Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:11]([CH2:13][NH2:14])[OH:12]>CC(C)=O>[C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:12][CH2:11][CH2:13][NH:14][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NCCO
Solvent: CC(C)=O
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)NCCO

Procedure:
To 730.7 g (5 moles) of diethyl oxalate was added dropwise at room temperature a solution of 61.1 g (1 mole) of ethanolamine in 500 ml of acetone and, after the addition finished, treatment of the mixture by distillation under reduced pressure to remove the formed ethanol and the acetone and an excess amount of diethyl oxalate yielded ethyl 2-hydroxyethyloxamate. A mixture of 80.5 g (0.5 moles) of this ethyl 2-hydroxyethyloxamate, 50.6 g (0.5 moles) of triethylamine (hereinafter, referred to as TEA), 20.0 g of water, and 1000 ml of dioxane was warmed under reflux for 8 hours and treated with solvent removal followed by dehydration yielded a triethylamine salt of 2-hydroxyethyloxamic acid. A mixture of 11.7 g (0.05 moles) of this triethylamine salt of 2-hydroxyethyloxamic acid and 5.1 g (0.05 moles) of TEA was treated with dehydration by molecular sieve and then, dissolved with warming into 300 ml of THF. To this THF solution was added dropwise under a refluxing condition during 0.5 hours a solution of 5.2 g (0.05 moles) of methacrylic acid chloride in 30 ml of THF and, after the addition finished, the mixture was further stirred under the condition for 6 hours and treated with fractional extraction to get methacryloyloxyet hyloxamic acid of the following structure: ##STR17## Besides, identification of the methacrylolyloxyethyloxamic acid 1 was carried out with 13C-NMR spectra analysis (ppm, in CDCL3) and the results were 17.93 for (2), 38.86 for (6); 62.35 for (5), 120.59 for (1), 138.86 for (3), 158.01 for (7), 160.56 for (8), and 167.06 for (4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][C:20]([CH3:25])([CH3:24])[C:21]([O:23][C@H:45]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:55])[F:56])=[C:49]([O:57][CH2:58][CH:59]3[CH2:60][CH2:61]3)[CH:48]=2)[CH2:44][C:43]2[C:42]([Cl:62])=[CH:41][N+:40]([O-:63])=[CH:39][C:38]=2[Cl:37])=[O:22])=[O:18])=[CH:15][C:14]=1[O:28][CH2:29][CH:30]1[CH2:31][CH2:32]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
To a mixture of 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)-2-methylpropanoic acid (300 mg, 0.636 mmol) and EDC (366 mg, 1.909 mmol) in dry DCM (10 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (267 mg, 0.636 mmol) and DMAP (78 mg, 0.636 mmol) were added, and the resulting solution was stirred at RT for 2 days. The solvent was evaporated and the residue was portioned between ethyl acetate and water; the organic phase was washed with 0.5N HCl, aqueous sat. NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH/32% NH4OH=95/5/0.5) to give (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)-2-methylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide as a white powder (168 mg, 0.192 mmol, 30.2% yield, MS/ESI+873.4 [MH]+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[N+]([O-])=O)[C:8]([O:10][CH3:11])=[O:9])([CH3:3])[CH3:2].[CH3:18][S-:19].[Na+].[Cl-].[Na+]>CN1CCN(C)C1=O.O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[S:19][CH3:18])[C:8]([O:10][CH3:11])=[O:9])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC(C)C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1ccc(SC)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
A solution of methyl 3-isopropoxy-4-nitrobenzoate (5.7 g) in N,N'-dimethylimidazolidinone (35 mL) is treated with sodium thiomethoxide (2 g), and the mixture is stirred at room temperature for 4 hours. The mixture is then diluted with water (250 mL) containing sodium chloride (47 g), and is extracted with ethyl acetate (2×100 mL). The combined organic extracts are washed with brine (100 mL), dried over magnesium sulfate and evaporated in vacuo, to give a brown oil. The oil is subjected to flash chromatography, eluting with a 1.9 v/v mixture of diethyl ether and pentane, to give methyl 3-isopropoxy-4-(methylthio)benzoate (4.0 g), in the form of a cream solid, m.p. 41-43° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][C@H:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@@H]2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: C[C@H]1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from (S)-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.32 g, 1.02 mmol), cyclohexene (0.26 mL, 2.54 mmol), and 1.0 M boron tribromide in dichloromethane (6.1 mL, 6.1 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by column chromatography on silica gel, eluting with dichloromethane, to yield 4-{[(S)-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.25 g, 0.72 mmol, 71%) as a white, solid, single enantiomer, m.p. 176-178° C.;
Reaction SMILES: [CH2:1]([O:9][C:10](=[O:20])[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10](=[O:20])[CH:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][O:13][C:27](=[O:29])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(=O)C(CO)c1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)C(COC(C)=O)c1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
To 60.4 g of 3-hydroxy-2-phenyl-propionic acid octyl ester in 150 ml of toluene is added at 4° C. 22.9 g (290 mmol) of pyridine followed by 22.8 g (290 mmol) of acetyl chloride dissolved in 50 ml of toluene. The reaction mixture is stirred for 2 hours at 4° C. The white precipitate is filtered off and washed with 100 ml of toluene to afford 70.5 g of 3-acetoxy-2-phenyl-propionic acid octyl ester used as crude material in the next step.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=O.C(N(CC)C(C)C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C)C=O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:9]1[CH2:10][CH2:11][O:12][CH:7]([CH2:6][NH2:5])[CH2:8]1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Reactant: Fc1cccc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NCC1CN(Cc2cccc(F)c2)CCO1
Temperature: 20 °C
Reaction time: 24 h
Yield: 47.3 %

Procedure:
A mixture of Intermediate 19 (0.300 g) and N,N-diisopropylethylamine (0.372 ml) in N,N-dimethylformamide (5 ml) was treated with 3-fluorobenzyl bromide (0.295 g). The solution was stirred at 20° C. under nitrogen for 24 h. The mixture was partitioned between dichloromethane (10 ml) and saturated aqueous potassium carbonate (10 ml). The phases were separated and the organic phase applied to an ion exchange cartridge (10 g Isolute SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (40 ml) followed by 10% 0.880 ammonia in methanol (40 ml) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in methanol (2 ml) and treated with aqueous 2N sodium hydroxide (2 ml). The solution was stirred at 20° C. for 24 h. The mixture was partitioned between dichloromethane (15 ml) and water (20 ml). The aqueous extract was washed with dichloromethane (15 ml) and the combined organic extracts concentrated to give the title compound as a colourless gum (0.150 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][C@@H:29]1[O:31][CH2:30]1>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([CH2:27][CH2:28][C@H:29]2[CH2:30][O:31]2)[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Reactant: BrCC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=S1(=O)N(CC[C@H]2CO2)Cc2ccccc2N1c1ccccc1F
Temperature: 40 °C
Reaction time: 14 h
Yield: 87.7 %

Procedure:
A solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.20 g, 0.72 mmol) in acetone (3 mL) was treated with potassium carbonate (0.11 g, 0.81 mmol), (S)-(−)-4-Bromo-1,2-epoxybutane (0.15 mL, 1.46 mmol) and was heated to 40° C. for two h then at room temperature for 14 h. The reaction mixture was diluted with ethyl ether (40 mL) and washed with 2 N sodium hydroxide (2×20 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to provided 1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.22 g, 86%) as a white solid.
Reaction SMILES: Br[C:2]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=2[Cl:33])=[CH:20][CH:19]=1)=[C:3]([NH:8][C:9]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC.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>[Cl:17][C:12]1[C:11]([C:9]([NH:8][C:3](=[C:2]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C(NC(=O)c1cccnc1Cl)=C(Br)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
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: ClCCl
Solvent: COCCOC
Product: COC(=O)C(NC(=O)c1cccnc1Cl)=C(c1ccccc1)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1

Procedure:
Tetrakis(triphenylphosphine)palladium (O) (10 mol %, 58 mg) was added to a mixture of the compound of Example 13, Isomer A (288 mg, 0.493 mmol) and phenyl boronic acid (90 mg, 0.74 mmol) in DME (10 ml) and sodium carbonate (2M, 0.986 mmol, 0.493 ml). The mixture was heated at 80° overnight, dlute with CH2Cl2 (200 ml), washed with diluted HCl and sodium hydrogen carbonate solution, dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2; CH2Cl2/MeOH, 93:7) gave the title compound as a white solid (133 mg). δH (DMSO-d6), 11.04 (1H, s, CONH), 10.40 (1H, s, CONH), 8.79 (2H, s, Cl2PyH), 8.48 (1H, dd, J 4.9, 1.9 Hz, PyH), 7.85 (1H, dd, J 7.5, 1.9 Hz, PyH), 7.66 (2H, d, J 8.7 Hz, ArH), 7.51 (1H, dd, J 7.5, 4.9 Hz, PyH), 7.39-7.35 (3H, m, ArH), 7.23 (2H, d, J 8.7 Hz, ArH), 7.07 (2H, m, ArH) and 3.45 (3H, s, CO2Me); m/z (ESI, 60V) 581 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:13])[C:6]=2[C:14]=1[F:15]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(C)NC(=O)Cn2cnc3ccc(F)c(F)c32)ccc1C(C)(C)C#N
Yield: 67 %

Procedure:
To a solution of (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (500 mg, 2.36 mmol) prepared according to scheme 2, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (477 mg, 2.36 mmol) prepared according to scheme 16 and DMAP (570 mg, 4.71 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (896 mg, 2.36 mmol) after 18 hours of stirring, the mixture is diluted with EtOAc (100 mL). The organic phase is washed with distilled water, dried over anhydrous MgSO4. The mixture is filtered and concentrated. The product is purified on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(6,7-difluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (627 mg, 67%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.48 (d, J=7.03 Hz, 3 H) 1.75 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.12 (s, 2H) 7.12-7.25 (m, 3H) 7.33 (d, J=8.20 Hz, 1H) 7.42 (ddd, J=8.89, 3.61, 1.17 Hz, 1H) 8.13 (s, 1H), MS [M+H], calcd: 397.2. found: 397.2.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1.[ClH:23].[C:24](=S)=[S:25]>C(O)C>[ClH:23].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:20][CH2:21][NH:22][C:24]2=[S:25])[CH2:15][CH2:14]1
Reactant: S=C=S
Reactant: NCCNC1CCN(CCC2COc3ccccc3O2)CC1
Agent: Cl
Solvent: CCO
Product: S=C1NCCN1C1CCN(CCC2COc3ccccc3O2)CC1
Reaction time: 5 h

Procedure:
To the stirred solution of 6 g of 1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-(2-aminoethylamino)-piperidine in 10 ml of 50% aqueous ethanol, 1.4 ml of carbon disulfide are added dropwise at 25°. The mixture is refluxed for one hour, a drop of concentrated hydrochloric acid is added and refluxing is continued for 5 hours. After cooling overnight the mixture is filtered and the residue washed with ethanol, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinthione hydrochloride melting at 292°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:1][C:2]1[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12

Procedure:
A 14.0 g amount of 4-amino-1,5-naphthalenedisulfonic acid is suspended in 100 ml of water and the solution is made basic with 5N sodium hydroxide. The solution is warmed and absolute ethyl alcohol is added until a solid is precipitated. The solid is collected by filtration and is washed with 85% aqueous ethyl alcohol, ethyl alcohol and ether, then dried in vacuo to yield 12.0 g of 4-amino-1,5-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.[ClH:20].[NH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[SH:27]>C(O)C>[ClH:20].[C:16]([C:7]1[CH:6]=[C:5]([C:3]2[CH2:2][S:27][C:23]3=[N:24][CH:25]=[CH:26][N:22]3[N:21]=2)[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: Nn1ccnc1S
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(C2=Nn3ccnc3SC2)cc(C(C)(C)C)c1O

Procedure:
A solution of 18.0 g (0.055 mol) of 2-bromo-1-(3,5-ditert.butyl-4-hydroxyphenyl)-ethanone and 7.6 g (0.05 mol) of 1-amino-2-mercaptoimidazole hydrochloride from step (a) in 150 ml of ethanol was refluxed for 9 hours. The residue remaining after evaporation of the solution was rendered alkaline by means of 50 ml of 2N sodium hydroxide solution and extracted with chloroform. In order to convert the product into the hydrochloride, an equimolar amount of ethereal hydrochloric acid was added to the dried chloroform phase, and the batch of crystals produced was filtered off under suction and crystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: Cc1ccc(C)c(C2CC(=O)C=C(N)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(C2CC(=O)c3c(C)ccnc3C2)c1
Temperature: 115 °C
Yield: 130.8 %

Procedure:
In a mixture of ethanol (35 ml) and toluene (90 ml) was dissolved 1-amino-5-(2,5-dimethylphenyl)cyclohexen-3-one (1.7 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (2.66 g) and granulated potassium hydroxide (440 mg). The mixture was stirred at 115° C. (bath temperature), and to the mixture was added granulated potassium hydroxide (90 mg), 30 minutes later; 1 hour later; and 1.5 hours, respectively. The reaction solution was stirred at the same temperature for 1 hour and cooled. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (40 ml) and water (20 ml). The mixture was shaken and separated ethyl acetate layer was washed with brine. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 7-(2,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.37 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([Cl:34])[CH:28]=1>>[Cl:34][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:23]=[CH:22][CH:21]=[C:10]([CH2:11][NH:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][C:30]=1[OH:33]
Reactant: Clc1nccc(-c2cccc(CNCCc3ccncc3)c2)n1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CNCCc4ccncc4)c3)n2)cc1Cl

Procedure:
Intermediate 173 from above was coupled with 4-(2-aminoethyl)-2-chlorophenol following procedure F. LC-MS showed the product had the expected M+H+ of 460. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.4 (d, 2H) 8.4 (s, 1H) 8.29 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H) 7.66-7.56 (m, 2H), 7.36 (d, 1H), 7.20 (d, 1H) 7.10 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 4.3 (s, 2H), 3.6 (t, 2H), 3.3 (t, 2H), 3.0 (t, 2H), 2.8 (t, 2H).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([C:17]([OH:21])([CH3:20])[CH2:18][OH:19])[CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]([CH3:25])=O>>[CH3:22][C:23]1([CH3:25])[O:21][C:17]([CH3:20])([C:13]2[CH:14]=[N:15][CH:16]=[C:11]([O:10][CH2:9][C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][O:19]1
Reactant: CC(O)(CO)c1cncc(OCC#Cc2ccccc2)c1
Reactant: CC(C)=O
Product: CC1(C)OCC(C)(c2cncc(OCC#Cc3ccccc3)c2)O1
Yield: 76 %

Procedure:
Using the procedure described in Example 1, 2-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]propane-1,2-diol was reacted with acetone to give 2,2,4-trimethyl-4-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]-1,3-dioxolane in 76% yield, as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3R,4R)-1-Benzyl-4-methyl-3-pyrrolidinecarboxylic acid (6.27 g) was suspended in dichloromethane (250 mL). To this suspension, cyclopropylamine (1.76 mL) and hydrochloric acid 1-ethyl-(3-dimethylaminopropyl)carbodiimide (12.2 g) were sequentially added and the mixture was stirred at room temperature for 4 hours. Subsequently, the reaction mixture was washed with water, was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The resulting residue was purified on a silica gel column (ethyl acetate: methanol=10:1) to give 3.32 g of (3R,4R)-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidinecarboxamide as a white crystal.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1.Cl>O>[C:9]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Meta-cresol (1 g, 9.0 mmol) and acetic anhydride (1.1 g, 10.8 mmol) were mixed in the presence of pyridine (3 ml) as a base at 0° C., and gradually heated to room temperature. After 30 minutes, 10˜15 ml of water is added thereto, and the mixture was neutralized by adding 1N HCl (30 ml) in three portions. The resultant mixture was extracted with organic solvent, washed, dried and purified by using column chromatography (eluent: hexane/ethyl acetate=6/1) to obtain 1.3 g (96%) of compound (3).