohwada,T.; Shudo,K. [Journal of the American Chemical Society, 1988, vol. 110, p. 1862]
[2]Arnold; Parham; Dodson [Journal of the American Chemical Society, 1949, vol. 71, p. 2439] Richter [Organic Syntheses, 1963, vol. Coll. Vol. IV, p. 482]
[3]von Dobeneck,H.; Kiefer,R. [Justus Liebigs Annalen der Chemie, 1965, vol. 684, p. 115 - 127]

5
[ 1989-33-9 ]
[ 24324-17-2 ]

Yield	Reaction Conditions	Operation in experiment
51%	With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane In chloroform at 60℃; for 1h; Inert atmosphere;
	With lithium aluminium tetrahydride
	With lithium aluminium tetrahydride In diethyl ether Heating;

Reference： [1]Location in patent: experimental part Sakai, Norio; Kawana, Keita; Ikeda, Reiko; Nakaike, Yumi; Konakahara, Takeo [European Journal of Organic Chemistry, 2011, # 17, p. 3178 - 3183]
[2]Krogh, Erik; Wan, Peter [Tetrahedron Letters, 1986, vol. 27, # 7, p. 823 - 826]
[3]Arlt, Michael; Boettcher, Henning; Riethmueller, Angelika; Schneider, Guenter; Bartoszyk, Gerd D.; Greiner, Hartmut; Seyfried, Christoph A. [Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 15, p. 2033 - 2038]

6
[ 76-93-7 ]
[ 1989-33-9 ]
[ 467-32-3 ]

Yield	Reaction Conditions	Operation in experiment
1: 73% 2: 11%	With sulfuric acid In chloroform Ambient temperature;

Reference： [1]Dao,L.H.; Malecki,M.; Hopkinson,A.C. [Journal of the American Chemical Society, 1986, vol. 108, p. 5237]

7
[ 1989-33-9 ]
[ 71-43-2 ]
[ 1603-73-2 ]

Yield	Reaction Conditions	Operation in experiment
60%	at 63℃; for 4h;

Reference： [1]Ohwada,T.; Shudo,K. [Journal of the American Chemical Society, 1988, vol. 110, p. 1862]

8
[ 110-52-1 ]
[ 1989-33-9 ]
[ 182438-97-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 9H-fluorene-9-carboxylic acid With n-butyllithium In tetrahydrofuran at 0℃; for 1h; Stage #2: 1,4-dibromo-butane In tetrahydrofuran at 0 - 20℃; for 30.5h; Further stages.;
85%	With n-butyllithium In tetrahydrofuran at 0 - 20℃; for 32h;	273. A. 1; 688. C A(1). To a solution of 9-fluorenecarboxylic acid (50 g, 240 mmol) in THF (1200 mL) at 0°C was added dropwise a solution of n-butyllithium (2.5M, 211 mL, 530 mmol) in THF. The yellow reaction was stirred at 0°C for 1 h, then 1,4-dibromobutane (31.3 mL, 260 mmol) was added dropwise over 30 min. The reaction was stirred at 0°C for 30 min, then the reaction was warmed to RT for 30 h. The reaction was extracted with water (3 x 750 mL). The combined aqueous layers were extracted with ethyl ether (800 mL). The aqueous layer was made acidic with HCl solution (1N, 500 mL), then extracted with dichloromethane (3 x 750 mL). The combined organic layers were dried over MgSO4. Evaporation gave title compound (71 g, 85%) as a white solid.
85%	Stage #1: 9H-fluorene-9-carboxylic acid With n-butyllithium In tetrahydrofuran at 0℃; for 1h; Stage #2: 1,4-dibromo-butane In tetrahydrofuran at 0 - 20℃; for 31h;	To a solution of 9-fluorenecarboxyiic acid (50 g, 240 mnioi) in THF (1200 rnL) at 0°C, was added dropwise a solution of n-butyi hthium (2.5M, 211 mL, 530 mrnoi) in THE The yellow reaction was stirred at 00 C. for 1 h, then 1 ,4-dihromobutane (31 3mL, 260 mnioi) was added dropwise over 30 nun. The reaction was stirred at 0°C. for30 mm, then the reaction was warmed to RT tbr 30 ii HC1 solution (IN, 500 mL) was added, then extracted with dichioromethane (3x750 mL) to give 9-(4-brornobutyl)-9H- fluorene-9-carboxylic acid (71 g, 85%) as a white solid.

82.5%	Stage #1: 9H-fluorene-9-carboxylic acid With n-butyllithium In tetrahydrofuran; hexane at 0 - 5℃; for 0.25h; Inert atmosphere; Stage #2: 1,4-dibromo-butane In tetrahydrofuran; hexane at 25 - 30℃;	1 EXAMPLE 1: Preparation of 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid To a solution of 9H-fluorene-9-carboxylic acid (200 gm, 0.95 moles) in tetrahydrofuran (8 L) was added n-BuLi (182.7 gm, 2.85 moles, 1.6 M solution in hexane) at about 0-5°C under nitrogen atmosphere and stirred for about 15 min at same temperature. The temperature of the reaction mass was raised to about 25-30°C and a solution of 1,4-dibromobutane (246.48 gm, 1.14 moles) in THF (0.5 L) was added. The reaction mass was stirred for about 8-12 hrs at about 25-30°C. After completion of the reaction, pH of the reaction mass was adjusted to about 2-3 with dilute hydrochloric acid and the product was extracted in toluene (4 L). The organic layer was dried under vacuum at about 60-65°C to afford a residue. The residue was dissolved in diisopropyl ether and the pH was adjusted to about 8-9 with a solution of sodium carbonate in water. The layers were separated and aqueous layer was washed with diisopropyl ether. The aqueous layer was acidified with dilute hydrochloric acid to pH of about 2-3 and the product was extracted with ethyl acetate. The organic layer distilled under vacuum at about 50-55°C to provide a residue which was stirred with n-heptane. The precipitated solid was filtered and dried under vacuum at about 50-55°C for 12 hrs to furnish 270 gm of 9-(4-bromobutyl)-9H-fluorene- 9-carboxylic acid as pale yellow solid (Yield 82.5 %, HPLC purity 96.30 %).
79.9%	With lithium diisopropyl amide In tetrahydrofuran at -5 - 25℃; for 20.5h; Inert atmosphere;	1.1 Example 1 Synthesis of 9- (4-bromobutyl) -9H-fluorene-9-carboxylic acid In a thermometer,(20.0 g, 95 mmol) and dry tetrahydrofuran (400 mL) were added successively to a dry three-necked flask equipped with a dropping funnel, followed by stirring and rinsing. 84 ml of lithium diisopropylamide (2.5 M, 210 mmol). Drop complete, -5 reaction 1h,Then dropwise1,4-Dibromobutane (12.2 ml, 100 mmol),-5 reaction 0.5h, rose to room temperature (25 ) reaction 20h, by adding 200ml water stirring 0.5h, part of the vacuum distillation of the solvent,The residue was washed with methyl tert-butyl ether (MTBE) (150 ml * 3). The aqueous layer was acidified with hydrochloric acid (1 N, 250 ml) and extracted with dichloromethane (200 ml x 3). The combined organic layers were washed with saturated aqueous NaHCO3 (150 ml x 3) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, Was recrystallized from 200 ml of petroleum ether / ethyl acetate (3: 1 by volume) to give the title compound (26.2 g, 79.9%) as a white solid (mp: 122-124 ° C).
	Stage #1: 9H-fluorene-9-carboxylic acid With n-butyllithium In tetrahydrofuran Stage #2: 1,4-dibromo-butane In tetrahydrofuran

Reference： [1]Robl; Sulsky; Sun; Simpkins; Wang; Dickson Jr.; Chen; Magnin; Taunk; Slusarchyk; Biller; Lan; Connolly; Kunselman; Sabrah; Jamil; Gordon; Harrity; Wetterau [Journal of Medicinal Chemistry, 2001, vol. 44, # 6, p. 851 - 856]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 144-145; 314
[3]Current Patent Assignee: HETERO DRUGS LIMITED - WO2016/71849, 2016, A1 Location in patent: Page/Page column 15
[4]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2016/55934, 2016, A1 Location in patent: Paragraph 0123
[5]Current Patent Assignee: TIANJIN INST PHARMACEUTICAL - CN106146385, 2016, A Location in patent: Paragraph 0031; 0032; 0033; 0034
[6]Sulsky, Richard; Robl, Jeffrey A.; Biller, Scott A.; Harrity, Thomas W.; Wetterau, John; Connolly, Fergal; Jolibois, Kern; Kunselman, Lori [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5067 - 5070]

9
[ 1989-33-9 ]
[ 26487-67-2 ]
2-(hexahydro-1H-azepin-1-yl)ethyl 2-fluorenylcarboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3244 - 3253

10
[ 1989-33-9 ]
[ 182438-98-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5067 - 5070
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 851 - 856
[3]Patent: WO2016/55934,2016,A1
[4]Patent: WO2016/71849,2016,A1
[5]Patent: WO2016/71849,2016,A1
[6]Patent: CN106146385,2016,A

11
[ 86-73-7 ]
[ 1989-33-9 ]

Yield	Reaction Conditions	Operation in experiment
69%		52 Example 52 Example 52 The reaction was effected in the same manner as Example 44 except for using fluorene instead of adamantane and that the pressure of the mixed gas was 10kg/cm2. The conversion of fluorene was 73%, and 9-carboxyfluorene (yield 69%) were formed.
	Multi-step reaction with 3 steps 1: potassium ethylate; methanol 2: acetic acid; sulfuric acid; water 3: acetic acid; aqueous hydrogen peroxide
	Multi-step reaction with 2 steps 1: diethyl ether

Multi-step reaction with 2 steps 1: nBuLi 2: (i) nBuLi, THF, hexane, (ii) /BRN= 1900390/

Reference： [1]Current Patent Assignee: DAICEL CORPORATION - EP897747, 1999, A1
[2]Campbell; Tucker [Journal of the Chemical Society, 1949, p. 2623,2626]
[3]Schlenk; Bergmann [Justus Liebigs Annalen der Chemie, 1928, vol. 463, p. 208]
[4]Peddle,G.J.D. [Journal of Organometallic Chemistry, 1967, vol. 9, p. 171 - 174]

12
[ 1989-33-9 ]
[ 4425-93-8 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 1172,1175

13
[ 1989-33-9 ]
[ 194219-32-4 ]

Yield	Reaction Conditions	Operation in experiment
15%	With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1h;	272. A Example 272; (E)-9-[4-(Dibutoxyphosphinyl)-2-butenyl]-N-propyl-9H-fluorene-9-carboxamide To a THF (150 ml) suspension of 9-fluorenecarboxylic acid (10 g, 0.048 mol) at 0°C under argon was added dropwise sodium bis(trimethylsilyl)amide (100 ml, 1 M in THF). After 30 min, 1,4-trans-2-butene (10.2 g, 0.048 mol) was added and the reaction allowed to stir for 1 h. The reaction mixture was quenched with 1N HCl and the aqueous layer extracted 3 times with EtOAc. The combined organics were dried over Na2SO4 and evaporated in vacuo to give an oily-solid residue (18 g). The residue was purified by flash column chromatography (SiO2, 10 by 25 cm), eluting with 6.5% MeOH:CH2Cl2 to give title compound (2.48 g, 15% yield) as an oily solid. MS: (CI, M+NH4+): m/z 360+.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 143

14
[ 5162-44-7 ]
[ 1989-33-9 ]
[ 194219-61-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 96.6667h;	291. A A. To a stirred solution of 12.6 g (60 mmol) of 9-fluorenecarboxylic acid in 600 mL of dry THF at 0° under argon was added, over 20 min, 53 mL of 2.5 M n-butyllithium in hexane (132.5 mmol). The mixture was stirred for 30 min and then 7.3 mL (72 mmol) of 4-bromo-1-butene were added. The reaction was sirred at 0°C for 10 min and then at room temperature for 2 days. Additional 4-bromo-1-butene (3.0 mL, 30 mmol) was added and stirring was continued for 2 days longer. Water (100 mL) was added and the mixture was concentrated to remove THF. Additional water was added and the mixture was extracted with ether (2 x 200 mL). The aqueous layer was layered with CH2Cl2 and acidified with 1N HCl (pH <2). After three extractions with CH2Cl2, the combined CH2Cl2 fraction was washed with water (2x), dried (MgSO4), and concentrated to give 14.5 g (92%) of title compound as an amorphous pale yellow solid.
	With lithium tert-butoxide In tetrahydrofuran at 0 - 20℃;	417. A A. To a solution of the 9H-fluorene carboxylic acid (8.0 g, 38 mmol) in THF at 0°C (150 ml) was added a 1 M solution of lithium tert-butoxide (76 ml, 76 mmol) in THF. Following the addition of base, the reaction mixture was stirred vigorously at RT for 2h. The reaction mixture was treated with 1-bromo-3-butene (8.00 g, 60 mmol) and stirred overnight. TLC indicated a trace of starting acid was still present. The reaction mixture was treated with an additional 5 mL (5 mmol) of lithium tert-butoxide and the mixture stirred overnight. The mixture was quenched with NH4Cl solution and the pH adjusted to 2 with KHSO4 solution. The mixture was diluted with ethyl acetate (400 mL) and washed with water. The organic layer was dried (MgSO4), and the solvent was removed in vacuo to give an off-white foam which was partially purified by trituration with hexane to give a white solid (9.5 g) of the structure

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 161
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 235

15
[ 1989-33-9 ]
[ 637-59-2 ]
[ 102591-83-3 ]

Yield	Reaction Conditions	Operation in experiment
67%	With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 16.2167h;	22. A Example 22; A. 9-(3-Phenylpropyl)-9H-fluorene-9-carboxylic acid To a solution of 10 g (48 mmol, 1 eq) of (9H)-flourene-9-carboxylic acid in 200 mL of THF at 0°C was added 40 mL (100 mmol, 2.1 eq) of a 2.5 M solution of n-butyllithium in hexanes dropwise over 15 min. (First equivalent resulted in precipitation of Li salt of the carboxylate; solution became homogeneous as dianion formed.) The resulting green solution of dianion was stirred at 0°C for 10 min and 10.1 mL (66 mmol, 1.4 eq) of 1-bromo-3-phenylpropane was added quickly over 3 min. The reaction was stirred at 0°C and allowed to warm to RT as the ice bath melted. After 16 h, the basic reaction mixture (pH ~14) was extracted with water (1 x 200 mL, 2 x 50 mL). The combined aqueous layers were acidified (to pH ~1) with 5 N HCl and extracted with ether (3 x 100 mL). The combined ether solutions were dried (MgSO4), filtered and concentrated to afford 16.4 g of a viscous golden oil. Flash chromatography of the oil on silica gel (250 g) eluted with 20% acetone in toluene containing 0.1 % acetic acid afforded 12.6 g of a yellow oil. The product was crystallized by slow evaporation of an ether/hexanes solution and then recrystallized from ether/hexanes to afford 10.5 g (67%) of title compound as a white crystalline solid. m.p. 123-125°C. TLC (silica gel, 10% MeOH in CH2Cl2, UV and I2) Rf = 0.67.
10.5 g (67%)	With n-butyllithium; acetic acid In tetrahydrofuran; toluene	22.A A. A. 9-(3-Phenylpropyl)-9H-fluorene-9-carboxylic acid To a solution of 10 g (48 mmol, 1 eq) of (9H)-flourene-9-carboxylic acid in 200 mL of THF at 0° C. was added 40 mL (100 mmol, 2.1 eq) of a 2.5M solution of n-butyllithium in hexanes dropwise over 15 min. (First equivalent resulted in precipitation of Li salt of the carboxylate; solution became homogeneous as dianion formed.) The resulting green solution of dianion was stirred at 0° C. for 10 min and 10.1 mL (66 mmol, 1.4 eq) of 1-bromo-3-phenylpropane was added quickly over 3 min. The reaction was stirred at 0° C. and allowed to warm to RT as the ice bath melted. After 16 h, the basic reaction mixture (pH ~14) was extracted with water (1200 mL, 250 mL). The combined aqueous layers were acidified (to pH ~1) with 5N HCl and extracted with ether (3*100 mL). The combined ether solutions were dried (MgSO4), filtered and concentrated to afford 16.4 g of a viscous golden oil. Flash chromatography of the oil on silica gel (250 g) eluted with 20% acetone in toluene containing 0.1% acetic acid afforded 12.6 g of a yellow oil. The product was crystallized by slow evaporation of an ether/hexanes solution and then recrystallized from ether/hexanes to afford 10.5 g (67%) of title compound as a white crystalline solid. m.p. 123°-125° C.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 49
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US5760246, 1998, A

16
[ 1989-33-9 ]
[ 107-14-2 ]
[ 182439-14-1 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 4.21667h;	297. A A. Butyllithium (18 mL, 2.5M in hexanes, 44 mmol) was added dropwise over 10 min to a solution of 9-fluorenecarboxylic acid (4.2 g, 20 mmol) in THF (200 mL) at 0°C under argon. The slightly heterogeneous dark yellow reaction was stirred at 0°C for 30 min, then chloroacetonitrile (1.5 mL, 24 mmol) was added dropwise over 3 min. The orange reaction was stirred at 0°C for 30 min, warmed to room temperature and stirred for 3 h. The reaction was extracted with water (2 x 100 mL) and the combined aqueous extracts were washed with Et2O (100 mL). The aqueous layer was acidified to pH<2 with 1N HCl and extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 4.7 g of a light yellow solid (mp 138-145°C). A portion (2.63 g) of the crude carboxylic acid was dissolved in CH2Cl2 (30 mL) under argon. N,N-Dimethylformamide (40 µL, 0.53 mmol) was added followed by oxalyl chloride (8.0 mL, 2.0M in CH2Cl2, 15.9 mmol). The reaction bubbled for a few minutes and was allowed to stir at room temperature for 1.5 h. The reaction was concentrated in vacuo then pumped under high vacuum to give the crude acid chloride. Triethylamine (4.4 mL, 31.8 mmol) was added to a suspension of 2,2,2-trifluoroethylamine hydrochloride (1.71 g, 12.7 mmol) in CH2Cl2 (20 mL) at 0°C under argon. The resulting thick slurry was stirred at 0°C for 5 min, then a solution of the crude acid chloride in CH2Cl2 (10 mL) was added dropwise over 5 min. The reaction was stirred at 0°C for 10 min, diluted with CH2Cl2 (50 mL), washed with 1N HCl (2 x 20 mL) and saturated NaHCO3 (30 mL), then dried over Na2SO4. Evaporation gave 3.5 g of a yellow foam which was purified by flash chromato-graphy on silica (150 g) eluting with CH2Cl2 to give title compound (2.74 g, 76%) as a white solid (mp 159-159.5).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 171-172

17
[ 1989-33-9 ]
[ 106-95-6 ]
[ 101451-35-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1.08333h;	93. A Alternative Preparation of Part A Compound To a THF (15 ml) supension of 9-fluorene carboxylic acid (5.28 g, 0.025 mol) at 0°C under argon was added sodium hexamethyldisilizane (50 mL, 0.05 mol, 1M in THF), initial solid formation, and the final greenish-brown solution stirred for 5 min.. Allyl bromide (2.3 mL, 0.0265 mol) was added and after 1 h the mixture was poured into cold water. The aqueous layer was extracted with EtOAc and the organic layer washed with water. The combined aqueous layers were brought to pH 1 with 3N HCl and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, and the volatiles removed in vacuo to give an oily-solid residue (6.96 g). The residue was crystallized from EtOH/water to give 2.81 g colorless solid. After concentrating the mother liquor, a second crop (1.04 g) and third crop (0.5 g) were obtained of Part A compound (4.35 g, 69% yield). mp 128-130°C.
	With n-butyllithium In tetrahydrofuran	121.a a. a. 9-allyl-9H-fluorene-9-carboxylic Acid 42 ml (0.096 mol) of a 2.5M butyl lithium solution are added dropwise at 0° C. under nitrogen to a solution of 10 g (0.048 mol) of 9-fluorenecarboxylic acid in 150 ml of THF and the mixture is stirred for 30 minutes. Then 4.67 ml (0.054 mol) of allyl bromide are added and the solution is stirred for four hours at ambient temperature. The reaction solution is poured into water and extracted with diethyl ether. The aqueous phase is acidified with 1N hydrochloric acid and extracted with dichloromethane. The organic phase is dried over sodium sulphate and freed from solvent. Yield: 2.4 g (20% of theory),
3.58 g	Stage #1: 9H-fluorene-9-carboxylic acid With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 1h; Stage #2: allyl bromide at -78 - 20℃;

With potassium hydroxide In 2-methoxy-ethanol at 20℃; for 2.25h;

93. A Example 93; 9-(2-Propenyl)-N-(2-pyridinylmethyl)-9H-fluorene-9-carboxamide; A. To a methoxyethanol solution (100 ml) of 9H-fluorene-9-carboxylic acid (10.83 g, 0.0515 mol) under argon was added solid KOH (6.8 g, 0.103 mol). After about 15 min the KOH had dissolved resulting in a blue-green colored solution. Allyl bromide (8.9 ml, 0.526 mol) was then added and stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc/H2O and the aqueous layer extracted twice with EtOAc. The aqueous layer was brought to pH 2 with 1N HCl, extracted twice with EtOAc, and the combined organics were dried over Na2SO4. Evaporation in vacuo gave 11.63 g of a brown colored oily-solid. The residue was co-evaporated with CH2Cl2, Et2O, EtOAc, and hexanes to give an orange colored solid 9.19 g (70% recovery). A portion of the material (400 mg) was purified by flash chromatography (twice, 3x13 cm), eluting with 3%MeOH:CH2Cl2 to give title compound as a colorless solid (160 mg). m.p. 128-130°C. MS: (CI, M+NH4+): m/z 268.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 74
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2003/166637, 2003, A1
[3]Current Patent Assignee: MEIJI HOLDINGS CO., LTD - EP1180514, 2002, A1 Location in patent: Example 127
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 74

18
[ 1989-33-9 ]
[ 107-08-4 ]
[ 182438-60-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 10h;	59. A A. A solution of (9H)-9-fluorenecarboxylic acid (12 g, 57 mmol) in 250 ml of THF was cooled to 0°C under an argon atmosphere and 2 equiv. (71.25 ml) of a 1.6 M n-butyl lithium solution in hexane was added followed by the addition of n-propyl iodide (7.5 ml, 13.1 g, 77 mmol). The reaction mixture was stirred at 0°C for 6 hrs. TLC, silica, MeOH:CH2Cl2 (1:9) showed starting acid still present, therefore, an additional 1 ml of n-propyl iodide was added and the reaction stirred for 4 hrs at 0°C. The reaction was quenched by adding 75 ml of water and the pH was adjusted to pH 1 with 3 N HCl. The reaction mixture was extracted with hexane (3x200ml) and the hexane extract washed with water, brine and dried over anhy. sodium sulfate. The solvents were evaporated yielding the crude product as a yellow oil which was dissolved in ~250 ml of ethanol and heated at reflux with Darco G-60, filtered through Celite and concentrated to approximately one half of the original volume. Water was slowly added until the mixture became cloudy. The mixture was reheated and slowly allowed to cool to room temperature yielding 10.5 grams (73%) of title compound as colorless crystals. m.p.120-122°C.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 63

19
[ 1476-11-5 ]
[ 1989-33-9 ]
[ 182438-67-1 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 3.41667h;	186. A Alternate Example 186; 9-[4-(Dibutoxyphosphinyl)butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide; A. Butyllithium (8.4 mL, 2.5M in hexane, 21 mmol) was added dropwise over 10 min to a solution of 9-fluorenecarboxylic acid (2.10 g, 10 mmol) in THF (50 mL) at 0 °C under argon. During addition of the first equivalent of BuLi, the reaction became thick with a white precipitate which became yellow and cleared after addition of the second equivalent. The reaction was stirred at 0 °C for 20 min, then cis-1,4-dichloro-2-butene (1.2 mL, 11 mmol) was added dropwise over 5 min. The reaction lightened in color during addition and was stirred at 0 °C for 3 h, then poured into 1N HCl (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (30 mL) then dried over MgSO4. Evaporation provided 3.5 g of a yellow oil containing crystalline solid. The crude residue was triturated with hexane (20 mL). The supernatant was decanted, and the residue pumped under high vacuum to give 2.93 g of title compound as a tan solid.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 109

20
[ 1989-33-9 ]
[ 2695-47-8 ]
[ 208660-76-8 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 18.5h;	290. A A. To a solution of 3.0 g (14.30 mmol) of 9-fluorenecarboxylic acid in 50 mL of THF, under argon at 0°C, was added dropwise 11.4 mL (28.60 mmol) of n-BuLi (2.5 M in hexanes). The anion was stirred for 0.5 h at which time 2.3 mL (17.16 mmol) of 6-bromo-1-hexene was added dropwise. The reaction gradually warmed to room temperature and was stirred for 18 h, at which time it was diluted with a 1:1 mixture of ethyl acetate/water (200 mL). The organics were washed with NaHCO3, water, brine, dried (Na2SO4) and evaporated. Flash chromatography was performed on 200 g of silica gel eluting with 95:5 dichloro-methane/isopropanol to provide 900 mg (22%) of title compound as a pale yellow solid. MS (CI-NH3, + ions) m/z 310 (M + NH4), 293 (M + H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 158-159

21
dibutyl(4-bromobutyl)phosphonate [ No CAS ]
[ 1989-33-9 ]
[ 194219-00-6 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃;	141. A A. To a suspension of fluorene-(9H)-9-carboxylic acid (0.45 g, 2.18 mmol) in THF (5 mL) at -78°C was added n-butyllithium in hexanes (1.70 mL, 4.20 mmol) dropwise at such a rate to maintain the internal temperature below -40°C. The resulting bright yellow solution was stirred at - 40°C for 0.5 h and treated with compound Example 11, Part B (0.60 g, 1.82 mmol). The mixture was slowly warmed to room temperature and stirred for 6 h when the mixture was treated with 0.1 g (10 mol%) of tetrabutylammonium iodide and allowed to stir overnight. The mixture was diluted with 0.1N HCl (25 mL, 2.50 mmol) and ethyl acetate (50 mL). The layers were separated, the organic fraction dried (Na2SO4) and concentrated to give 1 g of crude oil. This material could be purified by flash chromatography (silica gel, eluting with 5% MeOH:ethyl acetate) and crystallization from hexane/ethyl acetate/methylene chloride to gave title compound as a colorless solid. mp 123-125°C. TLC Silica gel (3:7:1 acetone/dichloromethane/acetic acid) Rf= 0.45.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 92

22
[ 1989-33-9 ]
[ 99067-72-8 ]
[ 194219-13-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With n-butyllithium In tetrahydrofuran at 0℃; for 4.91667h;	207. A. 1. b A(1)b.; 9-[3-(4-Nitrophenyl)-2-propenyl]-9-fluorenecarboxylic acid To a solution of 9-fluorenecarboxylic acid (1.0 g, 4.76 mmol) in THF (20 mL) at 0°C was added dropwise a solution of n-butyllithium (2.5M, 4.2 mL, 10.5 mmol) in THF. The dark reaction was stirred at 0°C for 20 min, then a solution of Part A(1)a chloride (1.04 g, 5.24 mmol) in THF (2 mL) was added dropwise over 5 min. The reaction was stirred at 0°C for 4.5 h and the dark color faded away gradually. Hydrochloric acid (1.0M, 2 mL) was added to quench the reaction. Ethyl acetate (200 mL) was added and the organic layer was washed with water (2 x 50 mL), brine (2 x 50 mL) and dried over MgSO4. Evaporation gave title compound (1.7 g, 87%) as a yellowish oil.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 122

23
[ 1989-33-9 ]
[ 99067-72-8 ]
C₂₄H₂₁NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 5.5h;	288. B B. Butyllithium (2.0 mL, 2.5M in hexane, 5.0 mmol) was added to a solution of 9-fluorenecarboxylic acid (480 mg, 2.3 mmol) in The (10 mL) at 0°C under argon over 5 min. The reaction went from a clear solution to a white suspension then to a yellow solution during addition. The reaction was stirred at 0°C for 20 min, whereupon a solution of Part A iodide (671 mg, 2.2 mmol) in THF (4 mL) was added dropwise over 5 min. The reaction was stirred at 0 °C for 1.5 h, warmed to room temperature, then stirred at room temperature for 3.5 h. The reaction was quenched with 1N HCl to pH ≈ 3, diluted with water (10 mL), then extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water and brine (10 mL each), then dried over MgSO4. Evaporation gave a residue, which was azeotroped'with toluene (10 mL) to give crude acid in the form of a dark foam

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 157

24
[ 769-42-6 ]
[ 1989-33-9 ]
5-(9-fluorenylcarbonyl)-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃;	5 EXAMPLE 5; 5-(9-fluorenylcarbonyl)-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione (Dtpf-OH) 5 A mixture of 1,3-dimethylbarbituric acid (2.5 g, 16.01 mmol), 9-fluorenylcarboxylic acid (5.05 g, 24.01 mmol), 4-dimethylaminopyridine (0.98 g, 8.00 mmol) in dry CH2Cl2 (15 ml) was cooled to 0 C. and 1,3-dicyclohexylcarbodiimide (3.30 g, 16.01 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (50 ml) and the combined solution was washed with 2 N HCl solution (5 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from recrystallised from MeOH giving 5-(9-fluorenyl-carbonyl)-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 5 (2.85 g, 69%). Rf 0.49 (EtOAc/hexane/TFA 10:25:0.1); FAB MS C20H16N2O4 (348.35) m/z (%) 349 [M+H]+ (100), 338 (32), 183 (72), 164 (71). 1NMR (CDCl3) d 17.33 (s, 1H, OH), 7.81 (d, 2H, 2 ArH), 7.42 (m, 4H, 4 ArH), 7.30 (d, 2H, 2 ArH), 6.92 (s, 1H, CH), 3.48, 3.40 (2s, 6H, 2 NCH3).

Reference： [1]Current Patent Assignee: VAST BIOSCIENCE - US6765089, 2004, B1 Location in patent: Page column 17

25
[ 62168-25-6 ]
[ 1989-33-9 ]
[ 182438-97-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; water	1.a a. a. 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic Acid 89 ml (0.11 mol) of a 1.6-Molar n-butyl-lithium solution in hexane are added dropwise to a solution of 21 g (0.1 mol) of 9-fluorenecarboxylic acid in 700 ml of tetrahydrofuran at 0° C. under nitrogen and stirred for one hour. Then, again at 0° C., 13.13 ml (0.11 mol) of dibromobutane are added and the solution is stirred for 30 hours at ambient temperature. After this time 50 ml of water are added and the mixture is stirred for 30 minutes. The solution is concentrated by evaporation, mixed with water and extracted with 250 ml of diethylether. The aqueous phase is acidified with 150 ml of 1N hydrochloric acid and extracted three times with 250 ml of dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent is eliminated. Yield: 18.5 g (53.6% of theory), Melting point: 123° C.
	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; water	I 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic Acid EXAMPLE I 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic Acid 89 ml (0.11 mol) of a 1.6 molar n-butyl-lithium solution in hexane are added dropwise at 0° C. to a solution of 21 g (0.1 mol) of 9-fluorenecarboxylic acid in 700 ml tetrahydrofuran under nitrogen and the mixture is stirred for one hour. Then, again at 0° C., 13.13 ml (0.11 mol) of dibromobutane are added and the solution is stirred for 30 hours at ambient temperature. After this time 50 ml of water are added and the mixture is stirred for 30 minutes. The solution is concentrated by evaporation, mixed with water and extracted with 250 ml of diethylether. The aqueous phase is acidified with 150 ml of 1N hydrochloric acid and extracted three times with 250 ml of dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent is eliminated. Yield: 18.5 g (53.6% of theory), melting point: 123° C.
	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; water	1.a a. a. 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid 89 ml (0.11 mol) of a 1.6 M butyllithium solution in hexane are added dropwise at 0° C. to a solution of 21 g (0.1 mol) of 9-fluorenecarboxylic acid in 700 ml tetrahydrofuran under nitrogen and stirred for one hour. Then, still at 0° C., 13.13 ml (0.11 mol) of dibromobutane are added and the solution is stirred for 30 hours at ambient temperature. After this time, 50 ml of water are added and the mixture is stirred for 30 minutes. The solution is evaporated down, combined with water and extracted with 250 ml of diethyl ether. The aqueous phase is acidified with 150 ml of 1N hydrochloric acid and extracted three times with 250 ml of dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent is removed. Yield: 18.5 g (53.6% of theoretical), Melting point: 123° C.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2003/166637, 2003, A1
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2003/114442, 2003, A1
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US6818644, 2004, B1

26
[ 139399-67-0 ]
[ 79-37-8 ]
[ 1989-33-9 ]
[ 190133-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N-methyl-acetamide; 1,3-dimethyl-2-imidazolidinone; dichloromethane;	Example 132 To a solution of 9-fluorenecarboxylic acid (158 mg) and dimethylformamide (1 drop) in dichloromethane (2 ml) was dropwise added oxalyl chloride (191 mg), and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was added to a solution of <strong>[139399-67-0]8-amino-3-bromoquinoline</strong> (112 mg) and triethylamine (152 mg) in 1,3-dimethyl-2-imidazolidinone (1 ml). The mixture was stirred for 3 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and crystallized from diethyl ether-diisopropyl ether to give 3-bromo-8-[(fluoren-9-yl)carbonylamino]quinoline (22 mg). mp: 196-198 C. NMR (CDCl3, delta): 5.03 (1H, s), 7.32-7.43 (3H, m), 7.45-7.55 (3H, m), 7.80-7.90 (4H, m), 8.20 (1H, s), 8.50 (1H, s), 8.75 (1H, d, J=7 Hz), 9.65 (1H, br s)

Reference： [1]Patent: US6008230,1999,A

27
[ 110-52-1 ]
[ 79-37-8 ]
[ 1989-33-9 ]
[ 373-88-6 ]
[ 182428-72-4 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; triethylamine; In tetrahydrofuran; hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	9-[4-[4-(Benzoylamino)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, monohydrochloride STR546 To a solution of 9-fluorenecarboxylic acid (50 g, 240 mmol) in THF (1200 mL) at 0 C. was added dropwise a solution of n-butyllithium (2.5M, 211 mL, 530 mmol) in THF. The yellow reaction was stirred at 0 C. for 1 h, then 1,4-dibromobutane (31.3 mL, 260 mmol) was added dropwise over 30 min. The reaction was stirred at 0 C. for 30 min, then the reaction was warmed to RT for 30 h. The reaction was extracted with water (3750 mL). The combined aqueous layers were extracted with ethyl ether (800 mL). The aqueous layer was made acidic with HCl solution (1N, 500 mL), then extracted with dichloromethane (3750 mL). The combined organic layers were dried over MgSO4. Evaporation gave title compound (71 g, 85%) as a white solid. STR547 To a solution of Part A acid (60 g, 173 mmol) and DMF (100 muL) in CH2 Cl2 (600 mL) under argon at 0 C. was added oxalyl chloride (104 mL, 2.0M in CH2 Cl2, 208 mmol) dropwise. The reaction was stirred at 0 C. for 10 min, then warmed to RT and stirred for 1.5 h. The reaction was concentrated in vacuo to give the crude acid chloride as a yellow oil. To a suspension of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (25.9 g, 191 mmol) in CH2 Cl2 (500 mL) at 0 C. under argon was added triethylamine (73 mL, 521 mmol) followed by dropwise addition of a solution of the crude acid chloride in CH2 Cl2 (15 mL). The reaction was stirred at 0 C. for 1 h, diluted with CH2 Cl2 (500 mL), and washed with water (2300 mL), 1N HCl (2300 mL), saturated NaHCO3 (2300 mL), and brine (2300 mL), then dried over MgSO4. Evaporation gave 80 g of a oil which was purified by flash chromatography on silica gel (2.5 kg). The crude product was loaded in a mixture of CH2 Cl2 and hexane, and eluted with a step gradient of 10% EtOAc/hexane (4 L) to 15% EtOAc/hexane (2 L) to 20% EtOAc/hexane (4 L). Pure fractions were combined and evaporated to give title compound (52.5 g, 71%) as a white solid (mp 88-92 C.).

Reference： [1]Patent: US5739135,1998,A

28
[ 79-37-8 ]
[ 1989-33-9 ]
[ 23418-85-1 ]
[ 373-88-6 ]
9-[4-[5-(benzoylamino)-2-pyridinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; triethylamine;N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; ethyl acetate;	EXAMPLE 274 9-[4-[5-(Benzoylamino)-2-pyridinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide STR281 Butyllithium (12.6 mL, 31.5 mmmol) was added dropwise over 5 min to a solution of 9-fluorenecarboxylic acid (3.0 g, 14.3 mmol) in THF (150 mL) at 0 C. under argon. The reaction went cloudy during addition, then cleared upon completion. The reaction was stirred at 0 C. for 30 min, then 3-butynyl p-toluenesulfonate (9.6 g, 42.9 mmol) was added dropwise. The amber reaction was warmed to RT, then stirred for 24 h. The reaction solution was extracted with water (275 mL). The combined aqueous layers were washed with Et2 O (50 mL), then acidified with 1N HCl (30 mL). The cloudy mixture was extracted with CH2 Cl2 (250 mL), and the combined organic layers were dried over MgSO4. Evaporation gave 1.85 g of a crude orange gummy solid. A portion (1.75 g) of crude acid product was dissolved in CH2 Cl2 (20 mL) under argon. A catalytic amount of DMF (26 muL, 0.33 mmol) was added, followed by oxalyl chloride (5.0 mL, 2.0M in CH2 Cl2, 10 mmol) slowly. After bubbling for a few minutes, the reaction was stirred at RT for 1.5 h, then concentrated in vacuo. The crude acid chloride was dissolved in CH2 Cl2 (20 mL) and added dropwise to a suspension of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (1.08 g, 8.02 mmol) and triethylamine (2.8 mL, 20 mmol) in CH2 Cl2 (30 mL) at 0 C. under argon. The reaction was stirred at 0 C. for 10 min, diluted with CH2 Cl2 (50 mL), washed with 1N HCl (2*20 mL) and saturated NaHCO3 (20 mL), then dried over Na2 SO4. Evaporation gave 2.24 g of a dark orange semi-solid, which was dissolved in 2:1 CH2 Cl2:10% EtOAc/hexane and purified by flash chromatography on silica gel (175 g) eluding with 10% EtOAc/hexane to provide title compound (1.16 g, 22%) as a yellow solid (mp 109-113 C.).

Reference： [1]Patent: US5760246,1998,A

29
[ 79-37-8 ]
[ 1989-33-9 ]
[ 373-88-6 ]
[ 626-87-9 ]
9-[4-[4-[[(1,1-Dimethylethoxy)carbonyl]amino]-1-piperidinyl]pentyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; sodium iodide; potassium carbonate; triethylamine; citric acid; In tetrahydrofuran; methanol; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; butanone;	9-[4-[4-[[(1,1-Dimethylethoxy)carbonyl]amino]-1-piperidinyl]pentyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide STR686 To a solution of 2.50 g (11.9 mmol) of 9-fluorenecarboxylic acid in 25 mL of THF under argon (evacuated and purged with argon three times) at -10 C., was added 10.0 mL of n-butyllithium (25.0 mmol, 2.5M in hexanes) over 10 min. A thick slurry formed initially followed by a yellow solution. After 40 min, 2.05 mL (15.0 mmol) of 1,4-dibromopentane was added. The reaction was allowed to warm to room temperature. After 60 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The organic extract was dried (MgSO4) and evaporated. Trituration of the residue in ethyl acetate/hexanes gave title compound as a white solid, 3.72 g, 87%. STR687 To a stirred solution of 1.80 g (ca. 5.0 mmol) of Part A compound in 10 mL of dichloromethane at room temperature under argon was added 0.65 mL of oxalyl chloride (7.5 mmol) followed by DMF (100 muL). After 1 h, the resulting solution was evaporated at less than 30 C. and the residue was then redissolved in 15 mL of dichloromethane. This solution was added to a solution of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (820 mg, 6.0 mmol) and 2.1 mL of triethylamine (15 mmol in 20 mL of dichloromethane under argon at 0 C. After 1 h, the reaction was quenched with 10% citric acid solution and extracted twice with ethyl acetate. The extracts were combined, dried (MgSO4) and evaporated. The crude product was dissolved in 25 mL of 2-butanone, 7.7 g (52 mmol) of sodium iodide was added and the reaction mixture was set to reflux for 48 h under argon. The solution was cooled, evaporated and the residue partitioned between ethyl acetate and 10% sodium bisulfite solution. The organic extract was dried (MgSO4) and evaporated. Purfication by flash chromatography on silica gel (515 cm column, 3:7 hexanes/dichloromethane as elutant) provided title compound as a white solid, 1.42 g, 58% yield, mp 102-106 C. STR688 A solution of Part B compound (1.27 g, 2.60 mmol), Example 1 Part B amine (680 mg, 3.38 mmol) and potassium carbonate (420 mg, 3.0 mmol) in 5 mL of DMF at room temperature under argon was heated to 50 C. After 15 h, the reaction was quenched with water, decanted and the oily residue extracted twice with ethyl acetate. The extracts were combined, washed once with water, once with saturated sodium bicarbonate solution, dried (Na2 SO4) and evaporated. Purification by flash chromatography on silica gel (515 cm column, 1:99 methanol/ethyl acetate as elutant) provided title compound as a white solid, 1.20 g, 82% yield, mp 58-60 C. Anal. Calcd for C31 H40 F3 N3 O3 +0.25 H2 O: C, 66.00; H, 7.24; F, 10.18; N, 7.45. Found: C, 66.00; H, 7.14; F, 10.39; N, 7.60. MS (electrospray, +ions) m/e 560.3 (M+H).

Reference： [1]Patent: US5739135,1998,A

30
[ 86-73-7 ]
[ 105-58-8 ]
[ 1989-33-9 ]

Yield	Reaction Conditions	Operation in experiment
80.7%	With hydrogenchloride; nitrogen; acetic acid In water; toluene	1 EXAMPLE 1 EXAMPLE 1 10% of a solution of 332 g (1.9 moles) of fluorene and 974 g (8.2 moles) of diethyl carbonate was added to a mixture of 974 g (8.2 moles) of diethyl carbonate and 120 g (4 moles) of sodium hydride in a reaction vessel and the mixture was heated at 65° C. with stirring. At the start of hydrogen evolution, nitrogen was introduced over the surface of the reaction mixture and the remaining 90% of the fluorene solution was added to the mixture at 65° C. over 90 minutes. The mixture was stirred at 60° C. for 4 hours and was cooled to 20° C. The reaction mixture was slowly poured into a mixture of 400 g (4 moles) of concentrated hydrochloric acid and 500 g of water cooled with water to prevent the temperature from rising above 40° C. The mixture was filtered and the filtrate was decanted. The organic phase was evaporated to dryness under reduced pressure and the distillate was 1700 ml of diethyl carbonate. A mixture of the distillation residue, 1,049 g of acetic acid and 420 g of 10% hydrochloric acid was refluxed for 4 hours and after about 30 minutes, crystals of fluorene-9-carboxylic acid began to precipitate from the refluxing mixture. After the 4 hours, the mixture was cooled to20° C. and was vacuum filtered. The recovered product was washed with 600 ml of toluene and then with 500 ml of water at which time the wash water was free of chloride ions. The 360 to 400 g of product was dried at 80° C. to obtain 322 g of fluorene-9-carboxylic acid in the form of light beige crystals melting at 226°-230° C. (80.7% yield based on fluorene).
72.7%	With hydrogenchloride; potassium ethoxide In water	3 EXAMPLE 3 EXAMPLE 3 A solution of 332 g (1.9 moles) of fluorene and 974 g (8.2 moles) of diethyl carbonate was added with cooling to keep the temperature no higher than 40° C. to a mixture of 584 g (4.6 moles) of diethyl carbonate and 186 g (2.2 moles) of potassium ethylate in a reaction vessel and the mixture was stirred at 65°-70° C. for 5 hours and was cooled to 20° C. The mixture was slowly poured into a solution of 220 g (2.2 moles) of hydrochloric acid and 500 g of water with cooling to keep the temperature at a maximum of 40° C. The product was then treated as in Example 1 to obtain 280 g of fluorene-9-carboxylic acid in the form of light-beige crystals melting at 227°-229° C. (72.7% yield based on fluorene).
10 g	Stage #1: 9H-fluorene With sodium hydride In toluene at 125℃; for 4h; Inert atmosphere; Reflux; Stage #2: Diethyl carbonate In toluene at 90℃; for 4.5h; Stage #3: With hydrogenchloride; water In toluene at 20 - 40℃;	1.A Example 1 Synthesis of fluorene-9methyl carboxylate-9-ethyl carboxylate Step A: to a 1000 mL three-necked flask were successively added 18 g sodium hydride, 50 g fluorene, 150 mL toluene under nitrogen, with mechanical stirring, the temperature was raised to 125° C. to reflux for 4 h; after cooling to 90° C., 146.1 g diethyl carbonate was slowly dropped to the flask over 1.5 h, then the reaction was continued for 3 h; after cooling to 20° C., a mixture of 60 g concentrated hydrochloric acid and 75 g water was slowly added dropwise, and the temperature was controlled to be no greater than 40° C.; the organic phase was separated by filtering and washed with water to neutral, followed by rotary evaporation to yield a red-brown liquid; the resulting liquid obtained by rotary evaporation, 157.4 g acetic acid and 63 g 10% hydrochloric acid were refluxed overnight; the mixture was cooled to 20° C., followed by liquid separation; 30% NaOH solution was added to the organic phase after rotary evaporation, which was adjusted to pH 8-9 and extracted with ethyl acetate, the aqueous phase was retained. Concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 5-6, which was extracted with ethyl acetate, the organic phase was retained for rotary evaporation; the products were dissolved in ethyl acetate and frozen for recrystallization; the crude products after filtration were washed with hexane to colorless crystals of about 10 g, melting point: 228230° C.

10 g

Stage #1: 9H-fluorene With sodium hydride In toluene at 125℃; for 4h; Inert atmosphere; Stage #2: Diethyl carbonate In toluene at 90℃; for 4.5h; Inert atmosphere; Stage #3: With hydrogenchloride; acetic acid In water; toluene Reflux;

1.A to a 1000 mL three-necked flask were successively added 18 g sodium hydride, 50 g fluorene, 150 mL toluene under nitrogen, with mechanical stirring, the temperature was raised to 125° C. to reflux for 4 h; after cooling to 90° C., 146.1 g diethyl carbonate was slowly added dropwise to the flask over 1.5 h, then the reaction was continued for 3 h; after cooling to 20° C., a mixture of 60 g concentrated hydrochloric acid and 75 g water was slowly added dropwise, and the temperature was controlled to be no greater than 40° C.; the organic phase was separated by filtering and washed with water to neutral, followed by rotary evaporation to yield a red-brown liquid; the resulting liquid obtained by rotary evaporation, 157.4 g acetic acid and 63 g 10% hydrochloric acid were refluxed overnight; the mixture was cooled to 20° C., followed by liquid separation; 30% NaOH solution was added to the organic phase after rotary evaporation, which was adjusted to pH 8 and extracted with ethyl acetate, the aqueous phase was retained. Concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 5, which was extracted with ethyl acetate, the organic phase was retained for rotary evaporation; the products were dissolved in ethyl acetate and frozen for recrystallization; the crude products after filtration were washed with hexane to give colorless crystals of about 10 g, melting point: 228230° C.

Reference： [1]Current Patent Assignee: RUETGERS GMBH - US4564700, 1986, A
[2]Current Patent Assignee: RUETGERS GMBH - US4564700, 1986, A
[3]Current Patent Assignee: BEIJING LIHE TECHNOLOGY; BEIJING LIHE ZHIXIN TECHNOLOGY; BEIJING LIHE TECH - US2017/88642, 2017, A1 Location in patent: Paragraph 0068
[4]Current Patent Assignee: BEIJING LIHE TECH; BEIJING LIHE TECHNOLOGY - US2017/283530, 2017, A1 Location in patent: Paragraph 0096

31
concentrated aqueous ammonium hydroxide [ No CAS ]
[ 1989-33-9 ]
[ 7471-95-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With thionyl chloride In tetrachloromethane; acetone	27.b (b) (b) Preparation of 9-aminocarbonylfluorene A mixture of 2409 g. of 9-fluorene carboxylic acid and 3.8 liters of thionylchloride in 3.8 liters of carbon tetrachloride was heated at refluxfor one hour. The mixture was cooled to room temperature and the solvent was removed by evaporation under reduced pressure to provide a solid. The solid thus formed was dissolved in 3.8 liters of acetone, and the solutionwas added portion-wise to a stirred solution of 32 liters of concentrated aqueous ammonium hydroxide. Following the addition, the precipitate which had formed was collected by filtration and crystallized from isopropanol to give 1588 g. of 9-aminocarbonyl fluorene. 66% yield. m.p. 250° C. Analysis calc. for C14 H11 NO. Theory: C, 80.36; H, 5.30; N, 6.69. Found: C, 80.10; H, 5.27; N, 6.45.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US4277495, 1981, A

32
[ 86-73-7 ]
Dry ice (CO₂) [ No CAS ]
[ 1989-33-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With n-butyllithium In tetrahydrofuran; hexane; toluene	27.a (a) (a) Preparation of 9-fluorene carboxylic acid To a stirred cold (-10° C.) solution of 1200 g. of fluorene in 6.7 liters of tetrahydrofuran were added dropwise over 2 hours 8 moles of n-butyl lithium in 3 liters of hexane. The temperature was maintained below 5° C. during the addition. Following complete addition, the reaction mixture was warmed to room temperature and diluted with 6 gallonsof toluene, followed by the slow addition of 24 liters of dry ice (CO2). The reaction mixture was stirred for sixteen hours at room temperature, and then was further diluted with water. The organic layer was separated and then extracted several times with 1 N sodium hydroxide. The aqueous alkaline extracts were combined, washed with diethyl ether, and then acidified with concentrated hydrochloric acid. The precipitate which formed was collected by filtration, washed with water and air dried at 55° C. to provide 1316 g. of 9-fluorene carboxylic acid. 87% yield. m.p. 224°-226° C. Analysis calc. for C14 H10 O2. Theory: C, 79.98; H, 4.79. Found: C, 79.74; H, 4.93.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US4277495, 1981, A

33
[ 1989-33-9 ]
[ 74-88-4 ]
[ 3300-16-1 ]

Yield	Reaction Conditions	Operation in experiment
16%	Stage #1: 9H-fluorene-9-carboxylic acid With sodium ethanolate In ethanol at 20℃; for 2.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide for 3h;	5.1.a EXAMPLE 5; [0078] tropenol 9-methylfluorene-9-carboxylate methobromide; [0079] 5.1.: 9-methylfluorene-9-carboxylic acid 3b; [0080] a) methyl 9-methylfluorene-9-carboxylate [0081] From 7.6 g (0.33 mol) of sodium and 300 mL of ethanol, a sodium ethoxide solution is prepared, to which 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid are added batchwise. After the addition has ended, the mixture is stirred for 2.5 hours at ambient temperature. Then it is evaporated to dryness, the residue is suspended in 600 mL of dimethylformamide, and 93.96 g (0.662 mol) of methyl iodide are added dropwise. The mixture is stirred for 3 hours at constant temperature. The cloudy solution is stirred into 500 mL of water and 300 mL of diethyl ether with cooling and extracted, the organic phase is washed with water and 10% sodium carbonate solution, dried, and evaporated to dryness. The residue is purified by column chromatography, eluent: cyclohexane-ethyl acetate (96:4). Yield: 12.61 g of white crystals (16% of theoretical yield); melting point: 108[deg.] C.-109[deg.] C.
16%	Stage #1: 9H-fluorene-9-carboxylic acid With ethanol; sodium at 20℃; for 2.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide for 3h;	4.1.a A sodium ethoxide solution is prepared from 7.6 g (0.33 mol) sodium and 300 mL of ethanol, and 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid is added batchwise thereto. After the addition has ended, it is stirred for 2.5 hours at ambient temperature. Then it is evaporated to dryness, the residue is suspended in 600 mL of dimethylformamide and 93.96 g (0.662 mol) of methyl iodide is added dropwise. The mixture is stirred for 3 hours at constant temperature. The cloudy solution is stirred into 500 mL of water and 300 mL diethyl ether with cooling and extracted; the organic phase is washed with water and 10% sodium carbonate solution, dried, and evaporated to dryness. The residue is purified by column chromatography, eluent: cyclohexane-ethyl acetate (96:4). Yield: 12.61 g of white crystals (16% of theoretical yield); melting point: 108° C.-109° C.
16%	Stage #1: 9H-fluorene-9-carboxylic acid With sodium ethanolate at 20℃; for 2.5h; Stage #2: methyl iodide In DMF (N,N-dimethyl-formamide) for 3h;	1.1.a A sodium ethoxide solution is prepared from 7.6 g (0.33 mol) of sodium and 300 mL of ethanol, to which 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid are added batchwise. After the addition has ended, the mixture is stirred for 2.5 hours at ambient (room) temperature. Then it is evaporated to dryness, the residue is suspended in 600 mL of dimethylformamide and 93.96 g (0.662 mol) of methyl iodide are added dropwise. The mixture is stirred for 3 hours at constant temperature. The cloudy solution is stirred into 500 mL of water and 300 mL of diethyl ether with cooling and extracted, the organic phase is washed with water and 10% sodium carbonate solution, dried, and evaporated to dryness. The residue is purified by column chromatography, eluent: cyclohexane-ethyl acetate 96:4. Yield: 12.61 g of white crystals (16% of theoretical); melting point: 108° C.-109° C

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2003/199539, 2003, A1 Location in patent: Page/Page column 6
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2003/207912, 2003, A1 Location in patent: Page 7
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2005/107417, 2005, A1 Location in patent: Page/Page column 10

34
[ 1989-33-9 ]
[ 373-88-6 ]
[ 109-64-8 ]
[ 194220-08-1 ]

Yield	Reaction Conditions	Operation in experiment
57.8%		A solution of (9-fluorenecarboxylic acid (20.0 g, 92.3 mmoles) in dry THF (90 ml) was placed under vacuum for 20 minutes to remove dissolved oxygen then cannulated into a cooled (0C, ice-salt bath) solution of 1.0 M lithium t-butoxide in THF (212 ml, 2.23 eq). The ice-bath was removed and the reaction mixture stirred at room temperature for 1.0 hr. after which the green suspension was treated with 1,3-dibromopropane (18.5 ml., 1.96 eq) via syringe. The dark mixture was stirred at room temperature for 19 hours then partitioned between 30% Heptane in EtOAc (300 ml) and H2O (250 ml), re-extracting the aqueous phase with H2O (3 x 70 ml). The combined aqueous extracts were acidified with 2.0 N HCl to pH 2.0, extracted with CH2Cl2 (4 x 190 ml) and the combined CH2Cl2 extracts were dried (anhydrous MgSO4), filtered, evaporated to dryness and dried in vacuo to give the crude acid as a syrup (32 g). The acid was dissolved in dry CH2Cl2 (190 ml), cooled to 0C (ice-salt bath), treated with dry DMF (0.32 ml, 0.4 eq) and (COCl)2 (8.2 ml, 94 mmoles), stirred at 0C for 5 minutes then at room temperature for 2.0 hours. Meanwhile, trifluoroethylamine hydrochloride (13.8 g, 102 mmoles) was dissolved in dry CH2Cl2 (225 ml), cooled to 0C (ice-salt bath), treated with Et3N (51.5 ml) and stirred for 10 minutes. The acid mixture was cannulated into the amine solution, and stirred at 0C, allowing the reaction mixture to come to room temperature overnight. The reaction mixture was washed sequentially with H2O (2 x 190 ml), 1.0 N HCl (320 ml), H2O (190 ml) and saturated NaHCO3 (190 ml), dried (anhydrous MgSO4), filtered, evaporated to dryness and dried in vacuo. The crude product mixture was chromatographed on a silica gel column (Merck, 4" x 13"), eluting the column with EtOAc:Hexane (1:4) to give title compound as a solid foam (22 g, 57.8 %). Rf 0.38 (Silica gel; EtOAc:Hexane-1:4; UV, PMA); m.p. 106-108C.

Reference： [1]Patent: EP904262,2004,B1 .Location in patent: Page 226

35
[ 1989-33-9 ]
[ 23418-85-1 ]
[ 373-88-6 ]
C₂₀H₁₆F₃NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%		Butyllithium (12.6 mL, 31.5 mmmol) was added dropwise over 5 min to a solution of 9-fluorene-carboxylic acid (3.0 g, 14.3 mmol) in THF (150 mL) at 0C under argon. The reaction went cloudy during addition, then cleared upon completion. The reaction was stirred at 0C for 30 min, then 3-butynyl p-toluenesulfonate (9.6 g, 42.9 mmol) was added dropwise. The amber reaction was warmed to RT, then stirred for 24 h. The reaction solution was extracted with water (2 x 75 mL). The combined aqueous layers were washed with Et2O (50 mL), then acidified with 1N HCl (30 mL). The cloudy mixture was extracted with CH2Cl2 (2 x 50 mL), and the combined organic layers were dried over MgSO4. Evaporation gave 1.85 g of a crude orange gummy solid. A portion (1.75 g) of crude acid product was dissolved in CH2Cl2 (20 mL) under argon. A catalytic amount of DMF (26 muL, 0.33 mmol) was added, followed by oxalyl chloride (5.0 mL, 2.0 M in CH2Cl2, 10 mmol) slowly. After bubbling for a few minutes, the reaction was stirred at RT for 1.5 h, then concentrated in vacuo. The crude acid chloride was dissolved in CH2Cl2 (20 mL) and added dropwise to a suspension of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (1.08 g, 8.02 mmol) and triethylamine (2.8 mL, 20 mmol) in CH2Cl2 (30 mL) at 0C under argon. The reaction was stirred at 0C for 10 min, diluted with CH2Cl2 (50 mL), washed with 1N HCl (2 x 20 mL) and saturated NaHCO3 (20 mL), then dried over Na2SO4. Evaporation gave 2.24 g of a dark orange semi-solid, which was dissolved in 2:1 CH2Cl2:10% EtOAc/hexane and purified by flash chromatography on silica gel (175 g) eluting with 10% EtOAc/hexane to provide title compound (1.16 g, 22%) as a yellow solid (mp 109-113C).

Reference： [1]Patent: EP904262,2004,B1 .Location in patent: Page 146-147

36
[ 1989-33-9 ]
[ 373-88-6 ]
[ 1119-51-3 ]
C₂₁H₂₀F₃NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		A solution of 9H-fluorene carboxylic acid (5.00 g, 23.7 mmol) in 24 mL of THF at -12C was purged and evacuated with argon three times. The solution was added via canula to an argon-purged solution of 50 mL of lithium t-butoxide (1 M in THF, 50.0 mmol) at -12C over 5 min. After 1 h, the solution was warmed to room temperature and Br(CH2)3CH=CH2 (5.6 mL, 48 mmol) was added in a steady stream. After 70 h, the reaction was quenched with 1 M hydrochloric acid and extracted twice with ethyl acetate. The organic extracts were combined, dried (MgSO4) and evaporated. The white solid was stirred and slurried in 25 mL of dichloromethane at room temperature while oxalyl chloride (3.5 mL, 40 mmol) and DMF (0.2 mL) were added. After 1 h, the yellow solution was evaporated twice from dichloromethane and redissolved in 20 mL of dichloromethane. This solution was added to a stirred solution of 1,1,1-trifluoroethylammonium chloride (4.10 g, 30.0 mmol) and Et3N (12.5 mL, 89.7 mmol) in 30 mL of dichloromethane at 0C under argon. After 1 h, the reaction was quenched with 10% citric acid solution. The organic extract was dried (MgSO4) and evaporated. Purification by flash Chromatography on silica gel (5x20 cm column, 1:1 hexane/dichlo-romethane) gave, after trituration in hexane, title compound, 5.40 g, 63% yield, as a white solid, mp 47-49C.

Reference： [1]Patent: EP904262,2004,B1 .Location in patent: Page 232

37
[ 107-10-8 ]
[ 1989-33-9 ]
[ 182438-56-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: 9H-fluorene-9-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.75h; Stage #2: propylamine In dichloromethane at -40 - 20℃; for 3h;	11. A Example 11; 9-[4-(Dibutoxyphosphinyl)butyl]-N-propyl-9H-fluorene-carboxamide; A. N-Propyl-9-fluorene-carboxamide A solution of 9-fluorene carboxylic acid (20.0 g, 95 mmol) in 200 mL of CH2Cl2 was treated with oxalyl chloride (12.5 g, 105 mmol) and 0.2 mL of DMF. After 0.75 h, the mixture was concentrated under reduced pressure to give a white solid. The solid was diluted with 100 mL of THF cooled to -40°C, treated with propylamine (11.8 g, 200 mmol). The suspension was stirred for 3 h at room temperature and diluted with ethyl acetate and water. The organic fraction was dried over Na2SO4 and concentrated to a white solid. The solid purified by trituration with hot hexanes and recrystalization from hot methanol to give 17.5 g (87%) of title compound as white flakes. mp 197-199°C . TLC Silica gel (3:7 ethyl acetate/hexane) Rf= 0.30. MS (CI-NH3, + ions) m/e 252 (M+H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 44

38
[ 107-10-8 ]
[ 1476-11-5 ]
[ 1989-33-9 ]
C₂₁H₂₂ClNO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: Z-1,4-dichlorobutene; 9H-fluorene-9-carboxylic acid With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 3.58333h; Stage #2: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.66667h; Stage #3: propylamine In dichloromethane at 0℃; for 0.183333h;	266. A A. Butyllithium (8.4 mL, 2.5M in hexane, 21 mmol) was added dropwise over 10 min to a solution of 9-fluorenecarboxylic acid (2.10 g, 10 mmol) in THF (50 mL) at 0°C under argon. During addition of the first equivalent of BuLi, the reaction became thick with a white precipitate which became yellow and cleared after addition of the second equivalent. The reaction was stirred at 0°C for 20 min, then cis-1,4-dichloro-2-butene (1.2 mL, 11 mmol) was added dropwise over 5 min. The reaction lightened in color during addition and was stirred at 0°C for 3 h, then poured into 1N HCl (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (30 mL) then dried over MgSO4. Evaporation provided 3.5 g of a yellow oil containing crystalline solid. The crude residue was triturated with hexane (20 mL). The supernatant was decanted, and the residue pumped under high vacuum to give 2.93 g of a tan solid. To a suspension of the crude acid prepared above (1.42g, 4.77 mmol) and N,N-dimethylformamide (5 drops) in CH2Cl2 (15 mL) at room temperature under argon was added oxalyl chloride (3.6 mL, 2.0M in CH2Cl2, 7.16 mmol). The reaction bubbled for 10 min, then the reaction was stirred at room temperature for 1.5 h, at which time all solids had dissolved. The reaction was concentrated in vacuo to give an orange oil. The crude acid chloride was dissolved in CH2Cl2 (15 mL) and cooled to 0°C. Propylamine (1.2 mL, 14.3 mmol) was added dropwise over 1 min, and the reaction was stirred at 0°C for 10 min. The reaction was partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with 1N HCl (2 x 20 mL) and brine (20 mL), then dried over MgSO4. Evaporation gave 1.7 g of an orange oil, which was purified by flash chromatography on silica gel (150 g) eluting with CH2Cl2 to give title compound (1.38 g, 84%) as a pale yellow oil.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 139

39
[ 107-10-8 ]
[ 1989-33-9 ]
[ 99067-72-8 ]
[ 194212-11-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: 9H-fluorene-9-carboxylic acid; 4-Iod-1-<4-nitro-phenyl>-butan With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 5.5h; Stage #2: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.66667h; Stage #3: propylamine In dichloromethane at 0℃; for 0.283333h;	204. A. 1. b A(1)b. 9-[4-(4-Nitrophenyl)butyl]-N-propyl-9H-fluorene-9-carboxamide Butyllithium (1.8 mL, 2.5M in hexane, 4.4 mmol) was added to a solution of 9-fluorenecarboxylic acid (purchased from Aldrich Chemical Co.) (420 mg, 2.0 mmol) in THF (10 mL) at 0°C under argon over 5 min. The reaction went from a clear solution to a white suspension then to a yellow solution during addition. The reaction was stirred at 0°C for 20 min, whereupon a solution of Part A(1)a iodide (671 mg, 2.2 mmol) in THF (4 mL) was added dropwise over 5 min. The reaction was stirred at 0°C for 1.5 h, warmed to RT, then stirred at RT for 3.5 h. The reaction was quenched with 1N HCl to pH <2, diluted with water (10 mL), then extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water and brine (10 mL each), then dried over MgSO4. Evaporation gave a residue, which was azeotroped with toluene (10 mL) to give 870 mg of a dark foam. To a solution of the crude acid prepared above containing 3 drops of DMF in CH2Cl2 (6 mL) at RT under argon was added oxalyl chloride (1.5 mL, 2.0M in CH2Cl2, 3.0 mmol). The reaction bubbled for 10 min, then was allowed to stir at RT for 1.5 h. The reaction was concentrated in vacuo to provide a dark oil, which was diluted with CH2Cl2 (5 mL) and cooled to 0°C under argon. Propylamine (493 µL, 6.0 mmol) was added dropwise over 2 min, and the reaction was stirred at 0°C for 15 min. The reaction was partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was washed with 1N HCl (2 x 5 mL) and brine (5 mL), then dried over MgSO4. Evaporation gave 974 mg of a brown oil, which was dissolved in a minimal amount of CH2Cl2 and purified by flash chromatography on silica gel (75 g) eluting with 20% EtOAc/hexane to afford title compound (705 mg, 82%) as a waxy, yellow solid. mp 109-110°C.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 120

40
[ 1989-33-9 ]
[ 100-46-9 ]
N-(phenylmethyl)-9H-fluorene-9-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 9H-fluorene-9-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.75h; Stage #2: benzylamine With pyridine In dichloromethane at 0 - 20℃; for 3h;	1. A Example 1; N-(Phenylmethyl)-9-(3-phenylpropyl)-9H-fluorene-9-carboxamide; A. N-(Phenylmethyl)-9H-fluorene-9-carboxamide A solution of 9-fluorene carboxylic acid (2.10 g, 10.0 mmol) in 50 mL of CH2Cl2 was treated with oxalyl chloride in dichloromethane (6.0 mL, 12.0 mmol) and two drops of DMF. After 0.75 h, the mixture was concentrated under reduced pressure to give a white solid. The solid was diluted with 50 mL of CH2Cl2, cooled to 0°C, treated with benzylamine (1.17 g, 11.0 mmol) and pyridine (0.87 g, 11 mmol). The transparent yellow solution was stirred for 3 h at room temperature and diluted with ethyl acetate and water. The organic fraction was dried over Na2SO4 and concentrated to a white solid. The solid purified by trituration with hexanes and recrystalization from hot methanol to give 2.60 g (86%) of title compound as white flakes. mp 195-200°C. TLC Silica gel (3:7 ethyl acetate/hexane) Rf= 0.30. Mass Spec. (CI-NH3, + ions) m/z 300 (M+H), 317 (M+NH4).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 40

41
[ 753-90-2 ]
[ 1989-33-9 ]
[ 107-14-2 ]
[ 182439-15-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 9H-fluorene-9-carboxylic acid; chloroacetonitrile With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 3.66667h; Stage #2: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.5h; Stage #3: trifluoroethylamine With triethylamine In dichloromethane at 0℃; for 0.25h;	265. A A. Butyllithium (18 mL, 2.5M in hexanes, 44 mmol) was added dropwise over 10 min to a solution of 9-fluorenecarboxylic acid (4.2 g, 20 mmol) in THF (200 mL) at 0°C under argon. The slightly heterogeneous dark yellow reaction was stirred at 0°C for 30 min, then chloroacetonitrile (1.5 mL, 24 mmol) was added dropwise over 3 min. The orange reaction was stirred at 0°C for 30 min, warmed to RT and stirred for 3 h. The reaction was extracted with water (2 x 100 mL) and the combined aqueous extracts were washed with Et2O (100 mL). The aqueous layer was acidified to pH<2 with 1N HCl and extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 4.7 g of a light yellow solid (mp 138-145°C). A portion (2.63 g) of the crude carboxylic acid was dissolved in CH2Cl2 (30 mL) under argon. N,N-Dimethylformamide (40 µL, 0.53 mmol) was added followed by oxalyl chloride (8.0 mL, 2.0M in CH2Cl2, 15.9 mmol). The reaction bubbled for a few minutes and was allowed to stir at RT for 1.5 h. The reaction was concentrated in vacuo then pumped under high vacuum to give the crude acid chloride. Triethylamine (4.4 mL, 31.8 mmol) was added to a suspension of 2,2,2-trifluoroethylamine hydrochloride (1.71 g, 12.7 mmol) in CH2Cl2 (20 mL) at 0°C under argon. The resulting thick slurry was stirred at 0 °C for 5 min, then a solution of the crude acid chloride in CH2Cl2 (10 mL) was added dropwise over 5 min. The reaction was stirred at 0°C for 10 min, diluted with CH2Cl2 (50 mL), washed with 1N HCl (2 x 20 mL) and saturated NaHCO3 (30 mL), then dried over Na2SO4. Evaporation gave 3.5 g of a yellow foam which was purified by flash chromatography on silica (150 g) eluting with CH2Cl2 to give title compound (2.74 g, 76%) as a white solid (mp 159-159.5).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 137

42
[ 1989-33-9 ]
[ 75-04-7 ]
[ 194218-93-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 9H-fluorene-9-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.75h; Stage #2: ethylamine In dichloromethane at 0 - 20℃; for 3h;	5. A Example 5; (E)-N-Ethyl-9-(3-phenyl-2-propenyl)-9H-fluorene-9-carboxamide; A. A solution of 9-fluorene carboxylic acid (2.10 g, 10.0 mmol) in 50 mL of CH2Cl2 was treated with oxalyl chloride in dichloromethane (6.0 mL, 12.0 mmol) and two drops of DMF. After 0.75 h, the mixture was concentrated under reduced pressure to give a white solid. The solid was diluted with 50 mL of CH2Cl2, cooled to 0°C, treated with ethylamine (1.0 g, 22 mmol). The transparent yellow solution was stirred for 3 h at room temperature and diluted with ethyl acetate and water. The organic fraction was dried over Na2SO4 and concentrated to a white solid. The solid purified by trituration with hexanes and recrystalization from hot methanol to give 2.60 g (86%) of title compound as white flakes. mp 233-234°C.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP904262, 2004, B1 Location in patent: Page 42

43
[ 1989-33-9 ]
[ 141-52-6 ]
[ 74-88-4 ]
[ 3300-16-1 ]

Yield	Reaction Conditions	Operation in experiment
16%	Stage #1: 9H-fluorene-9-carboxylic acid; sodium ethanolate In ethanol at 20℃; for 2.5h; Stage #2: methyl iodide In DMF (N,N-dimethyl-formamide) for 3h;	1.1.a From 7.6 g (0.33 mol) of sodium and 300 ml of ethanol a sodium ethoxide solution is prepared, to which 69.6 g (0. 33 mol) of 9-fluorenecarboxylic acid are added batchwise. After the addition has ended the mixture is stirred for 2.5 hours at ambient temperature. Then it is evaporated to dryness, the residue is suspended in 600 ml of DIMETHYLFORMAMIDE and 93.96 g (0.662 mol) of methyl iodide are added dropwise. The mixture is stirred for 3 hours at constant temperature. The cloudy solution is stirred into 500 ML of water and 300 ML of diethyl ether with cooling and extracted, the organic phase is washed with water and 10% sodium carbonate solution, dried and evaporated to dryness. The residue is purified by column chromatography, eluant: cyclohexane/ethyl acetate 96 : 4. Yield: 12. 61 g of white crystals (= 16% of theoretical); melting point: 108°-109°C.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2005/13967, 2005, A1 Location in patent: Page/Page column 23

44
[ 67-56-1 ]
[ 1989-33-9 ]
[ 74-88-4 ]
[ 3300-16-1 ]

Yield	Reaction Conditions	Operation in experiment
78.5%	Stage #1: 9H-fluorene-9-carboxylic acid With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0 - 20℃; Inert atmosphere; Reflux; Stage #2: methyl iodide In tetrahydrofuran; n-heptane; ethylbenzene at 20℃; for 2h; Stage #3: methanol With sulfuric acid for 2h; Reflux;
78.5%	Stage #1: 9H-fluorene-9-carboxylic acid With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; for 1.5h; Inert atmosphere; Reflux; Stage #2: methyl iodide In tetrahydrofuran; n-heptane; ethylbenzene at 20℃; Stage #3: methanol With sulfuric acid for 2h; Reflux;	I-1e EXAMPLE I-1e Preparation of 9-Methyl-9[H]-fluorene-9-carboxylic acid methyl ester EXAMPLE I-1ePreparation of 9-Methyl-9[H]-fluorene-9-carboxylic acid methyl esterLithium diisopropylamide (26.7 ml of a 2M solution in heptane/tetrahydrofurane/ethylbenzene, 0.053 mol) was added to a stirred solution of 9[H]-fluorene-9-carboxylic acid (5 g, 0.0237 mol) in THF (70 ml) at between 0 and 5° C. in N2 atmosphere. The mixture was warmed to room temperature and refluxed 1.5 hours. The reaction mixture was cooled to room temperature and a solution of CH3I (1.85 ml, 0.03 mol) in THF (1.85 ml) was added. The mixture was stirred overnight at room temperature and evaporated. To the residue in MeOH (70 ml) was added concentrated sulfuric acid (3.9 ml) in MeOH (25 ml), the mixture was refluxed for 2 hours and evaporated. The residue was partitioned between chloroform and saturated K2CO3 solution. The aqueous layer was extracted again with chloroform and the organic layers were combined, washed with water, dried over sodium sulphate and evaporated to dryness to obtain 5.73 g of a brown oil. This product was purified by column chromatography (silica gel, hexane/ethyl acetate 95:5) to yield 4.43 g (78.5%) of a pure product, structure confirmed by 1H-NMR. 1H-NMR (CDCl3): δ 1.80 (s, 3H), 3.60 (s, 3H), 7.50-7.65 (m, 4H), 7.75 (m, 2H), 8.0 (m, 2H).

Reference： [1]Prat, María; Fernández, Dolors; Buil, M. Antonia; Crespo, María I.; Casals, Gaspar; Ferrer, Manuel; Tort, Laia; Castro, Jordi; Monleón, Juan M.; Gavaldà, Amadeu; Miralpeix, Montserrat; Ramos, Israel; Doménech, Teresa; Vilella, Dolors; Antón, Francisca; Huerta, Josep M.; Espinosa, Sonia; López, Manuel; Sentellas, Sonia; González, Marisa; Albertí, Joan; Segarra, Victor; Cárdenas, Alvaro; Beleta, Jorge; Ryder, Hamish [Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5076 - 5092]
[2]Current Patent Assignee: ALMIRALL SA - US2015/246026, 2015, A1 Location in patent: Paragraph 0105; 0106

45
[ 1989-33-9 ]
[ 13500-53-3 ]
[ 1256282-36-6 ]

Reference： [1]European Journal of Organic Chemistry,2010,p. 5696 - 5704

46
[ 1989-33-9 ]
[ 503-60-6 ]
[ 1311194-16-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 9H-fluorene-9-carboxylic acid With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 3,3-dimethyl-allyl chloride In tetrahydrofuran; hexane at 0 - 20℃; for 14h;

Reference： [1]Takenaka, Kazuhiro; Akita, Mitsutoshi; Tanigaki, Yugo; Takizawa, Shinobu; Sasai, Hiroaki [Organic Letters, 2011, vol. 13, # 13, p. 3506 - 3509]

47
[ 1989-33-9 ]
[ 1417611-66-5 ]
[ 1417611-57-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6 6.6. cis/trans-9H-Fluorene-9-carboxylic acid 4-(methyl{4-[3-(3,4,5-trimethoxyphenyl)propyno-yl-oxy]cyclohexyl}amino)cyclohexyl ester (7a) General procedure: Following the procedure described for compound 8, to a solution of 11a (76.4 mg, 0.17 mmol) in dry CH2Cl2 cooled at 0° C were added in this sequence: 9H-fluorene-9-carboxylic acid (54.1 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP) (16.7 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (59.2 mg, 0.31 mmol). The reaction mixture was stirred at 0 °C for 1 h and then was kept at room temperature for 48 h. The mixture was treated with CH2Cl2 and the organic layer washed with water and then with a satured solution of NaHCO3. After drying with Na2SO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2/MeOH/NH4OH (97:3:0.3) as eluting system. The title compound (54 mg, 49% yield) was obtained as an oil. IR (neat): ν 1708 (CO) cm-1. 1H NMR (CDCl3): δ 7.76 (d, J = 7.6 Hz, 2H, aromatic); 7.64 (d, J = 7.6 Hz, 2H, aromatic); 7.41 (t, J = 7.6 Hz, 2H, aromatic); 7.32 (t, J = 7.6 Hz, 2H, aromatic); 6.85 (s, 2H, aromatic); 5.11 (br s, 1H, CHO); 4.82 (s, 1H, aliphatic); 4.75 (m, 1H, CHO); 3.88 (s, 3H, OCH3); 3.86 (s, 6H, 2OCH3); 2.76-2.52 (m, 2H, 2NCH); 2.29 (s, 3H, NCH3); 2.13-1.38 (m, 16H, 8CH2) ppm. 13C NMR (CDCl3): δ 170.27 (C); 153.67 (C); 153.16 (C); 141.43 (C); 140.74 (C); 128.08 (CH aromatic); 127.31 (CH aromatic); 125.54 (CH aromatic); 120.04 (CH aromatic); 114.32 (C); 110.38 (CH aromatic); 86.33 (C); 80.29 (C); 73.53 (CHO); 71.28 (CHO); 61.03 (OCH3); 58.60 (NCH); 56.27 (OCH3); 53.53 (CH aliphatic); 32.75 (NCH3); 30.70 (CH2); 29.01 (CH2); 26.71 (CH2) ppm. The oily product was transformed into the hydrochloride and recrystallized from absolute ethanol/anhydrous diethylether. Mp: 140-143 °C. Anal. (C39H44ClNO7) C, H, N. Compounds 7b, 7c and 7d were obtained in the same way from 11b, 11c and 11d respectively. Compounds 6a-d were obtained in the same way from 11a-d using 2,2-bis(4-methoxyphenyl)acetic acid40 and compounds 2a-d and 3a-d were obtained in the same way from 10a-d31 using 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid39 or 9H-fluorene-9-carboxylic acid, respectively. All compounds were transformed into the hydrochloride. Their chemical and physical characteristics are reported in Table S1; IR and 1H and 13C NMR spectra are reported in Tables S2 and S3 (Supplementary data).

Reference： [1]Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 456 - 465]

48
[ 1989-33-9 ]
[ 1417611-67-6 ]
[ 1417611-58-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6 6.6. cis/trans-9H-Fluorene-9-carboxylic acid 4-(methyl{4-[3-(3,4,5-trimethoxyphenyl)propyno-yl-oxy]cyclohexyl}amino)cyclohexyl ester (7a) General procedure: Following the procedure described for compound 8, to a solution of 11a (76.4 mg, 0.17 mmol) in dry CH2Cl2 cooled at 0° C were added in this sequence: 9H-fluorene-9-carboxylic acid (54.1 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP) (16.7 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (59.2 mg, 0.31 mmol). The reaction mixture was stirred at 0 °C for 1 h and then was kept at room temperature for 48 h. The mixture was treated with CH2Cl2 and the organic layer washed with water and then with a satured solution of NaHCO3. After drying with Na2SO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2/MeOH/NH4OH (97:3:0.3) as eluting system. The title compound (54 mg, 49% yield) was obtained as an oil. IR (neat): ν 1708 (CO) cm-1. 1H NMR (CDCl3): δ 7.76 (d, J = 7.6 Hz, 2H, aromatic); 7.64 (d, J = 7.6 Hz, 2H, aromatic); 7.41 (t, J = 7.6 Hz, 2H, aromatic); 7.32 (t, J = 7.6 Hz, 2H, aromatic); 6.85 (s, 2H, aromatic); 5.11 (br s, 1H, CHO); 4.82 (s, 1H, aliphatic); 4.75 (m, 1H, CHO); 3.88 (s, 3H, OCH3); 3.86 (s, 6H, 2OCH3); 2.76-2.52 (m, 2H, 2NCH); 2.29 (s, 3H, NCH3); 2.13-1.38 (m, 16H, 8CH2) ppm. 13C NMR (CDCl3): δ 170.27 (C); 153.67 (C); 153.16 (C); 141.43 (C); 140.74 (C); 128.08 (CH aromatic); 127.31 (CH aromatic); 125.54 (CH aromatic); 120.04 (CH aromatic); 114.32 (C); 110.38 (CH aromatic); 86.33 (C); 80.29 (C); 73.53 (CHO); 71.28 (CHO); 61.03 (OCH3); 58.60 (NCH); 56.27 (OCH3); 53.53 (CH aliphatic); 32.75 (NCH3); 30.70 (CH2); 29.01 (CH2); 26.71 (CH2) ppm. The oily product was transformed into the hydrochloride and recrystallized from absolute ethanol/anhydrous diethylether. Mp: 140-143 °C. Anal. (C39H44ClNO7) C, H, N. Compounds 7b, 7c and 7d were obtained in the same way from 11b, 11c and 11d respectively. Compounds 6a-d were obtained in the same way from 11a-d using 2,2-bis(4-methoxyphenyl)acetic acid40 and compounds 2a-d and 3a-d were obtained in the same way from 10a-d31 using 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid39 or 9H-fluorene-9-carboxylic acid, respectively. All compounds were transformed into the hydrochloride. Their chemical and physical characteristics are reported in Table S1; IR and 1H and 13C NMR spectra are reported in Tables S2 and S3 (Supplementary data).

Reference： [1]Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 456 - 465]

49
[ 1989-33-9 ]
[ 1417611-68-7 ]
[ 1417611-59-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6 6.6. cis/trans-9H-Fluorene-9-carboxylic acid 4-(methyl{4-[3-(3,4,5-trimethoxyphenyl)propyno-yl-oxy]cyclohexyl}amino)cyclohexyl ester (7a) General procedure: Following the procedure described for compound 8, to a solution of 11a (76.4 mg, 0.17 mmol) in dry CH2Cl2 cooled at 0° C were added in this sequence: 9H-fluorene-9-carboxylic acid (54.1 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP) (16.7 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (59.2 mg, 0.31 mmol). The reaction mixture was stirred at 0 °C for 1 h and then was kept at room temperature for 48 h. The mixture was treated with CH2Cl2 and the organic layer washed with water and then with a satured solution of NaHCO3. After drying with Na2SO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2/MeOH/NH4OH (97:3:0.3) as eluting system. The title compound (54 mg, 49% yield) was obtained as an oil. IR (neat): ν 1708 (CO) cm-1. 1H NMR (CDCl3): δ 7.76 (d, J = 7.6 Hz, 2H, aromatic); 7.64 (d, J = 7.6 Hz, 2H, aromatic); 7.41 (t, J = 7.6 Hz, 2H, aromatic); 7.32 (t, J = 7.6 Hz, 2H, aromatic); 6.85 (s, 2H, aromatic); 5.11 (br s, 1H, CHO); 4.82 (s, 1H, aliphatic); 4.75 (m, 1H, CHO); 3.88 (s, 3H, OCH3); 3.86 (s, 6H, 2OCH3); 2.76-2.52 (m, 2H, 2NCH); 2.29 (s, 3H, NCH3); 2.13-1.38 (m, 16H, 8CH2) ppm. 13C NMR (CDCl3): δ 170.27 (C); 153.67 (C); 153.16 (C); 141.43 (C); 140.74 (C); 128.08 (CH aromatic); 127.31 (CH aromatic); 125.54 (CH aromatic); 120.04 (CH aromatic); 114.32 (C); 110.38 (CH aromatic); 86.33 (C); 80.29 (C); 73.53 (CHO); 71.28 (CHO); 61.03 (OCH3); 58.60 (NCH); 56.27 (OCH3); 53.53 (CH aliphatic); 32.75 (NCH3); 30.70 (CH2); 29.01 (CH2); 26.71 (CH2) ppm. The oily product was transformed into the hydrochloride and recrystallized from absolute ethanol/anhydrous diethylether. Mp: 140-143 °C. Anal. (C39H44ClNO7) C, H, N. Compounds 7b, 7c and 7d were obtained in the same way from 11b, 11c and 11d respectively. Compounds 6a-d were obtained in the same way from 11a-d using 2,2-bis(4-methoxyphenyl)acetic acid40 and compounds 2a-d and 3a-d were obtained in the same way from 10a-d31 using 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid39 or 9H-fluorene-9-carboxylic acid, respectively. All compounds were transformed into the hydrochloride. Their chemical and physical characteristics are reported in Table S1; IR and 1H and 13C NMR spectra are reported in Tables S2 and S3 (Supplementary data).

Reference： [1]Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 456 - 465]

50
[ 1989-33-9 ]
[ 1417611-69-8 ]
[ 1417611-60-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6 6.6. cis/trans-9H-Fluorene-9-carboxylic acid 4-(methyl{4-[3-(3,4,5-trimethoxyphenyl)propyno-yl-oxy]cyclohexyl}amino)cyclohexyl ester (7a) General procedure: Following the procedure described for compound 8, to a solution of 11a (76.4 mg, 0.17 mmol) in dry CH2Cl2 cooled at 0° C were added in this sequence: 9H-fluorene-9-carboxylic acid (54.1 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP) (16.7 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (59.2 mg, 0.31 mmol). The reaction mixture was stirred at 0 °C for 1 h and then was kept at room temperature for 48 h. The mixture was treated with CH2Cl2 and the organic layer washed with water and then with a satured solution of NaHCO3. After drying with Na2SO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2/MeOH/NH4OH (97:3:0.3) as eluting system. The title compound (54 mg, 49% yield) was obtained as an oil. IR (neat): ν 1708 (CO) cm-1. 1H NMR (CDCl3): δ 7.76 (d, J = 7.6 Hz, 2H, aromatic); 7.64 (d, J = 7.6 Hz, 2H, aromatic); 7.41 (t, J = 7.6 Hz, 2H, aromatic); 7.32 (t, J = 7.6 Hz, 2H, aromatic); 6.85 (s, 2H, aromatic); 5.11 (br s, 1H, CHO); 4.82 (s, 1H, aliphatic); 4.75 (m, 1H, CHO); 3.88 (s, 3H, OCH3); 3.86 (s, 6H, 2OCH3); 2.76-2.52 (m, 2H, 2NCH); 2.29 (s, 3H, NCH3); 2.13-1.38 (m, 16H, 8CH2) ppm. 13C NMR (CDCl3): δ 170.27 (C); 153.67 (C); 153.16 (C); 141.43 (C); 140.74 (C); 128.08 (CH aromatic); 127.31 (CH aromatic); 125.54 (CH aromatic); 120.04 (CH aromatic); 114.32 (C); 110.38 (CH aromatic); 86.33 (C); 80.29 (C); 73.53 (CHO); 71.28 (CHO); 61.03 (OCH3); 58.60 (NCH); 56.27 (OCH3); 53.53 (CH aliphatic); 32.75 (NCH3); 30.70 (CH2); 29.01 (CH2); 26.71 (CH2) ppm. The oily product was transformed into the hydrochloride and recrystallized from absolute ethanol/anhydrous diethylether. Mp: 140-143 °C. Anal. (C39H44ClNO7) C, H, N. Compounds 7b, 7c and 7d were obtained in the same way from 11b, 11c and 11d respectively. Compounds 6a-d were obtained in the same way from 11a-d using 2,2-bis(4-methoxyphenyl)acetic acid40 and compounds 2a-d and 3a-d were obtained in the same way from 10a-d31 using 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid39 or 9H-fluorene-9-carboxylic acid, respectively. All compounds were transformed into the hydrochloride. Their chemical and physical characteristics are reported in Table S1; IR and 1H and 13C NMR spectra are reported in Tables S2 and S3 (Supplementary data).

Reference： [1]Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 456 - 465]

51
[ 1989-33-9 ]
C₂₅H₃₇NO₆ [ No CAS ]
C₃₉H₄₅NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6 6.6. cis/trans-9H-Fluorene-9-carboxylic acid 4-(methyl{4-[3-(3,4,5-trimethoxyphenyl)propyno-yl-oxy]cyclohexyl}amino)cyclohexyl ester (7a) General procedure: Following the procedure described for compound 8, to a solution of 11a (76.4 mg, 0.17 mmol) in dry CH2Cl2 cooled at 0° C were added in this sequence: 9H-fluorene-9-carboxylic acid (54.1 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP) (16.7 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (59.2 mg, 0.31 mmol). The reaction mixture was stirred at 0 °C for 1 h and then was kept at room temperature for 48 h. The mixture was treated with CH2Cl2 and the organic layer washed with water and then with a satured solution of NaHCO3. After drying with Na2SO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2/MeOH/NH4OH (97:3:0.3) as eluting system. The title compound (54 mg, 49% yield) was obtained as an oil. IR (neat): ν 1708 (CO) cm-1. 1H NMR (CDCl3): δ 7.76 (d, J = 7.6 Hz, 2H, aromatic); 7.64 (d, J = 7.6 Hz, 2H, aromatic); 7.41 (t, J = 7.6 Hz, 2H, aromatic); 7.32 (t, J = 7.6 Hz, 2H, aromatic); 6.85 (s, 2H, aromatic); 5.11 (br s, 1H, CHO); 4.82 (s, 1H, aliphatic); 4.75 (m, 1H, CHO); 3.88 (s, 3H, OCH3); 3.86 (s, 6H, 2OCH3); 2.76-2.52 (m, 2H, 2NCH); 2.29 (s, 3H, NCH3); 2.13-1.38 (m, 16H, 8CH2) ppm. 13C NMR (CDCl3): δ 170.27 (C); 153.67 (C); 153.16 (C); 141.43 (C); 140.74 (C); 128.08 (CH aromatic); 127.31 (CH aromatic); 125.54 (CH aromatic); 120.04 (CH aromatic); 114.32 (C); 110.38 (CH aromatic); 86.33 (C); 80.29 (C); 73.53 (CHO); 71.28 (CHO); 61.03 (OCH3); 58.60 (NCH); 56.27 (OCH3); 53.53 (CH aliphatic); 32.75 (NCH3); 30.70 (CH2); 29.01 (CH2); 26.71 (CH2) ppm. The oily product was transformed into the hydrochloride and recrystallized from absolute ethanol/anhydrous diethylether. Mp: 140-143 °C. Anal. (C39H44ClNO7) C, H, N. Compounds 7b, 7c and 7d were obtained in the same way from 11b, 11c and 11d respectively. Compounds 6a-d were obtained in the same way from 11a-d using 2,2-bis(4-methoxyphenyl)acetic acid40 and compounds 2a-d and 3a-d were obtained in the same way from 10a-d31 using 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid39 or 9H-fluorene-9-carboxylic acid, respectively. All compounds were transformed into the hydrochloride. Their chemical and physical characteristics are reported in Table S1; IR and 1H and 13C NMR spectra are reported in Tables S2 and S3 (Supplementary data).

Reference： [1]Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 456 - 465]

52
[ 1989-33-9 ]
C₂₅H₃₇NO₆ [ No CAS ]
C₃₉H₄₅NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6 6.6. cis/trans-9H-Fluorene-9-carboxylic acid 4-(methyl{4-[3-(3,4,5-trimethoxyphenyl)propyno-yl-oxy]cyclohexyl}amino)cyclohexyl ester (7a) General procedure: Following the procedure described for compound 8, to a solution of 11a (76.4 mg, 0.17 mmol) in dry CH2Cl2 cooled at 0° C were added in this sequence: 9H-fluorene-9-carboxylic acid (54.1 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP) (16.7 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (59.2 mg, 0.31 mmol). The reaction mixture was stirred at 0 °C for 1 h and then was kept at room temperature for 48 h. The mixture was treated with CH2Cl2 and the organic layer washed with water and then with a satured solution of NaHCO3. After drying with Na2SO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2/MeOH/NH4OH (97:3:0.3) as eluting system. The title compound (54 mg, 49% yield) was obtained as an oil. IR (neat): ν 1708 (CO) cm-1. 1H NMR (CDCl3): δ 7.76 (d, J = 7.6 Hz, 2H, aromatic); 7.64 (d, J = 7.6 Hz, 2H, aromatic); 7.41 (t, J = 7.6 Hz, 2H, aromatic); 7.32 (t, J = 7.6 Hz, 2H, aromatic); 6.85 (s, 2H, aromatic); 5.11 (br s, 1H, CHO); 4.82 (s, 1H, aliphatic); 4.75 (m, 1H, CHO); 3.88 (s, 3H, OCH3); 3.86 (s, 6H, 2OCH3); 2.76-2.52 (m, 2H, 2NCH); 2.29 (s, 3H, NCH3); 2.13-1.38 (m, 16H, 8CH2) ppm. 13C NMR (CDCl3): δ 170.27 (C); 153.67 (C); 153.16 (C); 141.43 (C); 140.74 (C); 128.08 (CH aromatic); 127.31 (CH aromatic); 125.54 (CH aromatic); 120.04 (CH aromatic); 114.32 (C); 110.38 (CH aromatic); 86.33 (C); 80.29 (C); 73.53 (CHO); 71.28 (CHO); 61.03 (OCH3); 58.60 (NCH); 56.27 (OCH3); 53.53 (CH aliphatic); 32.75 (NCH3); 30.70 (CH2); 29.01 (CH2); 26.71 (CH2) ppm. The oily product was transformed into the hydrochloride and recrystallized from absolute ethanol/anhydrous diethylether. Mp: 140-143 °C. Anal. (C39H44ClNO7) C, H, N. Compounds 7b, 7c and 7d were obtained in the same way from 11b, 11c and 11d respectively. Compounds 6a-d were obtained in the same way from 11a-d using 2,2-bis(4-methoxyphenyl)acetic acid40 and compounds 2a-d and 3a-d were obtained in the same way from 10a-d31 using 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid39 or 9H-fluorene-9-carboxylic acid, respectively. All compounds were transformed into the hydrochloride. Their chemical and physical characteristics are reported in Table S1; IR and 1H and 13C NMR spectra are reported in Tables S2 and S3 (Supplementary data).

Reference： [1]Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 456 - 465]

53
[ 1989-33-9 ]
C₂₅H₃₇NO₆ [ No CAS ]
C₃₉H₄₅NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6 6.6. cis/trans-9H-Fluorene-9-carboxylic acid 4-(methyl{4-[3-(3,4,5-trimethoxyphenyl)propyno-yl-oxy]cyclohexyl}amino)cyclohexyl ester (7a) General procedure: Following the procedure described for compound 8, to a solution of 11a (76.4 mg, 0.17 mmol) in dry CH2Cl2 cooled at 0° C were added in this sequence: 9H-fluorene-9-carboxylic acid (54.1 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP) (16.7 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (59.2 mg, 0.31 mmol). The reaction mixture was stirred at 0 °C for 1 h and then was kept at room temperature for 48 h. The mixture was treated with CH2Cl2 and the organic layer washed with water and then with a satured solution of NaHCO3. After drying with Na2SO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2/MeOH/NH4OH (97:3:0.3) as eluting system. The title compound (54 mg, 49% yield) was obtained as an oil. IR (neat): ν 1708 (CO) cm-1. 1H NMR (CDCl3): δ 7.76 (d, J = 7.6 Hz, 2H, aromatic); 7.64 (d, J = 7.6 Hz, 2H, aromatic); 7.41 (t, J = 7.6 Hz, 2H, aromatic); 7.32 (t, J = 7.6 Hz, 2H, aromatic); 6.85 (s, 2H, aromatic); 5.11 (br s, 1H, CHO); 4.82 (s, 1H, aliphatic); 4.75 (m, 1H, CHO); 3.88 (s, 3H, OCH3); 3.86 (s, 6H, 2OCH3); 2.76-2.52 (m, 2H, 2NCH); 2.29 (s, 3H, NCH3); 2.13-1.38 (m, 16H, 8CH2) ppm. 13C NMR (CDCl3): δ 170.27 (C); 153.67 (C); 153.16 (C); 141.43 (C); 140.74 (C); 128.08 (CH aromatic); 127.31 (CH aromatic); 125.54 (CH aromatic); 120.04 (CH aromatic); 114.32 (C); 110.38 (CH aromatic); 86.33 (C); 80.29 (C); 73.53 (CHO); 71.28 (CHO); 61.03 (OCH3); 58.60 (NCH); 56.27 (OCH3); 53.53 (CH aliphatic); 32.75 (NCH3); 30.70 (CH2); 29.01 (CH2); 26.71 (CH2) ppm. The oily product was transformed into the hydrochloride and recrystallized from absolute ethanol/anhydrous diethylether. Mp: 140-143 °C. Anal. (C39H44ClNO7) C, H, N. Compounds 7b, 7c and 7d were obtained in the same way from 11b, 11c and 11d respectively. Compounds 6a-d were obtained in the same way from 11a-d using 2,2-bis(4-methoxyphenyl)acetic acid40 and compounds 2a-d and 3a-d were obtained in the same way from 10a-d31 using 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid39 or 9H-fluorene-9-carboxylic acid, respectively. All compounds were transformed into the hydrochloride. Their chemical and physical characteristics are reported in Table S1; IR and 1H and 13C NMR spectra are reported in Tables S2 and S3 (Supplementary data).

Reference： [1]Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 456 - 465]

54
[ 1989-33-9 ]
C₂₅H₃₇NO₆ [ No CAS ]
C₃₉H₄₅NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6 6.6. cis/trans-9H-Fluorene-9-carboxylic acid 4-(methyl{4-[3-(3,4,5-trimethoxyphenyl)propyno-yl-oxy]cyclohexyl}amino)cyclohexyl ester (7a) General procedure: Following the procedure described for compound 8, to a solution of 11a (76.4 mg, 0.17 mmol) in dry CH2Cl2 cooled at 0° C were added in this sequence: 9H-fluorene-9-carboxylic acid (54.1 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP) (16.7 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (59.2 mg, 0.31 mmol). The reaction mixture was stirred at 0 °C for 1 h and then was kept at room temperature for 48 h. The mixture was treated with CH2Cl2 and the organic layer washed with water and then with a satured solution of NaHCO3. After drying with Na2SO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2/MeOH/NH4OH (97:3:0.3) as eluting system. The title compound (54 mg, 49% yield) was obtained as an oil. IR (neat): ν 1708 (CO) cm-1. 1H NMR (CDCl3): δ 7.76 (d, J = 7.6 Hz, 2H, aromatic); 7.64 (d, J = 7.6 Hz, 2H, aromatic); 7.41 (t, J = 7.6 Hz, 2H, aromatic); 7.32 (t, J = 7.6 Hz, 2H, aromatic); 6.85 (s, 2H, aromatic); 5.11 (br s, 1H, CHO); 4.82 (s, 1H, aliphatic); 4.75 (m, 1H, CHO); 3.88 (s, 3H, OCH3); 3.86 (s, 6H, 2OCH3); 2.76-2.52 (m, 2H, 2NCH); 2.29 (s, 3H, NCH3); 2.13-1.38 (m, 16H, 8CH2) ppm. 13C NMR (CDCl3): δ 170.27 (C); 153.67 (C); 153.16 (C); 141.43 (C); 140.74 (C); 128.08 (CH aromatic); 127.31 (CH aromatic); 125.54 (CH aromatic); 120.04 (CH aromatic); 114.32 (C); 110.38 (CH aromatic); 86.33 (C); 80.29 (C); 73.53 (CHO); 71.28 (CHO); 61.03 (OCH3); 58.60 (NCH); 56.27 (OCH3); 53.53 (CH aliphatic); 32.75 (NCH3); 30.70 (CH2); 29.01 (CH2); 26.71 (CH2) ppm. The oily product was transformed into the hydrochloride and recrystallized from absolute ethanol/anhydrous diethylether. Mp: 140-143 °C. Anal. (C39H44ClNO7) C, H, N. Compounds 7b, 7c and 7d were obtained in the same way from 11b, 11c and 11d respectively. Compounds 6a-d were obtained in the same way from 11a-d using 2,2-bis(4-methoxyphenyl)acetic acid40 and compounds 2a-d and 3a-d were obtained in the same way from 10a-d31 using 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid39 or 9H-fluorene-9-carboxylic acid, respectively. All compounds were transformed into the hydrochloride. Their chemical and physical characteristics are reported in Table S1; IR and 1H and 13C NMR spectra are reported in Tables S2 and S3 (Supplementary data).

Reference： [1]Orlandi, Francesca; Coronnello, Marcella; Bellucci, Cristina; Dei, Silvia; Guandalini, Luca; Manetti, Dina; Martelli, Cecilia; Romanelli, Maria Novella; Scapecchi, Serena; Salerno, Milena; Menif, Hayette; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 456 - 465]

55
[ 124-38-9 ]
[ 1940-57-4 ]
[ 1989-33-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	With bis(tricyclohexylphosphine)nickel(II) dichloride; tetra-(n-butyl)ammonium iodide; zinc In N,N-dimethyl acetamide at 20℃; Schlenk technique;

Reference： [1]León, Thierry; Correa, Arkaitz; Martin, Ruben [Journal of the American Chemical Society, 2013, vol. 135, # 4, p. 1221 - 1224]

56
[ 1989-33-9 ]
[ 73283-56-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane; iodine In chloroform at 20 - 60℃; for 0.1h; Sealed tube; Inert atmosphere;
	With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane; iodine In chloroform at 60℃; Inert atmosphere;

Reference： [1]Moriya, Toshimitsu; Yoneda, Shinichiro; Kawana, Keita; Ikeda, Reiko; Konakahara, Takeo; Sakai, Norio [Journal of Organic Chemistry, 2013, vol. 78, # 21, p. 10642 - 10650]
[2]Moriya, Toshimitsu; Shoji, Kohei; Yoneda, Shinichiro; Ikeda, Reiko; Konakahara, Takeo; Sakai, Norio [Synthesis, 2013, vol. 45, # 23, p. 3233 - 3238]

57
[ 870449-55-1 ]
[ 1989-33-9 ]
(E)-3-(methyl(3-((3-(3,4,5-trimethoxyphenyl)acryloyl)oxy)propyl)amino)propyl 9H-fluorene-9-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6.1.8. General procedure for the synthesis of diester compounds (1-26) General procedure: A solution of the suitable methylhydroxyaminoester 54-68 (0.250 mmol) in 5 mL of an. CH2Cl2 was cooled at 0 °C and 0.360 mmol of the appropriate carboxylic acid, 0.083 mmol of 4-dimethylaminopiridine (DMAP) and 0.500 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) were added. The reaction mixture was stirred for 1 h at 0 °C and 48 h at room temperature. Then CH2Cl2 was added and the organic layer was washed twice with a saturated solution of NaHCO3. Afterdrying with Na2SO4, the solvent was removed under reduced pressure. The crude product was then purified by flash chromatography using the appropriate eluting system, yielding the desired compound as an oil. All the compounds were transformed into the corresponding hydrochloride or oxalate as white solid. The salts were crystallized from abs. ethanol/petroleum ether.

Reference： [1]Dei, Silvia; Coronnello, Marcella; Floriddia, Elisa; Bartolucci, Gianluca; Bellucci, Cristina; Guandalini, Luca; Manetti, Dina; Romanelli, Maria Novella; Salerno, Milena; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [European Journal of Medicinal Chemistry, 2014, vol. 87, p. 398 - 412]

58
[ 1989-33-9 ]
(E)-5-((3-hydroxypropyl) (methyl)amino)pentyl 3-(3,4,5-trimethoxyphenyl)acrylate [ No CAS ]
(E)-3-(methyl(5-((3-(3,4,5-trimethoxyphenyl)acryloyl)oxy)pentyl)amino)propyl 9H-fluorene-9-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.3%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 49h;	6.1.8. General procedure for the synthesis of diester compounds (1-26) General procedure: A solution of the suitable methylhydroxyaminoester 54-68 (0.250 mmol) in 5 mL of an. CH2Cl2 was cooled at 0 °C and 0.360 mmol of the appropriate carboxylic acid, 0.083 mmol of 4-dimethylaminopiridine (DMAP) and 0.500 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) were added. The reaction mixture was stirred for 1 h at 0 °C and 48 h at room temperature. Then CH2Cl2 was added and the organic layer was washed twice with a saturated solution of NaHCO3. Afterdrying with Na2SO4, the solvent was removed under reduced pressure. The crude product was then purified by flash chromatography using the appropriate eluting system, yielding the desired compound as an oil. All the compounds were transformed into the corresponding hydrochloride or oxalate as white solid. The salts were crystallized from abs. ethanol/petroleum ether.

Reference： [1]Dei, Silvia; Coronnello, Marcella; Floriddia, Elisa; Bartolucci, Gianluca; Bellucci, Cristina; Guandalini, Luca; Manetti, Dina; Romanelli, Maria Novella; Salerno, Milena; Bello, Ivan; Mini, Enrico; Teodori, Elisabetta [European Journal of Medicinal Chemistry, 2014, vol. 87, p. 398 - 412]

59
[ 1989-33-9 ]
[ 33757-48-1 ]
3-(9H-fluoren-9-ylidene)-2-(quinolin-8-yl)isoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With palladium(II) trifluoroacetate; 2,2-dimethylpropanoic anhydride In toluene at 130℃; for 12h; Inert atmosphere; Schlenk technique; Sealed tube;
62%	With palladium(II) trifluoroacetate; 2,2-dimethylpropanoic anhydride In toluene at 130℃; for 12h; Inert atmosphere;	29 The benzamides 1a (0.1mmol), formic acid fluorene 2l (0.2mmol), pivalic anhydride (0.2 mmol), palladium trifluoroacetate (0.01mmol) was added 20mL reaction tube, in inert atmosphere, was added toluene (1 mL), and the reaction tube sealed plug polytetrafluoroethylene. Then in an oil bath of 130 was heated for 12 hours. After completion of the reaction, cooled to room temperature, filtered through celite, rinsed with 20mL of ethyl acetate until the filtrate was colorless, and the combined organic phases, containing the rotational solvent was removed to give 3- (9H-fluoren-9-ylidene) -2- (quinolin-8-yl) isoindolin-1-one (3al) a mixture of crude product by flash column chromatography to obtain 3Al, yield 62%

Reference： [1]Liang, Hong-Wen; Ding, Wei; Jiang, Kun; Shuai, Li; Yuan, Yi; Wei, Ye; Chen, Ying-Chun [Organic Letters, 2015, vol. 17, # 11, p. 2764 - 2767]
[2]Current Patent Assignee: THIRD MILITARY MEDICAL UNIVERSITY - CN104650033, 2016, B Location in patent: Paragraph 0187-0190

60
[ 4753-59-7 ]
[ 1989-33-9 ]
9-(4-acetoxybutyl)-9H-fluorene-9-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 9H-fluorene-9-carboxylic acid With n-butyllithium In tetrahydrofuran at -30 - 20℃; Stage #2: 4-Bromobutyl acetate In tetrahydrofuran at 20℃; for 17h;	1 Example 1 Preparation of 9-(4-Acetoxybutyl)-9H-fluorene-9-carboxilic acid of Formula V. Tetrahydrofuran (1700 ml) was added to the 9H-fluorene-9-carboxylic acid (100gm) at room temperature then the reaction mass was cooled to -20 to -30°C. n-butyllithium (67 gm) was added slowly at -20 to -30°C for 60 to 90 minutes and maintained for 60 to 70 minutes at -20 to -30°C. 4-bromobutyl acetate (185 gm) was added then the reaction mass was cooled to room temperature and maintained for 17 hours. After completion of the reaction, DM water was added to the reaction mixture and stined for 30 minutes at room temperature to yield 9-(4-acetoxybutyl)-9H-fluorene-9-carboxilicacid of Formula V.

Reference： [1]Current Patent Assignee: HETERO DRUGS LIMITED - WO2016/71849, 2016, A1 Location in patent: Page/Page column 17; 18

61
[ 1989-33-9 ]
N-(3,4,5-trimethoxybenzylidene)-4-ethylphenylamine [ No CAS ]
1-(4-ethylphenyl)-4-(3,4,5-trimethoxyphenyl)spiro[azetidine-3,9'-fluoren]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; triethylamine In dichloromethane at 20℃;	General procedure for the synthesis of 2-azetidinones (5a-m) General procedure: EEDQ (1.3 mmol) was added to a solution of the substituted acetic acid (1.3 mmol), the Schiff base (1.0 mmol), and Et3N (5.0 mmol) in dry CH2Cl2 (15 mL) at room temperature, and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4) and filtered, and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from 95% EtOH.

Reference： [1]Zavar, Saleheh; Zarei, Maaroof; Saraei, Mahnaz [Synthetic Communications, 2016, vol. 46, # 24, p. 2031 - 2036]

62
[ 1989-33-9 ]
[ 58896-43-8 ]
1-(4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)spiro[azetidine-3,9'-fluoren]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; triethylamine In dichloromethane at 20℃;	General procedure for the synthesis of 2-azetidinones (5a-m) General procedure: EEDQ (1.3 mmol) was added to a solution of the substituted acetic acid (1.3 mmol), the Schiff base (1.0 mmol), and Et3N (5.0 mmol) in dry CH2Cl2 (15 mL) at room temperature, and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4) and filtered, and the solvent was removed under reduced pressure. The crude residue was purified by crystallization from 95% EtOH.

Reference： [1]Zavar, Saleheh; Zarei, Maaroof; Saraei, Mahnaz [Synthetic Communications, 2016, vol. 46, # 24, p. 2031 - 2036]

63
[ 1989-33-9 ]
[ 349-65-5 ]
N-(2-methoxy-5-(trifluoromethyl)phenyl)-9H-fluorene-9-carboxamide [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 16513 - 16521

64
[ 110-52-1 ]
[ 753-90-2 ]
[ 1989-33-9 ]
[ 182438-98-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; dicyclohexyl-carbodiimide;	Example 2 Preparation of 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide Tetrahydrofuran (2400 ml) was added to 9H-fluorene-9-carboxylic acid (100 gm) under stirring. The solution was cooled to 0 to -5 C. and a solution of n-butyllithium (60.9 gm) in n-hexane (340 ml) was then added slowly. The reaction mass was maintained for 1 hour at 0 to -5 C. and 1,4-dibromo butane (133.5 gm) was added to the reaction mass slowly. The reaction mass was maintained for 40 minutes at 0 to -5 C. and temperature of the reaction mass was raised to room temperature. The reaction mass was maintained for 15 hours at room temperature and then cooled to 0 to 5 C. To the reaction mass was added hydrochloric acid solution (1N, 1000 ml) at 0 to -5 C. slowly and temperature of the reaction mass was raised to room temperature. The layers were separated and the aqueous layer was extracted with ethyl acetate. Combined organic layers were dried with sodium sulfate and the solvent was distilled off under vacuum to obtain a residual solid. The residual solid obtained was dissolved in n-hexane (1000 ml) and stirred for 2 hours. The separated solid was filtered and then dried to obtain 98.6 gm of 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid. 2,2,2-Trifluoroethyl amine (3.1 gm) was dissolved in water (20 ml) and pH was adjusted to 10.5 to 11.0 with sodium hydroxide solution (10%). The solution was extracted three times with methylene chloride. Combined organic layers were dried with sodium sulfate and 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid was added to the organic layer. The reaction mass was cooled to 0 to 5 C. and a solution of N,N'-dicyclohexylcarbodiimide (11.3 gm) in methylene chloride (60 ml) was then added. The reaction mass was maintained for 2 hours at 0 to 5 C. and the temperature of the reaction mass was raised to room temperature for 30 minutes. The reaction mass was cooled to -5 C., maintained for 30 minutes and filtered to obtain a wet solid. The wet solid was dissolved in n-hexane (30 ml) and cooled to 0 to 5 C. The contents were stirred for 2 hours and filtered. The solid obtained was dried to obtain 8 gm of 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide. Yield: 64.8% Chromatographic purity (by HPLC): 90.25%

Reference： [1]Patent: US2017/57917,2017,A1

65
[ 110-52-1 ]
[ 1989-33-9 ]
[ 373-88-6 ]
[ 182438-98-8 ]

Yield	Reaction Conditions	Operation in experiment
155 g		A mixture of 9H-fluorene-9-carboxylic acid compound of formula-2a (100 gm), 1,4-dibromobutane (308 gm) and toluene (1000 ml) was stirred for 15 mm at 25-30C undernitrogen atmosphere. Cooled the reaction mixture to 5-10C, sodium tert.butoxide (100.5 gm) was slowly added to it and stirred the reaction mixture for 3 hrs at the same temperature. Water was added to the reaction mixture at 25-30C and stirred for 15 mm at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with water. Both the organic and aqueous layers were separated and washed the aqueouslayer with toluene. Acidified the aqueous layer using aqueous hydrochloric acid solution at25-30C aiid stirred the reaction mixture for 20 mm at the same temperature. Dichioromethane was added to the reaction mixture at 25-30C and stirred for 15 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous citric acid solution. Distilled off the solvent completely from theorganic layer. Dichioromethane (500 ml) was added to the reaction mixture at 25-30C and stirred for 15 mm at the same temperature. N,N-dimethylformamide (6.9 gm) followed by oxalyl chloride (66.4 gm) were slowly added to the reaction mixture at 25-30C and stirred for 2 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under nitrogen atmosphere and co-distilled with dichloromethane under reducedpressure. Dichloromethane (500 ml) was added to the obtained compound at 25-30C and stirred for .15 mm at the same temperature. The obtained compound was slowly added to a pre-cooled mixture of water (500 ml), <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> (64.4 gm) and sodium carbonate (75.6 gm) at 5-10C and stirred the reaction mixture for 45 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organiclayer with aqueous hydrochloric acid solution followed by with aqueous sodium bicarbonate solution and then finally washed with water. Distilled off the solvent completely from the organic layer and then co-distilled with n-heptane under reduced pressure. n-Heptane (100 ml) and isopropanol (5 ml) were added to the reaction mixture at 25-30C. Heated the reaction mixture to 55-60C and stirred for 1 hr at the same temperature. Cooled the reaction ttiture to 25-30C and stirred for 1 hr at the same temperature. Filtered the precipitatedsolid, washed with n-heptaene and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-5.Yield: 155.0 gm; M.R: 95-102C.

Reference： [1]Patent: WO2017/98522,2017,A1 .Location in patent: Page/Page column 18; 19; 24; 25

66
[ 23144-52-7 ]
[ 1989-33-9 ]
C₂₂H₂₅ClO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.22 g	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1-methyl-pyrrolidin-2-one at 25 - 30℃; for 4h; Inert atmosphere;	2.1 Step 1: Synthesis of Intermediate E In a 3-port reactor equipped with a thermometer, 11.49 g (54.65 mmol) of 9-anthracenecarboxylic acid and 75 mL of N-methyl-2-pyrrolidone were placed under a nitrogen gas stream to obtain a homogeneous solution. At this time, 7.50 g (45.55 mmol) of 8-chloro-1-n-octanol was added. Subsequently, 1.33 g (10.89 mmol) of N,N-dimethyl-4-aminopyridine was added. Subsequently, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 12.57 g (65.59) was added while maintaining the internal temperature of the reaction liquid at 20 to 30 ° C for 5 minutes. After mmol), the whole was further stirred at 25 ° C for 4 hours. After completion of the reaction, 250 mL of a saturated brine was added to the reaction mixture, and extracted twice with ethyl acetate 250 mL. The organic layer was collected, dried over anhydrous sodium sulfate and filtered over sodium sulfate. After removing the solvent from the filtrate by a rotary evaporator, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:20 (volume ratio)) to obtain 14.22 g of a yellow oil. Intermediate product E of the substance. The yield was 87.5 mol%.

Reference： [1]Current Patent Assignee: ZEON CORPORATION - TW2018/41897, 2018, A Location in patent: Paragraph 0288-0291

67
[ 1989-33-9 ]
C₆₄H₇₅N₃O₁₅S [ No CAS ]
C₇₈H₈₃N₃O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.68 g	With dmap; diisopropyl-carbodiimide In chloroform at 20 - 30℃; for 4h; Inert atmosphere;	9.3 Step 3: Synthesis of Polymerizable Compound 9 (Another Example of Compound represented by Formula (III-1)) In a three-port reactor equipped with a thermometer, the intermediate product T synthesized in the above step 2 was charged with 6.00 g (5.18 mmol) and chloroform (120 mL) under a nitrogen gas stream to obtain a homogeneous solution. at this time, 1.31 g (6.22 mmol) of 9-fluorene carboxylic acid was added. Subsequently, 0.152 g (1.24 mmol) of N,N-dimethyl-4-aminopyridine was added. Subsequently, after adding the N,N'-diisopropylcarbodiimide 0.863 g (6.84 mmol) for 5 minutes while maintaining the internal temperature of the reaction liquid at 20 to 30 ° C, the whole was stirred at 25 ° C. 4 hours. After completion of the reaction, 250 mL of a saturated saline solution was added to the reaction mixture, and the mixture was extracted twice with chloroform (250 mL). The organic layer was collected, dried over anhydrous sodium sulfate and filtered over sodium sulfate. After removing the solvent from the filtrate by evaporation on a rotary evaporator, the obtained residue was purified by silica gel column chromatography (chloroform: THF = 95:5) to obtain 5.68 g of the polymerizable compound 9 as a yellow solid. The yield was 81.2 mol%.

Reference： [1]Current Patent Assignee: ZEON CORPORATION - TW2018/41897, 2018, A Location in patent: Paragraph 0358; 0365-0367

68
[ 1989-33-9 ]
C₆₆H₇₉N₃O₁₅S [ No CAS ]
C₈₀H₈₇N₃O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.23 g	With dmap; diisopropyl-carbodiimide In chloroform at 20 - 30℃; for 4h; Inert atmosphere;	10.3 Step 3: Synthesis of Polymerizable Compound 10 (Another Example of Compound represented by Formula (III-1)) In a three-port reactor equipped with a thermometer, an intermediate product V synthesized in the above step 2: 6.00 g (5.06 mmol) and 120 mL of chloroform were placed under a nitrogen gas stream to obtain a homogeneous solution. At this time, 1.28 g (6.07 mmol) of 9-anthracenecarboxylic acid was added. Subsequently, 0.148 g (1.21 mmol) of N,N-dimethyl-4-aminopyridine was added. Subsequently, after adding N,N'-diisopropylcarbodiimide 0.842 g (6.68 mmol) for 5 minutes while maintaining the internal temperature of the reaction liquid at 20 to 30 ° C, the whole was stirred at 25 ° C. 4 hours. After completion of the reaction, 250 mL of a saturated saline solution was added to the reaction mixture, and the mixture was extracted twice with chloroform (250 mL). The organic layer was collected, dried over anhydrous sodium sulfate and filtered over sodium sulfate. After the solvent was evaporated from the filtrate by a rotary evaporator, the obtained residue was purified by silica gel column chromatography (chloroform: THF=95:5) to obtain 6.23 g of the polymerizable compound 10 as a yellow solid. The yield was 89.4 mol%.

Reference： [1]Current Patent Assignee: ZEON CORPORATION - TW2018/41897, 2018, A Location in patent: Paragraph 0368; 0375-0377

69
[ 1989-33-9 ]
C₇₀H₈₇N₃O₁₅S [ No CAS ]
C₈₄H₉₅N₃O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.26 g	With dmap; diisopropyl-carbodiimide In chloroform at 20 - 30℃; for 4h; Inert atmosphere;	11.3 Step 3: Synthesis of Polymerizable Compound 11 (Another Example of Compound represented by Formula (III-1)) In a three-port reactor equipped with a thermometer, an intermediate product Y synthesized in the above step 2: 6.00 g (4.83 mmol) and 120 mL of chloroform were placed under a nitrogen gas stream to obtain a homogeneous solution. At this time, 1.22 g (5.79 mmol) of 9-anthracenecarboxylic acid was added. Subsequently, 0.142 g (1.16 mmol) of N,N-dimethyl-4-aminopyridine was added. Subsequently, after adding the N,N'-diisopropylcarbodiimide 0.804 g (6.37 mmol) for 5 minutes while maintaining the internal temperature of the reaction liquid at 20 to 30 ° C, the whole was stirred at 25 ° C. 4 hours. After completion of the reaction, 250 mL of a saturated saline solution was added to the reaction mixture, and the mixture was extracted twice with chloroform (250 mL). The organic layer was collected, dried over anhydrous sodium sulfate and filtered over sodium sulfate. After removing the solvent from the filtrate by evaporation on a rotary evaporator, the obtained residue was purified by silica gel column chromatography (chloroform: THF = 95:5) to obtain 6.26 g of the polymerizable compound 11 as a yellow solid. The yield was 90.3 mol%.

Reference： [1]Current Patent Assignee: ZEON CORPORATION - TW2018/41897, 2018, A Location in patent: Paragraph 0378; 0385-0387

70
[ 1989-33-9 ]
C₆₅H₇₇N₃O₁₅S [ No CAS ]
C₇₉H₈₅N₃O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.30 g	With dmap; diisopropyl-carbodiimide In chloroform at 25 - 30℃; for 4h; Inert atmosphere;	14.3 Step 3: Synthesis of Polymerizable Compound 14 (Another Example of Compound represented by Formula (III-1)) In a three-port reactor equipped with a thermometer, an intermediate product E1 synthesized in the above step 2: 6.00 g (5.12 mmol) and 120 mL of chloroform were placed under a nitrogen gas stream to obtain a homogeneous solution. At this time, 1.29 g (6.14 mmol) of 9-anthracenecarboxylic acid was added. Subsequently, 0.150 g (1.23 mmol) of N,N-dimethyl-4-aminopyridine was added. Subsequently, after adding the N,N'-diisopropylcarbodiimide 0.853 g (6.76 mmol) for 5 minutes while maintaining the internal temperature of the reaction liquid at 20 to 30 ° C, the whole was stirred at 25 ° C. 4 hours. After completion of the reaction, 250 mL of a saturated saline solution was added to the reaction mixture, and the mixture was extracted twice with chloroform (250 mL). The organic layer was collected, dried over anhydrous sodium sulfate and filtered over sodium sulfate. After removing the solvent from the filtrate by evaporation on a rotary evaporator, the obtained residue was purified by silica gel column chromatography (chloroform: THF = 95:5) to obtain 5.30 g of the polymerizable compound 14 as a yellow solid. The yield was 75.9 mol%.

Reference： [1]Current Patent Assignee: ZEON CORPORATION - TW2018/41897, 2018, A Location in patent: Paragraph 00402; 0409-0411

71
[ 1989-33-9 ]
C₅₄H₆₃N₃O₁₁S [ No CAS ]
C₆₈H₇₁N₃O₁₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.07 g	With dmap; diisopropyl-carbodiimide In chloroform at 20 - 30℃; for 4h; Inert atmosphere;	12.3 Step 3: Synthesis of Polymerizable Compound 12 (Another Example of Compound represented by Formula (III-1)) In a three-port reactor equipped with a thermometer, an intermediate product A1 synthesized in the above step 2: 6.00 g (6.24 mmol) and 120 mL of chloroform were placed under a nitrogen gas stream to prepare a homogeneous solution. At this time, 1.57 g (7.48 mmol) of 9-anthracenecarboxylic acid was added. Subsequently, 0.183 g (1.50 mmol) of N,N-dimethyl-4-aminopyridine was added. Subsequently, after adding N,N'-diisopropylcarbodiimide 1.04 g (8.23 mmol) for 5 minutes while maintaining the internal temperature of the reaction liquid at 20 to 30 ° C, the whole was further stirred at 25 ° C. 4 hours. After completion of the reaction, 250 mL of a saturated saline solution was added to the reaction mixture, and the mixture was extracted twice with chloroform (250 mL). The organic layer was collected, dried over anhydrous sodium sulfate and filtered over sodium sulfate. After removing the solvent from the filtrate by evaporation on a rotary evaporator, the obtained residue was purified by silica gel column chromatography (chloroform: THF=95:5) to obtain 6.07 g of the polymerizable compound 12 as a yellow solid. The yield was 84.3 mol%.

Reference： [1]Current Patent Assignee: ZEON CORPORATION - TW2018/41897, 2018, A Location in patent: Paragraph 0388; 0395-0397

72
[ 1989-33-9 ]
C₇₂H₉₁N₃O₁₅S [ No CAS ]
C₈₆H₉₉N₃O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.05 g	With dmap; diisopropyl-carbodiimide In chloroform at 20 - 30℃; for 4h; Inert atmosphere;	19.3 Step 3: Synthesis of Polymerizable Compound 19 (Another Example of Compound represented by Formula (III-1)) In a three-port reactor equipped with a thermometer, an intermediate product K1 synthesized in the above step 2: 6.00 g (5.06 mmol) and 120 mL of chloroform were placed under a nitrogen gas stream to obtain a homogeneous solution. At this time, 1.28 g (6.07 mmol) of 9-anthracenecarboxylic acid was added. Subsequently, 0.148 g (1.21 mmol) of N,N-dimethyl-4-aminopyridine was added. Subsequently, after adding N,N'-diisopropylcarbodiimide 0.842 g (6.68 mmol) for 5 minutes while maintaining the internal temperature of the reaction liquid at 20 to 30 ° C, the whole was stirred at 25 ° C. 4 hours. After completion of the reaction, 250 mL of a saturated saline solution was added to the reaction mixture, and the mixture was extracted twice with chloroform (250 mL). The organic layer was collected, dried over anhydrous sodium sulfate and filtered over sodium sulfate. After removing the solvent from the filtrate by evaporation on a rotary evaporator, the obtained residue was purified by silica gel column chromatography (chloroform: THF = 95:5) to obtain 5.05 g of the polymerizable compound 19 as a yellow solid. The yield was 68.3 mol%.

Reference： [1]Current Patent Assignee: ZEON CORPORATION - TW2018/41897, 2018, A Location in patent: Paragraph 0440; 0447-0449

73
[ 1989-33-9 ]
C₂₀H₁₈O₃ [ No CAS ]
C₃₄H₂₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h;	2-6 (Example 2-6) Synthesis of H-22 To a solution of H-26 (150 mg, 0.49 mmol), fluorene-9-carboxylic acid (124 mg, 0.588 mmol), and 4-dimethylaminopyridine (6.0 mg, 0.049 mmol) in dichloromethane (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) was added at room temperature, and the resulting mixture was stirred at the same temperature for 8 hours. Water was added to the mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, followed by filtration, and concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 6:1), to obtain H-22 as pale yellow crystals (191 mg, 0.384 mmol, 78 %). Regarding H-22, the NMR measurement spectrum and the result of mass spectrometry by HR-ESI-MS were as follows. 1H NMR (400 MHz, CDCl3) δ 3.26 (1H, dd, J = 14.2, 8.7 Hz), 3.45 (1H, dd, J = 14.2, 4.1 Hz), 4.85 (1H, s), 5.12 (1H, d, J = 12.3 Hz), 5.19 (1H, d, J = 12.3 Hz), 5.44 (1H, dd, J = 8.7, 4.1 Hz), 7.02 (1H, td, J = 7.3, 0.9 Hz), 7.12-7.21 (5H, m), 7.26-7.40 (5H, m), 7.43-7.53 (3H, m), 7.55 (1H, s), 7.66-7.73 (4H, m), 7.80-7.85 (1H, m); 13C NMR (100 MHz, CDCl3) δ 37.3, 53.0, 67.2, 73.6, 119.86, 119.88, 125.5, 125.6, 125.7, 126.0, 127.2, 127.3, 127.6, 127.7, 128.0, 128.12, 128.16, 128.19, 128.3, 128.4, 128.5, 133.1, 133.3, 135.0, 140.0, 140.1, 141.3, 141.4, 169.1, 170.5; HRESIMS calcd for C34H26O4Na [M+Na]+ 521.1729, found 521.1732. The chemical structure of H-22 found was as follows.
78%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h;	2.2-2 (Example 2-2) Synthesis of H-31 To a solution of H-26 (150 mg, 0.49 mmol), fluorene-9-carboxylic acid (124 mg, 0.588 mmol), and 4-dimethylaminopyridine (6.0 mg, 0.049 mmol) in dichloromethane (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) was added at room temperature, and the resulting mixture was stirred at the same temperature for 8 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 6:1) to give H-22 as a pale yellow crystal (191 mg, 0.384 mmol, 78%). (0191) The measured NMR spectrum and HR-ESI-MS result of H-22 are described below. 1H NMR (400 MHz, CDCl3) δ 3.26 (1H, dd, J = 14.2, 8.7 Hz), 3.45 (1H, dd, J = 14.2, 4.1 Hz), 4.85 (1H, s), 5.12 (1H, d, J = 12.3 Hz), 5.19 (1H, d, J = 12.3 Hz), 5.44 (1H, dd, J = 8.7, 4.1 Hz), 7.02 (1H, td, J = 7.3, 0.9 Hz), 7.12-7.21 (5H, m), 7.26-7.40 (5H, m), 7.43-7.53 (3H, m), 7.55 (1H, s), 7.66-7.73 (4H, m), 7.80-7.85 (1H, m); 13C NMR (100 MHz, CDCl3) δ 37.3, 53.0, 67.2, 73.6, 119.86, 119.88, 125.5, 125.6, 125.7, 126.0, 127.2, 127.3, 127.6, 127.7, 128.0, 128.12, 128.16, 128.19, 128.3, 128.4, 128.5, 133.1, 133.3, 135.0, 140.0, 140.1, 141.3, 141.4, 169.1, 170.5; HRESIMS calcd for C34H26O4Na [M+Na]+ 521.1729, found521.1732

Reference： [1]Current Patent Assignee: TOKYO UNIVERSITY OF PHARMACY AND LIFE SCIENCES - EP3549930, 2019, A1 Location in patent: Paragraph 0181-0184
[2]Current Patent Assignee: THE UNIVERSITY OF TOKYO - EP3679930, 2020, A1 Location in patent: Paragraph 0185; 0190-0192

74
[ 1989-33-9 ]
C₂₀H₁₈O₃ [ No CAS ]
C₃₄H₂₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 17h;	2-65 (Example 2-65) Synthesis of H-420 To a solution of H-414 (200 mg, 0.654 mmol), fluorene-9-carboxylic acid (165 mg, 0.785 mmol), and 4-dimethylaminopyridine (8 mg, 0.065 mmol) in dichloromethane (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.85 mmol) was added at room temperature, and the resulting mixture was stirred at room temperature for 17 hours. Water was added to the mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, followed by filtration, and concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 9:1), to obtain H-420 as a pale yellow oily substance (128 mg, 0.257 mmol, 39 %). Regarding H-420, the NMR measurement spectrum and the result of mass spectrometry by HR-ESI-MS were as follows. 1H NMR (400 MHz, CDCl3) δ3.52 (1H, dd, J = 14.6, 9.6 Hz), 3.74 (1H, dd, J = 14.6, 4.1 Hz), 4.79 (1H, s), 5.14 (2H, s), 5.46 (1H, dd, J = 9.6, 4.1 Hz), 7.10-7.15 (2H, m), 7.19-7.25 (4H, m), 7.29-7.52 (9H, m), 7.68-7.72 (2H, m), 7.77 (1H, d, J = 8.2 Hz), 7.85-7.89 (1H, m), 8.02-8.09 (1H, m); HRESIMS calcd for C34H26O4Na [M+Na]+ 521.1729, found 521.1730. The chemical structure of H-420 found was as follows.

Reference： [1]Current Patent Assignee: TOKYO UNIVERSITY OF PHARMACY AND LIFE SCIENCES - EP3549930, 2019, A1 Location in patent: Paragraph 0423-0426

75
[ 124-38-9 ]
[ 6630-65-5 ]
[ 1989-33-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With samarium; chloro-trimethyl-silane; tetra-(n-butyl)ammonium iodide In acetonitrile at 20℃; for 2h; Electrochemical reaction; Cooling with ice;

Reference： [1]Bazzi, Sakna; Schulz, Emmanuelle; Mellah, Mohamed [Organic Letters, 2019, vol. 21, # 24, p. 10033 - 10037]

76
[ 1989-33-9 ]
[ 68375-92-8 ]
C₁₈H₉⁽²⁾H₈BrO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 9H-fluorene-9-carboxylic acid With n-butyllithium In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: 1,4-dibromobutane-1,1,2,2,3,3,4,4-d<SUB>8</SUB> In tetrahydrofuran at 0 - 20℃; for 24h; Inert atmosphere;	1.2 Dissolve Compound 1 (4.2g, 20.0mmol) in 100ml of anhydrous tetrahydrofuran, under nitrogen protection, slowly add n-butyllithium (2.5M, 18mL) at 0 °C, incubate for 1 hour, then add Compound 2 (5.4 g, 24.1 mmol). After completion, the temperature was raised to room temperature for 24 h. The reaction was monitored. After the reaction was completed, 100 ml of ice water was added to the ice bath. The reaction solution was extracted with ethyl acetate (80 ml x 3). The organic phases were combined. It was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The crude column chromatography gave 4.8 g of compound 3 in 68% yield.

Reference： [1]Current Patent Assignee: NANJING SUSTGREEN BIOTECHNOLOGY - CN111187200, 2020, A Location in patent: Paragraph 0013-0014

77
[ 140695-07-4 ]
[ 1989-33-9 ]
C₂₈H₂₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 48h;	1-4 (Example 1-4) Synthesis of H-85 To a solution of H-34 hydrochloride (200 mg, 0.753 mmol) and 9-fluorenecarboxylic acid (174 mg, 0.83 mmol) in DMF (2 mL), N-methylmorpholine (229 mg, 0.25 mL, 2.26 mmol) at room temperature and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg, 0.98 mmol) at the same temperature were added, and the resulting mixture was stirred at the same temperature for 2 days. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate, 20:1) to give H-85 as a pale yellow powder (137 mg, 0.325 mmol, 43%).The measured NMR spectrum and HR-ESI-MS result of H-85 are described below. 1H NMR (400 MHz, CDCl3) δ 3.05 (1H, dd, J = 14.1, 6.4 Hz), 3.20 (1H, dd, J = 14.1, 5.5 Hz), 3.65 (3H, s), 4.75 (1H, s), 4.88 (1H, ddd, J = 7.8, 6.4, 5.5 Hz), 5.70 (1H, d, J = 7.8 Hz), 6.89 (1H, dd, J = 8.3, 1.9 Hz), 7.13-7.26 (3H, m), 7.34-7.48 (5H, m), 7.53-7.60 (3H, m), 7.70-7.79 (3H, m); HRESIMS calcd for C28H23NO3Na [M+Na]+ 444.1576, found 444.1575.

Reference： [1]Current Patent Assignee: TOKYO UNIVERSITY OF PHARMACY AND LIFE SCIENCES - EP3680233, 2020, A1 Location in patent: Paragraph 0173-0175

78
C₂₀H₁₉NO₂*HCl [ No CAS ]
[ 1989-33-9 ]
C₃₄H₂₇NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 48h;	1-8 (Example 1-8) Synthesis of H-105 To a solution of H-47 hydrochloride (280 mg, 0.82 mmol) and 9-fluorenecarboxylic acid (190 mg, 0.90 mmol) in DMF (2 mL), N-methylmorpholine (332 mg, 0.36 mL, 3.28 mmol) at room temperature and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg, 1.07 mmol) at the same temperature were added, and the resulting mixture was stirred at the same temperature for 2 days. Water was added to the mixture, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate, 10:1) to give H-105 as a white crystal (213 mg, 0.429 mmol, 52%).The measured NMR spectrum and HR-ESI-MS result of H-105 are described below. 1H NMR (400 MHz, CDCl3) δ 3.07 (1H, dd, J = 13.7, 6.4 Hz), 3.17 (1H, dd, J = 13.7, 5.4 Hz), 4.74 (1H, s), 4.93 (1H, ddd, J = 7.8, 6.4, 5.4 Hz), 5.00 (1H, d, J = 12.3 Hz), 5.08 (1H, d, J = 12.3 Hz), 5.71 (1H, d, J = 7.8 Hz), 6.80 (1H, dd, J = 8.7, 1.9 Hz), 7.09-7.18 (5H, m), 7.26-7.52 (10H, m), 7.68-7.76 (3H, m), 7.80-7.85 (1H, m); HRESIMS calcd for C34H27NO3Na [M+Na]+ 520.1889, found 520.1887.

Reference： [1]Current Patent Assignee: TOKYO UNIVERSITY OF PHARMACY AND LIFE SCIENCES - EP3680233, 2020, A1 Location in patent: Paragraph 0185-0187

79
2-(2,5-di(thiophen-2-yl)-1H-pyrrol-1-yl)ethanamine [ No CAS ]
[ 1989-33-9 ]
N-(2-(2,5-di(thiophen-2-yl)-1H-pyrrol-1-yl)ethyl)- 9H-fluorene-9-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at -2 - 20℃; Inert atmosphere;	2-(2,5-di(thiophen-2-yl)-1H-pyrrol-1-yl)ethanamine (55 mg, 0.20 mmol), fluorene 9-carboxylic acid (FCAc) (84 mg, 0.40 mmol) and 4-dimethylaminopyridine (DMAP) (6.0 mg, 0.05 mmol) were added to CH 2 Cl 2 (5.0 mL) under stirring and argon atmosphere. The mixture was cooled with ice-salt bath ( -2 to 0 °C). Then a so- lution of N, N’-Dicyclohexylcarbodiimide (DCC) (41 mg, 0.20 mmol) in CH 2 Cl 2 (10 mL) was added dropwise. After this, the ice bath was removed, and the reaction mixture stirred for 20 h at room temperature. Dicyclohexylurea precipitated and was removed by filtration. The filtrate was extracted with CH 2 Cl 2 (5 ×15 mL) and H 2 O, the organic solution was dried with anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel using hex- ane/ethyl acetate 8:2 as eluent, to afford SNSFCA as grayish solid (65 mg, 73% yield), Scheme 1 . m.p.: 191 ±1 °C; 1 H NMR (600 MHz, CDCl 3 , (ppm)) : 7.8 (d, J = 7.56 Hz, 2 H), 7.5 (dd, J = 0.72, 7.56 Hz, 2 H), 7.4 (t, J = 7.47 Hz, 2 H), 7.3 (d, J = 1.08, 7.47 Hz, 2 H), 7.2 (d, J = 1.08 Hz, 2 H), 7.0 (dd, J = 3.54, 5.16 Hz, 2 H), 6.9 (dd, J = 1.08, 3.54 Hz, 2 H), 6.3 (s, 2 H), 5.1 (s, 1 H), 4.7 (s, 1 H), 4.3 (t, J = 6.51 Hz, 2 H), 3.2 (q, J = 6.34 Hz, 2 H) (see Supplementary Material, Fig. S1); 13 C NMR (150 MHz, CDCl 3 , (ppm)): 172.0, 141.3, 141.1, 134.2, 128.6, 128.2, 127.7, 127.5, 126.2, 125.5, 125.4, 120.1, 111.4, 55.6, 43.8, 39.5 (see Supplementary Ma- terial, Fig. S2); FTIR (ATR) (cm -1 ) : 3270 and 3100 ( v N-H amide), 3060 ( v C-H aromatic ring), 2960-2850 ( v s C-H and v as C-H), 1652 ( v C = O amide), 1608 ( v C = C aromatic ring), 1540 ( v C-N and N-H amide), 1440 ( v C = C aromatic ring), 1210 ( v C-N amide), 1075 ( v C = C thiophene ring), 840 ( C-H / ’ thiophene ring), 730 ( C-H pyrrole ring) and 678 ( C-H thiophene ring) (see Supplementary Material, Fig. S3).

Reference： [1]Neto, Jorge L.; da Silva, Luis P.A.; da Silva, Joel B.; Ferreira, Raul L.; da Silva, Ana Júlia C.; da Silva, Júlio C.S.; de Oliveira, Ítalo N.; Lima, Dimas J.P.; Ribeiro, Adriana S. [Electrochimica Acta, 2021, vol. 379]

80
[ 1989-33-9 ]
4-ethylbenzene-1,2-dithiol [ No CAS ]
C₂₂H₁₈S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With indium(III) iodide; 1,1,3,3-Tetramethyldisiloxane In toluene at 60℃; for 3h; Inert atmosphere; Sealed tube;	Dithioacetalization of 9-Fluorenecarboxylic acid with Benzene-1,2-dithiols and Subsequent Oxidation of Dithioacetals: General Procedure General procedure: A magnetic stirrer bar, 9-fluorenecarboxylic acid (105 mg, 0.500 mmol), dithiol (0.6 mmol), InI3 (12 mg, 0.0025 mol), and TMDS (134 mg, 1.00 mmol) were successively added to a freshly distilled toluene solution (2.0 mL) in a screw-capped test tube under an N2 atmosphere. The test tube was sealed with a cap incorporating a PTFE septum and was then heated at 60 °C for 3 h. After the reaction, the resultant mixture was quenched with a saturated NaOH aqueous solution (3 mL). The aqueous layer was extracted with ethyl acetate (3 mL × 3).The combined organic phases were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford the crude dithioacetal, which then was dissolved in CH2Cl2 (10 mL). DDQ (300 mg, 1.30 mmol) was added, and the dark green solution was stirred at room temperature for 16 h. The resultant product was washed with saturated NaOH aqueous solution (5 mL) and CH2Cl2 (10 mL). The orange organic phase was dried over anhydrous Na2SO4, filtered, and then evaporated under reduced pressure. The crude solid was recrystallized from hexane to give the corresponding 9-(1,3-dithiol-2-ylidene)-fluorene derivative.