Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)C=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:54](=O)=O>CS(C)=O>[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH:54]=[CH:10][CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])[CH:43]=[CH:44][C:45]=1[O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 2 g of oily sodium hydride (60%) and 90 ml of dimethyl sulfoxide was stirred for 1 hour at 55°-60° C. and then allowed to cool to room temperature. To the mixture was added dropwise a mixture of 11 g of (4-carboxybutyl)triphenylphosphonium bromide and 25 ml of dimethyl sulfoxide at room temperature. Thereafter, the mixture was stirred for 30 minutes at room temperature and then to the reaction mixture was added dropwise a mixture of 8 g of 3,4-dibenzyloxybenzaldehyde and 30 ml of dimethyl sulfoxide. After further stirring the mixture for one hour at room temperature, 5 g of dry ice was added to the reaction mixture and after further adding thereto 250 ml of water and 50 ml of an aqueous 10% hydrochloric acid solution, the product was extracted with 300 ml of ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide a sticky product. The product was applied to silica gel (150 ml) column chromatography and eluted with a mixture of n-hexane and ether (1:1) to provide 8.5 g of 6-(3,4-dibenzyloxyphenyl)-5-hexenoic acid. The product was dissolved in 30 ml of ethanol and catalytically reduced using 1 g of 10% palladium-carbon as a catalyst until the absorption of hydrogen stopped. Then, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to provide 3.8 g of 6-(3,4-dihydroxyphenyl)hexanoic acid. Melting point 109° C. ##STR53##
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[CH2:20][CH3:21])C.[BH4-].[Li+]>O1CCCC1>[Br:19][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([CH2:20][CH3:21])[CH:15]=1)[NH:12][C:11]1[C:6]([CH2:5][CH2:4][OH:3])([CH2:22][CH3:23])[O:7][CH2:8][CH2:9][C:10]2=1
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(CC)cc(Br)cc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(Br)cc2c3c([nH]c12)C(CC)(CCO)OCC3
Temperature: 90 °C
Yield: 81.7 %

Procedure:
To a solution of (6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (5.2 g, 13.2 mmol) in tetrahydrofuran at room temperature under nitrogen was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was heated at 90° C. (oil bath) for 5 hours. After cooling to room temperature, it was quenched with 5% hydrochloric acid solution until the excess lithium borohydride was destroyed. Water was added and the mixture extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50% ethyl acetate/hexane) to give the title compound (3.80 g, 82% yield). 1H NMR (CDCl3) δ 8.07 (s, 1H), 7.64 (d, 1H), 7.26 (d, 1H), 4.17 (m, 2H), 3.86 (m, 2H), 2.94 (m, 3H), 2.87 (dt, 1H), 2.76 (t, br, 1H), 2.36 (m, 1H), 2.24 (m, 1H), 2.13 (m, 2H), 1.49 (t, 3H), 1.08 (t, 3H). ES-MS (m/z) 352 [M+1]+, 350 [M−1]−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[O:32][CH:33]=2)[N:3]=1.O>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:22][OH:21])=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[O:32][CH:33]=2)[N:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(OCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(N)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
65 mg (0.12 mmol) of the compound from Example 101A are dissolved in 6 ml of acetic acid, and 3 ml of water are added. The mixture is stirred at RT for 30 min. The mixture is then heated to 70° C. and stirred at this temperature for a further 30 min A clear solution is formed. The mixture is then freed from the solvent on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=1.C([Li])CCC.[C:42](Cl)(=[O:48])OCC(C)C.C([N:52](CC)CC)C.N>C1(C)C=CC=CC=1.CO.CCCCCC>[Si:20]([O:19][CH:9]([C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:42]([NH2:52])=[O:48])=[N:3][CH:4]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)ncc1C(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1c(F)ccc(F)c1F
Reactant: CC(C)COC(=O)Cl
Agent: N
Agent: [Li]CCCC
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(C(N)=O)ncc1C(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1c(F)ccc(F)c1F
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a solution of 2-bromo-5-[[[tert-butyl(diphenyl)silyl]oxy](2,3,6-trifluoro phenyl)methyl]-4-methylpyridine (75.6 g, 133 mmol) in toluene (1200 ml), a hexane solution of n-butyllithium (1.60 M, 99.4 ml, 159 mmol) was added in an argon atmosphere at −78° C. The reaction mixture was stirred for 30 minutes at −50° C., and then cooled again to −78° C., and carbon dioxide was bubbled therein. After stirring for 30 minutes at the same temperature, the reaction mixture was allowed to warm to 0° C., water and then 1 N hydrochloric acid were added thereto, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (1000 ml), and isobutyl chlorocarbonate (25.3 ml, 195 mmol) and then triethylamine (36.2 ml, 260 mmol) were added thereto at −5° C. After stirring the mixture for 30 minutes at the same temperature, a 7 N methanol solution of ammonia (100 ml, 700 mmol) was added, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the resulting residue. After the organic layer was separated, the organic layer was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, and the organic layer was dried over anhydrous sodium sulfate and filtered. Subsequently, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain the title compound (50.0 g, 93.5 mmol, 70%) as a pale brown oily substance.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:53](O)=[O:54])[C:48]1=[O:60])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:58])([CH3:57])[CH3:59])[C:53]([NH:1][C@@H:2]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:54])[C:48]1=[O:60])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 70A (0.013 g, 0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.224 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 5% methanol in ethyl acetate to give the title compound (0.009 g, 30% yield). 1H NMR (300 MHz, CDCl3), δ ppm 0.96 (s, 9 H), 1.00 (s, 9 H), 1.27 (m, 1 H), 2.62 (dd, J=13.79, 8.64 Hz, 1 H), 2.85 (m, 5 H), 3.03 (q, J=8.58 Hz, 1 H), 3.39 (m, 1 H), 3.64 (m, 4 H), 3.82 (d, J=9.19 Hz, 1 H), 3.94 (m, 1 H), 4.00 (s, 1 H), 4.11 (m, 2 H), 4.35 (m, 2 H), 5.31 (m, 1 H), 6.13 (m, 2 H), 7.10 (m, 5 H), 7.21 (m, 2 H), 7.33 (m, 7 H), 7.74 (m, 2 H), 7.89 (d, J=8.46 Hz, 2 H), 8.68 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]3S[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[O:11])[CH3:9])=[CH:3][CH:2]=1.[S:26](=[O:30])(=O)(O)[OH:27].OO.C([O-])(O)=O.[Na+]>C(O)(=O)C.CN1C(=O)CCC1.O>[O:27]=[S:26]1(=[O:30])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:18][C:19]=2[C:15]2[CH:14]=[C:13]([NH:12][C:10]([CH:8]([CH3:9])[CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:11])[CH:25]=[CH:24][C:16]1=2
Reactant: O=S(=O)(O)O
Reactant: CC(Cc1ccncc1)C(=O)Nc1ccc2sc3ccccc3c2c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O
Product: CC(Cc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-[(2-Pyrid-4-yl-1-methylethyl)carbonylamino]dibenzothiophene (Example 11; 0.39 g, 1.13 mmol) was dissolved in glacial acetic acid (10 ml) and concentrated sulphuric acid (0.5 ml) at 60° C. 30% aqueous hydrogen peroxide (1.3 ml) was added in one portion and the solution was stirred at 60° C. for two hours. The mixture was allowed to cool and then poured into water (50 ml). The mixture was made basic by the addition of solid NaHCO3 and extracted with DCM (2×50 ml). The combined organic layers were washed with brine (50 ml), dried and evaporated in vacuo to leave a pale yellow solid. NMP: 8.45 (d, 2H), 8.3 (d, 1H), 8.0 (d, 1H), 7.95 (d, 1H), 7.9 (d, 1H), 7.8 (t, 1H), 7.7 (dd, 1H), 7.65 (t, 1H), 7.25 (d, 2H), 3.0 (m, 2H), 2.7 (m, 1H), 1.15 (d, 3H); m/z 379.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([C:17]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[OH:25])([CH3:8])[CH2:5][CH2:4]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[CH2:32]=O>C(O)(C)C>[OH:1][CH2:2][CH:3]1[O:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([C:17]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:18])[CH3:19])[CH:14]=[C:13]([CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:12]=2[OH:25])([CH3:8])[CH2:5][CH2:4]1
Reactant: C=O
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(OCC2(C)CCC(CO)O2)c1
Reactant: C1COCCN1
Solvent: CC(C)O
Product: CC(C)(C)CC(C)(C)c1cc(CN2CCOCC2)c(O)c(OCC2(C)CCC(CO)O2)c1
Yield: 51.4 %

Procedure:
A solution of 3.7 g (10 mmole) of 2-(5-hydroxymethyl-2-methyl-2-tetrahydrofuranylmethoxy)-4-t-octylphenol, 1 ml (12 mmole) of morpholine and 0.35 g (12 mmole) of paraformaldehyde in 25 ml of isopropanol was heated under reflux for 18 hours. The solvent was removed by evaporation in vacuo and the residue was extracted with diethyl ether. The resulting ethereal solution was washed with water, followed by saturated sodium chloride solution, and then dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography over silica gel, eluting with ethyl acetate, to give 2.31 g of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:9][N:8]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[C:5]2=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1n[nH]c2ncc(Br)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CON(C)C(=O)c1nn(C2CCCCO2)c2ncc(Br)cc12
Yield: 93.2 %

Procedure:
To a solution of 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XIX) (0.250 g, 0.88 mmol) in dry DCM (10 mL) was added 3,4-dihydro-2H-pyran (0.179 mL, 1.98 mmol) and PPTS (22 mg, 0.08 mmol) and refluxed 5 h under nitrogen. Another equivalent of 3,4-dihydro-2H-pyran (0.179 mL, 1.98 mmol) and PPTS (22 mg, 0.08 mmol) was added and the solution was further heated at refluxed overnight under nitrogen. The solution was cooled, diluted with DCM, washed subsequently with a saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 5-bromo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XX) as a viscous liquid (302 mg, 0.82 mmol, 93% yield). 1H NMR (CDCl3) δ ppm 1.51-1.62 (m, 2H), 1.91-2.13 (m, 2H), 2.33-2.44 (m, 2H), 3.40 (s, 3H), 3.66 (m, 1H), 3.75 (s, 3H), 3.87-3.98 (m, 1H), 6.07 (dd, J=10.07 Hz, J=2.52 Hz, 1H), 8.57 (d, J=3.01 Hz, 1H), 8.73 (d, J=3.01 Hz, 1H); ESIMS found for C14H17BrN4O3 m/z 369.4 (M+H).
Reaction SMILES: [NH3:1].[C:2]([O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([C:27](ON3C(=O)CCC3=O)=[O:28])=[C:25]([CH2:37][OH:38])[N:24]=[C:23]2[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:17][CH:16]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]>O1CCCC1>[C:2]([O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[C:26]([C:27]([NH2:1])=[O:28])=[C:25]([CH2:37][OH:38])[N:24]=[C:23]2[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:19][CH:20]=1)=[O:8])([CH3:3])([CH3:5])[CH3:4]
Reactant: N
Reactant: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CCCCc1nc(CO)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
0.5 ml of concentrated aqueous ammonia was added to a solution of 0.60 g of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate [prepared as described in step (a) above] in 6 ml of tetrahydrofuran, and the title compound started to separate immediately. The solvent was removed by distillation under reduced pressure, and the resulting residue was washed with diethyl ether and with water, to afford 0.38 g of the title compound as a powder, melting at 222°-224° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2Cl.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(Br)cccc2c1NCc1ccc(OC)cc1
Temperature: 120 °C
Yield: 50.5 %

Procedure:
To a solution of ethyl 8-bromo-4-chloroquinoline-3-carboxylate (1.8 g, 5.72 mmol) in DMF (10 mL) were added p-methoxybenzyl amine (860 mg, 6.27 mmol) and DIPEA (2.22 g, 17.21 mmol) and the reaction mixture was heated at 120° C. for 4 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.2 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 9.11 (br s, 1H), 8.89 (s, 1H), 8.46-8.43 (d, J=8.7 Hz, 1H), 8.12-8.09 (d, J=7.8 Hz, 1H), 7.38-7.33 (t, J=8.4 Hz, 1H), 7.27-7.24 (d, J=8.4 Hz, 2H), 6.91-6.89 (d, J=8.1 Hz, 2H), 8.17 (d, 2H), 4.26-4.24 (q, J=7.2, 14.1 Hz, 2H), 3.72 (s, 3H), 1.29-1.24 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1.[Cl-].O>O1CCCC1>[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([N:14]([C:2](=[O:4])[CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1
Reactant: CC(C)(C)[O-]
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1N(C(C)=O)c1ccccc1
Temperature: 0 °C
Yield: 22.1 %

Procedure:
0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.25 g (3.5 mmol) of acetyle chloride is then added and the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is washed with water to neutrality. The solution is dried over magnesium sulfate and then concentrated. A honey-like product is obtained which is purified by chromatography on a silica column. The purified product crystallizes from diisopropyl ether. 0.25 g of Compound 23 is obtained in the form of a white powder melting at 132° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]([C:15]1[C:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[N:17][CH:18]=[CH:19][CH:20]=1)#N.[OH-:31].[Na+]>CCOCC.C(OCC)(=O)C.O>[CH3:29][N:28]([CH3:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:16]1[C:15]([C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:31])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: [OH-]
Reactant: CN(C)CCCCCCOc1ncccc1C#N
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: CN(C)CCCCCCOc1ncccc1C(=O)c1ccccn1
Reaction time: 0.5 h

Procedure:
To a solution of 3.5 g of 2-bromopyridine in 20 ml of anhydrous ether is added dropwise 16.9 ml of n-butyllithium at -50° C. to -70° C., and the mixture is stirred for 30 minutes. To the mixture is added dropwise a solution of 4.9 g of 3-cyano-2-(6-dimethylaminohexyloxy)pyridine in 5 ml of anhydrous ether at -50° C. to -60° C. The mixture is stirred for 1 hour. Under ice-cooling, water and ethyl acetate are added thereto. After the ethyl acetate layer is dried over anhydrous magnesium sulfate, the solvent is distilled off. A dilute hydrochloric acid is added to the residue, and stirred at 40° C. for 10 minutes. After the completion of the reaction, the reaction mixture is rendered alkaline with 4N sodium hydroxide and extracted with toluene After the extract is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off. The residue is converted into the fumarate in ethanol, and the fumarate is recrystallized from ethanol to give 2-(6-dimethylaminohexyloxy)-3-picolinoylpyridine 3/2 fumarate, m.p. 132°-134° C. (Decomposition)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][CH:12]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][O:33][CH3:34])=[CH:27][CH:26]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>C(Cl)Cl>[CH3:42][S:43]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][CH:12]1[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][O:33][CH3:34])=[CH:29][CH:30]=1)(=[O:45])=[O:44]
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2CCCCCCCCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
To a solution of (3RS,4RS)-4-(9-hydroxynonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chroman (222 mg, 0.470 mmol) and triethylamine (0.135 ml, 0.961 mmol) in CH2Cl2 (5 ml) at 0° C. under nitrogen was added methanesulfonyl chloride (0.055 ml, 0.71 mmol). The resulting solution was stirred at 0° C. for 45 min, and then poured into H2O. The mixture was extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to afford (3RS,4RS)-4-(9-methanesulfonyloxynonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chroman (255 mg, 99%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH2:10][NH:11][CH3:12].[OH-].[Na+]>C(Cl)Cl>[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH2:10][N:11]([CH3:12])[C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CNCC(OC)OC
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=C(C)C(=O)N(C)CC(OC)OC

Procedure:
Using the above procedure, a methacrylamide monomer was prepared from 23.23 g methacryloyl chloride, 24.53 g N-methylaminoacetaldehyde dimethyl acetal, 42 g NaOH (20% aqueous solution), and 90 ml methylene chloride.