Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CCC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:19]([O:11][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=1[F:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCBr
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCCCOc1c(F)c(F)cc(F)c1F
Yield: 99.6 %

Procedure:
To 20.0 g of 2,3,5,6-tetrafluorophenol (1) dissolved in 100 mL of MEK there were added 18.3 g of potassium carbonate, 4.26 g of TBAB and 25.6 g of bromooctane dissolved in 50 mL of MEK, with heating under reflux for 4 hours. After cooling and addition of water, the organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 33.4 g (120 mmol) of 4-octyloxy-2,3,5,6-tetrafluorobenzene (8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[CH3:10].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=O.C>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][C:11]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH3:10]
Reactant: COc1ccc(N)cc1C
Reactant: COC(=O)C=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CNc1ccc(OC)c(C)c1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 4-methoxy-3-methylaniline (5 g, 0.0364 mol), methyl glyoxylate (5.5 g, 0.0619 mol) and palladium over charcoal (3.7 g; 10%) in methanol (300 ml) was stirred under a hydrogen atmosphere for 1 hour. The suspension was filtered through hyflo and evaporated to give a yellow solid. This was triturated with ether at ~-78° C. and filtered to give the title compound as a pale yellow solid (3.8 g, 50%) m.p. 69°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[CH:8][CH:7]=[C:6]2Br.C([Li])(C)(C)C.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([OH:32])([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc2cccc(Br)c2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C3(O)CCN(Cc4ccccc4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A solution of 5.0 gm (21.1 mMol) 6-methoxy-4-bromonaphthalene in 120 mL tetrahydrofuran was first cooled to −78° C. and then 27.3 mL (46.4 mMol) tert-butyllithium (1.7 M in pentane) were added and the resulting solution stirred for about 1.5 hours. At this point a solution of 4.1 mL (22.1 mMol) 1-benzylpiperidin-4-one in 30 mL tetrahydrofuran was added and the reaction mixture was allowed to warm gradually to room temperature. After 3 hours the reaction was quenched by the addition of 2 N sodium hydroxide. The resulting mixture was extracted with diethyl ether. The organic extracts were combined, washed with saturated aqueous sodium chloride, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 0 to 2% methanol. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to provide 4.62 gm (63%) of the desired compound as a white solid.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:4]([NH:6][C@H:7]([C:15]([O:17]C)=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].O[Li].O.N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C(NCC(OCC1C=CC=CC=1)=O)=O)CC1C=CC=CC=1)=O)C.C(=O)(O)[O-]>C1COCC1.O>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:4]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To methyl ester 21 (1.64 g, 4.27 mmol) dissolved in 25 mL of THF and cooled to 0° C. was added LiOH.H2O (0.25 g, 140 mol %) dissolved in 8 mL of water. The resulting solution was cooled to 0° C., added to the THF solution of 27, stirred at 0° C. for 0.5 h, then poured into 50 mL of saturated aqueous bicarbonate. The basic mixture was then extracted with 50 mL of ether which was discarded. The water layer was acidified with 1N HCl to pH 2 and extracted with 2×100 mL of ether. The organic extracts were combined, dried, and evaporated to give a thick white foam, which was crystallized from ether/hexane affording 1.53 g, 97% of 11 as a white powder; mp 126°-127° C.; [α]25D +39.8° (c 2.1, CHCl3); 1H NMR δ 11.5-11.1 (br s, 1H), 7.40-7.10 (m, 10H), 6.80 (d, 1H, J=5), 5.49 (d, 1H, J=4), 5.07 (s, 2H), 4.49-4.46 (m, 1H), 4.25-4.23 (m, 1H), 3.18 (dd, 1H, J=14, 5.5), 3.03 (dd, 1H, J=14, 6.5), 1.28 (d, 3H, J=7). Anal. Calcd for C24H22N3O5 : C, 64.8; H, 6.0,; N, 7.6. Found: C, 64.8; H, 6.0; N, 7.4.
Reaction SMILES: N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:22]1[CH2:26][CH2:25][NH:24][C:23]1=[O:27].Br[C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1>C(Cl)(Cl)Cl.[Cu](I)I.CO.O1CCOCC1>[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:22]1[CH2:26][CH2:25][N:24]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[C:23]1=[O:27]
Reactant: Brc1ccc2ccccc2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3ccccc3c2)C1=O
Temperature: 110 °C
Yield: 72.9 %

Procedure:
Copper iodide (21.5 mg, 0.113 mmol), trans-1,2-diamino cyclohexane (0.041 mL, 0.339 mmol) and potassium carbonate (313 mg, 2.26 mmol) were added to 1,4-Dioxane (15 mL) previously sparged with argon (10 minutes). The reaction mixture was sparged with argon for a further 10 minutes, followed by the addition of 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 200 mg, 1.13 mmol) and 2-bromo naphthalene (234 mg, 1.13 mmol). The resulting mixture was heated to reflux at 110° C. for 15 hours. The reaction was monitored by TLC (10% MeOH in chloroform). The reaction mixture was filtered through a celite and the bed was washed with chloroform. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography (using silica gel of mesh size of 60-120, 1% MeOH in chloroform as eluent) afforded 250 mg (73% yield) of 1-(4-methyl-pyridin-3-yl)-3-naphthalen-2-yl-imidazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].O.[NH3:18]>O1CCOCC1>[NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([NH2:18])=[O:8]
Reactant: N
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])cc1OC
Solvent: C1COCCO1
Solvent: O
Product: COc1cc([N+](=O)[O-])c(N)cc1C(N)=O
Reaction time: 40 h

Procedure:
To a solution of 5.66 g of methyl 5-amino-2-methoxy-4-nitrobenzoate in 200 ml of dioxane was added 50 ml of 28 % ammonia water, and then the mixture was allowed to stand at room temperature for 40 hours. The solvent was evaporated under reduced pressure, and the residue was recrystallized from dioxane to give the title compound, m.p. 250°-257° C., yield of 4.30 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:16]1[C:15]([O:21][CH3:22])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1c(Cl)cccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(Cl)cccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of 4-(3-chloro-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (273 mg, 0.835 mmol) in CH2Cl2 (4 mL) was added TFA (4 mL) at RT. The reaction was stirred at room temperature for 1 hour and concentrated to give a reddish brown oil. Purification by SiO2 chromatography (10% MeOH/CH2Cl2 with 1% NH4OH) gave 1-(3-Chloro-2-methoxy-phenyl)-piperazine as a pale yellow solid/oil (137 mg, 0.604 mmol, 72%). MS: APCI: M+1: 227.1 (Exact Mass: 226.09).
Reaction SMILES: [I-].C(C[P+](C)(C)C)#N.[S:9]1[C:13]2[CH:14]=[C:15]([CH2:18]O)[CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1.[CH:20]1[NH:26][C:25]2[N:27]([C@@H:30]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:32]([OH:37])[C@H:31]3[OH:38])[CH:28]=[N:29][C:24]=2[C:22](=[S:23])[N:21]=1.CCN(C(C)C)C(C)C>C(#N)CC.O.CN(C=O)C>[S:9]1[C:13]2[CH:14]=[C:15]([CH2:18][S:23][C:22]3[N:21]=[CH:20][N:26]=[C:25]4[C:24]=3[N:29]=[CH:28][N:27]4[C@@H:30]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:32]([OH:37])[C@H:31]3[OH:38])[CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1
Reactant: OCc1ccc2ncsc2c1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(=S)nc[nH]c32)[C@H](O)[C@@H]1O
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: O
Product: OC[C@H]1O[C@@H](n2cnc3c(SCc4ccc5ncsc5c4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
(Cyanomethyl)trimethylphosphonium iodide (45 mg) was added to a mixture of 40 (Burger, A.; Sawhney, S. N. J. Med. Chem. 1968, 11, 270-273) (33 mg, 0.2 mmol), 6-mercaptopurine riboside (42 mg, 0.2 mmol) and DIPEA (0.04 ml) in 0.43 ml of propionitrile. The mixture was heated at 90° C. and few drops of DMF were added to obtain a clear solution. Stirring was continued overnight at 90° C. The mixture was cooled to room temperature, water was added and slowly a pale brown precipitate was formed. The solid was collected and dried under vacuum. 1H NMR (CD3OD): δ9.20, 8.74 (2×s, 2H), 8.59 (s, 1), 8.18 (s, 1H), 7.98 (d, 1H, J=8.78 Hz), 7.67 (d, 1H, J=8.77 Hz), 6.07 (d, 1H, J=5.11 Hz), 4.84 (s, 2H), 4.72 (m, 1H), 4.35 (m, 1H), 4.17 (m, 2H), 3.83 (m, 1H);13C-NMR (CDCl3/d6-DMSO): 6161.5, 157.1, 153.5, 152.8, 149.5, 144.6, 137.4, 135.2, 129.0, 124.0, 123.7, 90.6, 87.6, 75.7, 72.2, 63.0, 33.2, 19.4; Mp=decomp. 140° C.; HRMS calc. for C18H18N5O4S2 m/Z=432.5100 (M+H), found 432.0787.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[O:15]=[C:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1>C1COCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 1-bromo-4-methoxybenzene (0.88 g, 4.7 mmol) in THF (50 mL) was added n-butyllithium (2.9 mL, 4.7 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 2 h, then added to a flask containing tert-butyl 4-oxoazepane-1-carboxylate (1 g, 4.7 mmol) in THF, cooled to −78° C. The reaction mixture was stirred at −78° C. for 30 min and then at 0° C. for 15 min. It was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate as the eluant to yield tert-butyl 4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate (0.68 g, 45%). LCMS: R.T. 0.96 min. LCMS (ES-API), m/z 320 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=CC=2OC)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].C1(NN)CCC1>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Agent: NNC1CCC1
Product: N#Cc1cnn(C2CCC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-cyclobutylhydrazine provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.50 (s, 1H), 4.48-4.40 (m, 1H), 4.23 (m, 2H), 2.70-2.58 (m, 2H), 2.48-2.35 (m, 2H), 1.97-1.79 (m, 2H). MS: (M+H m/z 163.1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1(B2OC(C)(C)C(C)(C)O2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1C1=CCCCC1
Temperature: 80 °C
Yield: 38.6 %

Procedure:
A solution of 1.00 g (6.31 mmol) of 2-chloro-3-nitro-pyridine in toluene (50 mL) and EtOH (25 mL) was treated with 1.58 g (7.57 mmol) of 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 25.2 mL (50.4 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 729 mg (0.631 mmol) of Pd(PPh3)4, and heated to 80° C. for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with water (1×75 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with CH2Cl2 afforded 497 mg (39%) of the title compound as a yellow solid: 1H-NMR (CD3OD; 400 MHz): δ 8.70 (dd, 1H, J=5.2, 1.6 Hz), 8.20 (dd, 1H, J=8.4, 1.6 Hz), 7.51-7.46 (m, 1H), 5.81 (sept, 1H, J=2.4 Hz), 2.44-2.37 (m, 2H), 2.19-2.12 (m, 2H), 1.84-1.76 (m, 2H), 1.74-1.66 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([Cl:11])[CH:3]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:6]=2[CH:5]=[C:4]([Cl:11])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1cc(Br)c2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc2c(Br)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 4-bromo-6-chloro-1H-benzo[d]imidazole 109c (3.5 g, 15 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (360 mg, 15 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (2.7 g, 16.5 mmol). The reaction was stirred at room temperature for 2 h. Water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×80 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 116a as a brown solid (4.2 g, 77%). MS-ESI: [M+H]+ 361.0
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([F:21])[CH:20]=1>>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:13])[CH:11]=[N:12][C:2]=1[O:22][C:17]1[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=1)[CH3:8]
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Product: CCOC(=O)c1cc(F)cnc1Oc1cc(F)cc(F)c1
Yield: 23 %

Procedure:
The title compound was prepared from ethyl 2-chloro-5-fluoronicotinate and 3,5-difluorophenol in 23% yield following the procedure described in preparation 72.
Reaction SMILES: [C:1]([S:9][CH:10]([CH:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:17]([O:19]C(C)(C)C)=[O:18])[CH2:11][C:12]([NH:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([S:9][CH:10]([CH:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:17]([OH:19])=[O:18])[CH2:11][C:12]([NH:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CC(SC(=O)c1ccccc1)C(CC(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)CC(SC(=O)c1ccccc1)C(CC(C)C)C(=O)O

Procedure:
2-(1-Benzoylmercapto-2-[methylaminocarbonyl]ethyl)-4-methylpentanoic acid, tert-butyl ester (D11; 0.5 g) was treated with trifluoroacetic acid (10 ml) at 0° C. for 2h and evaporated to dryness in vacuo to give 2-(1-benzoylmercapto-2-[methylaminocarbonyl]ethyl)4-methylpentanoic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1>ClCCl.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:19][CH:20]=1
Reactant: O=C(O)C(=O)c1ccc(C#CCOc2ccc3ccccc3c2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: O=C(O)C(=O)c1ccc(CCCOc2ccc3ccccc3c2)cc1
Yield: 63.1 %

Procedure:
A suspension of 4-[3-(2-naphthalenyloxy)-1-propynyl]-alpha-oxobenzeneacetic acid (0.13 g) in dichloromethane (19 mL) was hydrogenated over 10 % palladium on carbon (0.016 g) at atmospheric pressure. The resulting mixture was filtered twice through a pad of celite to remove insoluble materials, then the tiltrate was evaporated and the residue was crystallized from ethyl acetate-hexane to afford 0.083 g of 4-[3-(2-naphthalenyloxy) propyl]-alpha-oxobenzeneacetic acid, mp 151°-154° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](O)=O.[Li+].[Cl-].[Li][O:16][C:17]([CH3:19])=O.Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:4]([C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[O:16][CH2:17][C:19]1[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]=1)[CH:5]=[CH2:6]
Reactant: O=C(O)C=Cc1ccccc1Br
Reactant: [Li]OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=CCc1ccccc1OCc1ccccc1

Procedure:
A mixture containing 2-bromocinnamic acid (250 mg, 1.10 mmol), the product of step 1 (271 mg, 1.1 equiv.), Pd(OAc)2 (8 mg, 0.03 equiv.), LiCl (47 mg, 1 equiv.), LiOAc (280 mg, 2.5 equiv.) and Bu4NCl (611 mg, 2 equiv.) in DMF (2 ml) was degassed and heated to 100 C. o.n. 0.5 N HCl was then added and the product was extracted in EtOAc, washed with 0.5 N HCl, dried over Na2SO4 and concentrated to dryness. Recrystallization from ether:hexane afforded the title product as a white solid. Yield: 251 mg, 62%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>CO.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Br)cc(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(OC)cc(-c2cccc(F)c2)c1
Temperature: 70 °C
Yield: 88 %

Procedure:
A suspension of methyl 3-bromo-5-methoxy-benzoate (3.2 g, 13.1 mmol, 1.0 eq), 3-fluorophenylboronic acid (2.0 g, 14.4 mmol, 1.1 eq) K2CO3 (7.2 g, 52.2 mmol, 4.0 eq) and Pd(PPh3)4 (754 mg, 0.65 mmol, 0.05 eq) in a mixture of methanol (10 mL) and dioxane (50 mL) was heated at 70° C. for 4 h under N2. After cooling, the resulting mixture was concentrated and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:20) to give the title compound as an oil (3.0 g, 88%).
Reaction SMILES: C(=O)([O-])[O-].[CH:5]1[C:10](N=C=S)=[CH:9][C:8]2[C:14]([O:16][C:17]3([C:27]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=4[O:25][C:19]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:18]3=4)[C:7]=2[CH:6]=1)=[O:15].C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O)(=O)C.O=C[C@@H]([C@H]([C@@H]([C@@H](C(O)=O)O)O)O)O.C1(=O)OC(=O)CC1>O.CS(C)=O>[CH:5]1[CH:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]([C:17]2[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[O:25][C:26]3[C:27]=2[CH:28]=[CH:29][C:30]([CH:31]=3)=[O:32])[CH:6]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The HA-AM obtained in the aforementioned (Example 5-1) was dissolved in distilled water (Milli Q water), so as to prepare a solution of a concentration of 20.0 mg/ml. Thereafter, a 0.2 M carbonate buffer (pH 9.0) was added to the prepared solution, resulting in a concentration of 10.0 mg/ml. Thereafter, fluorescein isothiocyanate (hereinafter also referred to as “FITC”; manufactured by Pierce) that was 0.07 mole times to an HA unit (1 unit=a repeating unit, N-acetylglucosamine-glucuronic acid) was dissolved in DMSO that was 1/10 the volume of an HA-AM solution. The DMSO solution was then added to the above solution, and the obtained mixture was then stirred in the dark at room temperature for 1 hour. Thereafter, succinic anhydride (manufactured by Wako Pure Chemical Industries, Ltd.) that was 40 mole times to the HA unit was dissolved in DMSO that was 1/10 the volume of the HA-AM solution. The DMSO solution was then added to the above solution, and the obtained mixture was then stirred in the dark at room temperature for 30 minutes. Thereafter, the resultant was roughly purified by gel filtration using a PD-10 column (manufactured by Amersham Biosciences), and it was then dialyzed against large excess amount of 0.5 M NaCl aqueous solution for purification (Spectrapore 4; molecular weight cut off (MWCO): 12 k-14 kDa). Furthermore, the external dialysis solution was exchanged with large excess amount of distilled water (Milli Q water), and dialysis was carried out in the dark for purification. The obtained aqueous solution was freeze-dried, so as to obtain fluorescein-labeled HA-AM-SUC.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=1>[OH-].[Na+]>[O:15]([C:7]1[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][C:6]=1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CNS(=O)(=O)c1cc(C(=O)OC)cc(N2CCCC2)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CNS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1

Procedure:
54 g of the methyl ester obtained according to (b) are suspended in 50 ml of 1 N NaOH and heated, while stirring, on the steam bath. When a clear solution has formed, the whole is allowed to cool and the free acid is precipitated with the aid of 1 N-HCl. The 4-phenoxy-3-(1-pyrrolidinyl)-5-methylsulphamoylbenzoic acid melting at 245°-248° C. with decomposition is obtained by recrystallisation from methanol/water.