Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[CH:11]=[N:15]/[OH:16])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1
Reactant: CC1(C)OB(O)c2cc(C=O)ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2cc(/C=N/O)ccc21
Reaction time: 2 h

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (9.0 g, 47.4 mmol) and NH2OH.HCl (3.92 g, 56.9 mmol) in THF (100 mL) and H2O (25 mL) at rt was added NaOAc (5.83 g, 71.1 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude compound (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])=[CH:4][CH:3]=1.Cl.[Cl:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28]Cl>>[ClH:23].[N:1]1([C:2]2[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[NH:12][C:11]3=[O:21])=[CH:4][CH:3]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Agent: Cl
Product: O=C1NC(=O)c2ccccc2C1=CNc1ccc(N2CCNCC2)cc1
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A dry mixture of 4-[(4-Amino-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (140 mg, 0.5 mmol) and bis(chloroethyl)amine hydrochloride (90 mg, 0.5 mmol) is placed in a microwave at 900 W for 10 minutes. The crude product, 4-[(4-piperazin-1-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione hydrochloride (192 mg), thus obtained is used as such for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.FC(F)(F)C(O)=[O:33].[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline (compound 383) (30 mg) was dissolved in dichloromethane (1.5 ml) to prepare a solution. Trifluoroacetic acid (1 ml) was added to the solution at 0° C., and the mixture was then stirred at 0° C. for 2 hr. The reaction solution was made alkaline by the addition of a 1 N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (21 mg, yield 67%).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[NH:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1.O1CCCC1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>O>[CH3:3][CH:4]1[CH2:5][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:8][N:9]1[C:22]([O:23][CH2:24][CH3:25])=[O:26]
Reactant: CC1CN(Cc2ccccc2)CCN1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(Cc2ccccc2)CC1C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
580 Parts of a sodium hydroxide solution 1N in water were cooled in an ice bath and then there were added 44 parts of 3-methyl-1-(phenylmethyl)piperazine and 82.8 parts of tetrahydrofuran. A solution of 27.13 parts of ethyl carbonochloridate in 103.5 parts of tetrahydrofuran was added dropwise at a temperature at about 5° C. Upon completion, stirring was continued for 4 hours in an ice bath. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 55 parts (87.8%) of ethyl 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate as a residue (int. 36).
Reaction SMILES: [C:1]1(C=CC=C(O)C=1)O.COC1C=CC(C(Cl)=O)=CC=1.[OH:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:29].CI>>[OH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:1])[CH:24]=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:29]
Reactant: COc1ccc(C(=O)c2ccc(O)cc2O)cc1
Reactant: Oc1cccc(O)c1
Agent: COc1ccc(C(=O)Cl)cc1
Solvent: CI
Product: COc1ccc(C(=O)c2ccc(OC)cc2O)cc1

Procedure:
Synthesized from resorcinol and 4-methoxybenzoyl chloride according to an analogous synthetic method to Preparation Example 66, (2,4-dihydroxyphenyl)(4-methoxyphenyl)methanone (9.7 g) and methyl iodide (13.1 g) were used according to an analogous synthetic method to Example 383 to provide the title compound (7.0 g).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][CH:4]([CH3:27])[CH:5]([NH:10][C:11]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:12])[C:6]([O:8][CH3:9])=[O:7]>CCO.C1COCC1.O.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[S:14][C:13]([C:11]([NH:10][CH:5]([CH:4]([CH3:27])[CH3:3])[C:6]([O:8][CH3:9])=[O:7])=[O:12])=[N:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)s1)C(C)C
Temperature: 80 °C
Yield: 92.3 %

Procedure:
Ammonium chloride (1.04 g) and iron (777 mg) were added to a solution of Methyl 3-methyl-2-(5-(4-nitrophenyl)thiazole-2-carboxamido)butanoate (Intermediate 2, step C, 2.15 g) in EtOH (21.5 ml), THF (8.6 ml), and Water (8.6 ml). The reaction mixture was refluxed at 80° C. for 3 hours. It was then cooled, filtered through celite and the solvent was removed under reduced pressure to get dark brown residue. The residue was taken in water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and concentrated to get dark brown residue which was purified by column on silica gel in 2.5:7.5 EtOAc:chloroform to get yellow sticky solid which was crystallized in DCM/pet ether to yield 1.82 g (91%) of the title compound. 1HNMR (DMSO-d6, 300 MHz): δ 8.59 (d, 1H), 8.15 (s, 1H), 7.42 (d, 2H), 6.63 (d, 2H), 5.76 (bs, 2H), 4.31 (m, 1H), 3.67 (s, 3H), 2.27 (m, 1H), 0.91 (d, 6H); MS (ES+): m/z 334 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:18]1CCOCC1.ClC(OCC(C)C)=O>O1CCCC1>[C:14]([C@@H:9]1[CH2:10][C:11](=[CH2:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:16])[NH2:18]
Reactant: CN1CCOCC1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
(S)-1-(tert-Butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (1.05 g, 4.48 mmol) and N-methylmorpholine (0.64 mL, 5.83 mmol) were dissolved in tetrahydrofuran (25 mL) and cooled to −15° C. in a dry ice/acetone bath. Isobutyl chloroformate (0.65 mL, 4.93 mmol) was added dropwise and the solution was stirred for 15 minutes. The internal temperature was lowered to −25° C. and ammonia (g) was bubbled through the solution for 2 minutes, then the flask was transferred to an ice bath and stirred for another 20 minutes. The solution was poured into brine and extracted into ethyl acetate, dried over magnesium sulfate, filtered and concentrated. This residue was triturated with ether/hexanes, filtered, and dried to give 0.97 g (81%) of (S)-tert-butyl 2-carbamoyl-4-methylenepyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:17]([S:19]Cl)=[O:18]>>[O:18]=[C:17]1[NH:1][C:2]([C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:19]1
Reactant: O=C(Cl)SCl
Reactant: CCOC(=O)C=C(N)C(F)(F)C(F)(F)F
Product: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 46.3 %

Procedure:
Preparation of Ethyl 2-Chloro-4-Pentafluoroethyl-5-Thiazolecarboxylate To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil; dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo -4-pentafluoroethyl-5-thiazole-carboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoro-ethyl-5-thiazolecarboxylate, nD25 =1 4460.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[N:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[N:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2nn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2nn1

Procedure:
Ethyl 6-nitrocinnolin-3-yl carboxylate (150 mg.) was dissolved in ethanol (20 ml.), and 30% w/w palladium on charcoal catalyst (20 mg.) was added. The solution was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure until the theoretical uptake had taken place. The catalyst was filtered off and the ethanol solution was evaporated to dryness, yielding a yellow solid. This solid was purified by chromatography on a column of Kieselgel 60 (E. Merck, Darmstadt) using ethyl acetate as eluent. The appropriate fractions were combined and evaporated to dryness to give ethyl 6-aminocinnolin-3-yl carboxylate, m.p. 204°-206° C.
Reaction SMILES: [F:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([F:7])[C:3]([F:6])([F:5])[F:4].[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>>[N+:14]([C:10]1[CH:9]=[C:8]([C:2]([F:7])([F:1])[C:3]([F:5])([F:4])[F:6])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)C(F)(F)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(C(F)(F)C(F)(F)F)c1
Temperature: 45 °C

Procedure:
74 G. (0.4 moles) of pentafluoroethylbenzene is cooled to 5° C. and treated dropwise with a mixture of 22 g. (0.33 moles) of concentrated nitric acid and 33 g. (0.32 moles) of concentrated sulfuric acid. The temperature is maintained at 5°-15° C. during the 1 hour addition period and then raised to 45° C. for 1 hour. The reaction mixture is cooled and poured onto ice. The aqueous mixture is extracted with ether, the ether extracts washed with water, dried over sodium sulfate, and the residue is distilled at 0.35 mm. of Hg at 74°-75° C. The yield is 84 g. (87%) of m-nitro-pentafluoroethylbenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C(Cl)Cl>[CH3:16][S:17]([N:6]1[CH:5]=[C:4]([NH2:1])[CH:8]=[N:7]1)(=[O:19])=[O:18]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1cc(N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (250 mg, 2.2 mmol) in DCM (5 mL) were added triethylamine (0.46 mL, 1.5 eq) and methanesulfonyl chloride (0.20 mL, 1.2 eq). After stirring for 1 h at rt, water was added and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 5 mL methanol and palladium on carbon added under an inert atmosphere. The reaction mixture was stirred overnight at rt under an hydrogen atmosphere. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give 1-(methylsulfonyl)-1H-pyrazol-4-amine as a brown oil (0.34 g, 2.1 mmol, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][CH3:17].C([Li])CCC.[P:23](Cl)([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[P:23](=[O:24])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]
Reactant: COc1cccc(OC)c1-c1ccccc1Br
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Product: CCOP(=O)(OCC)c1ccccc1-c1c(OC)cccc1OC
Temperature: -78 °C
Yield: 65 %

Procedure:
To a 250-mL round-bottom flask equipped with a magnetic stir bar was added 2′-bromo-2,6-dimethoxybiphenyl (see Buchwald S L, Journal of the American Chemical Society 2005; 127:4685-4696) (7.02 g, 24.0 mmol, 1 equiv). Degassed, anhydrous tetrahydrofuran was added (80 mL) followed by N,N,N′,N′-tetramethylethylene-1,2-diamine (4.31 mL, 28.7 mmol, 1.2 equiv). The resulting solution was cooled to −78° C., and then n-butyllithium (11.5 mL, 28.7 mmol, 1.2 equiv, 2.5 M in hexanes) was added in a dropwise fashion. After the addition of 5 mL of n-butyllithium the reaction slurry could no longer be stirred. The reaction flask was warmed to 0° C. at which point the slurry became free-flowing. The remainder of the n-butyllithium (˜6.5 mL) was added over the course of 10 minutes. The reaction was stirred for 90 minutes at 0° C., and then the aryllithium intermediate was quenched with diethyl chlorophosphate (4.15 mL, 28.7 mmol, 1.2 equiv). The reaction was re-cooled to −78° C. and stirred for 1 hour, then the cooling bath was removed and the flask was warmed to room temperature. At that point, the reaction solution was diluted with pH 7 phosphate buffer (100 mL). The reaction mixture was worked up by separating the phases and washing the aqueous layer with ethyl acetate (4×60 mL). The combined organic fractions were then washed once with brine (150 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by column chromatography (120-g column; gradient: 1.5 column volumes dichloromethane, ramp up to 88:12 dichloromethane:acetone over 10.5 column volumes, hold at 88:12 for 6 column volumes), the product was isolated as a white solid (5.49 g, 78 area % by HPLC, 65% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (dd, J=14.1, 7.7 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.46-7.37 (m, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.24-7.18 (m, 1H), 6.60 (d, J=8.4 Hz, 2H), 3.98-3.77 (m, 4H), 3.70 (s, 6H), 1.17 (t, J=7.1 Hz, 6H). 31P NMR (CDCl3, 202 MHz) δ ppm 15.2 (s).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][C:37]([F:49])([F:48])[C:38]([F:47])([F:46])[C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:30]([O:32]CC)=[O:31])([CH3:13])[C@@H:11]([OH:50])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][C:37]([F:48])([F:49])[C:38]([F:46])([F:47])[C:39]([F:44])([F:45])[C:40]([F:41])([F:42])[F:43])[C:30]([OH:32])=[O:31])([CH3:13])[C@@H:11]([OH:50])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@@H]12)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@]12C[C@H](CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 60 °C
Yield: 83.7 %

Procedure:
Ethyl 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate (747 mg, 1.02 mmol) was dissolved in a mixed solvent of ethanol (5 ml) and water (5 ml). To this solution, NaOH (82 mg, 2.04 mmol) was added, and the resulting mixture was heated for 15 hours at 60° C. After cooling, 2N aqueous hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→3/1→2/1) to give 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid (600 mg, Yield 84%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>C1(C)C=CC=CC=1>[C:10]12([C:6]3[CH:7]=[C:8]([C:10]45[CH2:19][CH:14]6[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]6)[CH2:11]4)[CH2:17]5)[C:1]([OH:2])=[CH:3][C:4]=3[OH:5])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2
Reactant: Oc1cccc(O)c1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Product: Oc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 110 °C
Reaction time: 48 h
Yield: 13.5 %

Procedure:
Into a 250-mL 3-neck flask, equipped with nitrogen inlet, thermocouple and condenser, were added resorcinol (11.00 g, 100.0 mMol), bromoadmantane (44.02 g, 205.1 mMol) and toluene (150 mL). The mixture was heated to 110° C. and became a clear solution. The reaction was allowed to continue for 48 h, at which time TLC showed that all the resorcinol had disappeared. The solvent was removed and the solid was crystallized from hexanes (150 mL). The disubstituted product was obtained in 66.8% yield (25.26 g) as a white solid. Another 5.10 g product was obtained by silica gel column chromatography of the concentrated mother liquor after the first crop. The total yield of the product was 80.3%. Characterization of the product was by proton NMR, HPLC, FTIR and MS.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][N:24]([CH3:27])[S:23]3(=[O:29])=[O:28])[CH:18]=2)[NH:13][CH:12]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][N:24]([CH3:27])[S:23]3(=[O:29])=[O:28])[CH:18]=2)[NH:13][CH:12]=1
Reactant: CN1CCN(CCc2ccc3[nH]cc(CCNC(=O)OC(C)(C)C)c3c2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CCc2ccc3[nH]cc(CCN)c3c2)S1(=O)=O
Yield: 53.2 %

Procedure:
A solution of the product from Step 1 (916 mg) in anhydrous dichloromethane (15 ml) and trifluoroacetic acid (4.5 ml) was stirred at room temperature under a nitrogen atmosphere for 1 hour. Solvents were removed under vacuum and the residue was azeotroped with toluene-methanol. Flash chromatography of the crude product (silica gel, dichloromethane-methanol-ammonia, 90:10:1) gave 372 mg (59%) of the title compound as a colourless thick oil which solidified on standing; δH (250 MHz, CDCl3) 8.16 (1H, br s, indole N--H), 7.45 (1H, s, Ar--H), 7.28 (1H, d, J=8.3 Hz, Ar--H), 7.05 (1H, dd, J=8.3 and 1.5 Hz, Ar--H), 7.02 (1H, d, J=1.8 Hz, Ar--H), 3.35 (2H, dd, J=9.8 and 7.1 Hz, --CH2N--), 3.26 (4H, s, --NCH2CH2N-- ), 3.08--2.99 (4H, m, --CH2 --), 2.88 (2H, t, J=6.2 Hz, Ar--CH2CH2NH2), 2.75 (3H, s, --NMe); m/z (CI) 323 (M+ +1). (Found: m/z 323.1543. C15H23N4O2S requires: m/z 323.1542).
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1)#N.[OH-:24].[Na+].[CH2:26]([OH:28])[CH3:27].Cl>O>[C:26]([C:27]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1)([OH:24])=[O:28]
Reactant: CCO
Reactant: CCOC(=O)Cc1ccc2occ(-c3ccc(C#N)cc3)c2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc2occ(-c3ccc(C(=O)O)cc3)c2c1

Procedure:
A mixture of 5 g. of the product of step A in 50 ml. of 30 percent sodium hydroxide solution and 20 ml. of ethanol is heated at its reflux temperature for 30 minutes, and 75 ml. of water is added. The solution is heated at its reflux temperature for three hours, then poured into 125 ml. of 6 N hydrochloric acid. The solid is separated by filtration and recrystallized from acetic acid to provide 3-(4-carboxyphenyl)benzofuran-5-acetic acid, m.p. 278°-281° C.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@@H:6]1[C@@H:5]2[CH2:1][C@@H:2]([CH:3]=[CH:4]2)[C@@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
The title compound was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-endo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (610 mL). The mixture was stirred for 10 min. Quinine (10.87 g, 33.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred at −55° C. for 16 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (400 mL). The layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×200 mL), aqueous saturated brine solution (100 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.95 g, 30.3 mmol, 99% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.31 (1H, d, J=8.5 Hz), 1.98 (1H, d, J=8.6 Hz), 2.51 (2H, d, J=1.6 Hz), 2.95 (2H, bs), 3.52 (3H, s), 6.17-6.21 (2H, m), 12.16 (1H, s).