Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(=O)([O-])O.[Na+].[CH:28]1(CBr)[CH2:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[CH2:28]1[CH2:31][CH:30]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][C@H:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:29]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: BrCC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)[C@H]1O5
Yield: 66.1 %

Procedure:
A slurry of noroxymorphone (Example 5, 220 mg; 0.766 mmol), sodium hydrogen carbonate (77 mg; 0.92 mmol), cyclobutylmethyl bromide (160 mg; 1.07 mmol) and NMP (1 mL) was stirred under a nitrogen atmosphere at 90° C. for 19 h. Then the reaction mixture was cooled and quenched with water (10 mL). After adjusting the pH to 9, the product was extracted with DCM (3×5 mL). The combined organic layers were washed with water, brine and dried over MgSO4. Column chromatography afforded 180 mg (66%) of nalbuphone as a white solid; mp 170-172° C. (acetone), [lit. 173-174° C. (chloroform)]xxii; Rf 0.64 (ethyl acetate+20% methanol); [α]20D=−180.44 (c=1.0, MeOH); IR(CHCl3) v 3561, 3454, 2966, 2931, 2830, 1720, 1616, 1457, 1318, 1142, 1057, 944 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.74 (d, J=8.0 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 5.64 (bs, 1H, OH), 4.72 (s, 1H), 3.11 (d, J=18.4 Hz, 1H), 3.04 (ddd, J=14.4, 14.4, 3.6 Hz, 1H), 2.92 (d, J=4.9 Hz, 1H), 2.57 (m, 5H), 2.42 (ddd, J=12.4, 12.4, 4.4 Hz, 1H), 2.33 (d, J=14.4 Hz, 1H), 2.20 (ddd, J=12.0, 12.0, 2.2 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 1H), 1.90 (m, 2H), 1.87 (m, 2H), 1.66 (ddd, J=13.6, 13.6, 2.2 Hz, 1H), 1.56 (d, J=12.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 209.68, 143.45, 138.69, 129.02, 124.34, 119.87, 117.71, 90.58, 70.31, 62.74, 60.48, 50.93, 43.74, 36.18, 33.73, 31.32, 30.69, 27.00, 26.79, 22.96, 18.76; MS (FAB+) m/z (%): 41 (27), 69 (9), 98 (5), 300 (88), 355 (38), 356 (100); HRMS calcd for C21H26NO4 356.1856. found 356.18552.
Reaction SMILES: [C:1]([N:5]1[C:9]([S-:10])=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Na+].Cl[CH2:13][C@H:14]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][C@@H:16]([CH2:22][C:23]([O:25][C:26]([CH3:35])([CH3:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24])[CH2:15]1>>[C:1]([N:5]1[C:9]([S:10][CH2:13][C@H:14]2[O:19][C:18]([CH3:20])([CH3:21])[O:17][C@@H:16]([CH2:22][C:23]([O:25][C:26]([CH3:34])([CH3:35])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:24])[CH2:15]2)=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Reactant: CC(C)(C)n1nnnc1[S-]
Agent: [Na+]
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CSc2nnnn2C(C)(C)C)OC(C)(C)O1

Procedure:
The procedure was carried out in the same manner as in Example 11, except that sodium 1-tert-butyl tetrazole-5-thiolate (3.6 g) prepared in Example 8 was used in place of sodium 1-phenyl-1H-tetrazole-5-thiolate, and 3.5 g of 2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate was used in place of 30 g thereof. The title compound was obtained (4.6 g).
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])[C:14]([CH3:17])([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+].O.Cl>CO>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:13]([OH:12])[C:14]([CH3:16])([CH3:15])[CH3:17])([O-:26])=[O:25]
Reactant: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
A mixture of single diastereomer (R or S)-1-(2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (658 mg, 1.68 mmol) and K2CO3 (241 mg, 1.74 mmol) in methanol (23 mL) was heated to reflux for 30 minutes. Water (5 mL) was added and the solution was neutralized to pH 7 with 1M HCl. Solvent was removed in vacuo and the residue was taken into a mixture of ethyl acetate (20 mL) and water (10 mL). The organic phase was separated, dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield single enantiomer (R or S)-1-(2-nitrophenyl)-2,2-dimethyl-1-propanol (325 mg, 92%) as a light yellow oil. 1H NMR was identical to that of the racemic alcohol. The absolute configuration of the single enantiomer alcohol is not determined.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:22]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(CCc2coc3cccc(O)c23)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.8 %

Procedure:
To a solution of 3-[2-(4-carboxyphenyl)ethyl]-4-hydroxybenzofuran (0.25 g) in tetrahydrofuran (1 mL) were added benzyl alcohol (96 mg), triphenylphosphine (0.26 g) and diethyl azodicarboxylate (40% toluene solution, 0.43 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.26 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:26])[C:17]([CH3:25])([CH3:24])[C:18](=O)[CH:19](Br)[CH2:20][CH3:21]>C(O)C>[CH3:14][O:15][C:16](=[O:26])[C:17]([CH3:25])([C:18]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[S:8][C:19]=1[CH2:20][CH3:21])[CH3:24]
Reactant: CCC(Br)C(=O)C(C)(C)C(=O)OC
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)(C)C(=O)OC

Procedure:
A mixture of 4-Trifluoromethyl-thiobenzamide (12.3 g, 60 mmol) and the crude product from step A (16.6 g, 66 mmol) in ethanol (600 mL) is heated to reflux for 3 days. Solvent is evaporated and the residue is purified by chromatography on silica gel yielding the title compounds (14.5 g).
Reaction SMILES: C(O[CH2:5][O:6][CH:7]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.[I:26][C:27]1[C:28](=[O:34])[NH:29][C:30](=[O:33])[NH:31][CH:32]=1.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:19]([O:18][CH2:17][CH:7]([O:6][CH2:5][N:31]1[CH:32]=[C:27]([I:26])[C:28](=[O:34])[NH:29][C:30]1=[O:33])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: CC(=O)OCOC(COCc1ccccc1)COCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(=O)n(COC(COCc2ccccc2)COCc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a suspension of 2-O-(acetoxymethyl)-1,3-di-O-benzylglycerol (44; prepared according to Martin J. C., Dvorak C. A., Smee D. F., Matthews T. R., Verheyden J. P. H. (1983) 9-[(1,3-Dihydroxy-2-propoxy)methyl]quanine: a new potent and selective antiherpes agent, J. Med. Chem. 26, 759-761) (2.038 g, 5.9 mmol) and 5-iodouracil (2.106 g, 8.85 mmol) in anhydrous CH2Cl2 (25 mL) at room temperature was added N,O-bis-(trimethylsilyl)acetamide (BSA, 5.46 mL, 22.13 mmol), and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting clear solution was cooled to 0° C., and SnCl4 (1 M solution in CH2Cl2, 5.9 mL, 5.9 mmol) was added. The mixture was stirred at room temperature overnight, and then poured into a mixture of saturated aqueous NaHCO3 and CHCl3. The aqueous layer was extracted with CHCl3, and the combined organic phase was evaporated. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (97:3) to give the title compound 45 as a yellow oil (2.935 g, 95%). 1H NMR (CDCl3) δ 8.59 (s, 1H, NH), 7.82 (s, 1H, H-6), 7.36-7.26 (m, 10H, arom.), 5.28 (s, 2H, CH2N), 4.50 (s, 4H, 2 CH2), 3.99 (m, 1H, CHO), 3.52 (m, 4H, 2 CH2O).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:26])([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[C:12]([F:19])([F:18])[S:13][CH2:14][CH2:15][O:16][CH3:17].[CH3:27]I.O>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([O:26][CH3:27])([C:12]([F:18])([F:19])[S:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSC(F)(F)C(Cn1cncn1)(OC)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 60% sodium hydride (131 mg, 3.29 mmol) in N,N-dimethylformamide (50 ml), 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol (1.0 g, 2.74 mmol) was added dropwise under ice cooling. The resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture, methyl iodide (516 mg, 3.56 mmol) was added dropwise under ice cooling and the resulting mixture was stirred at room temperature for one hour. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate and then distilled off under reduced pressure. The residue was separated and purified by a silica gel column (chloroform:n-hexane=50:1), whereby 1-{2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxy-3-[(2-methoxyethyl)thio]propyl}-1H-1,2,4-triazole (894 mg, yield: 86.0%) was obtained as a yellow oil.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[F:28])[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.[ClH:30].CCOCC.C(OCC)C>CO.Cl>[ClH:30].[F:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[CH2:20][NH:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(F)ccc1F)c1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1ccc(F)c(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
The general procedure described in Example 4-A was followed using 2,5-difluoro-benzylamine as the amine in the preparation of the first intermediate and DMAP (1 equiv.) to give the BOC-protected compound. The protecting group was removed by dissolving (2,5-difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester (99.6 mg, 0.24 mmol) in methanol (1 mL) and treating it with 1.0M HCl/Ether (3.68 mL, 3.68 mmol) and stirring the reaction mixture overnight at ambient temperature. Additional 1.0M HCl/ether (2 mL) was added to the reaction mixture and stirring continued overnight at room temperature. The reaction was still not complete, therefore conc. HCl (2 drops) was added and the resulting mixture stirred at ambient temperature overnight. Diethyl ether (20 mL) was added to the reaction mixture and stirring continued for 1 h. The solids were filtered from the reaction mixture, washed with Ether, and dried under high vacuum to give the title compound 4-P (64 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15][C:16]([CH3:25])=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:15][C:16]([CH3:25])=[CH:17][C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: CC(=Cc1ccc(C)cc1)CBr
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=Cc1ccc(C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Yield: 57 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-(3-bromo-2-methyl-1-propenyl)-4-methylbenzene, the title compound was synthesized according to Reference Example 17b. Yield: 57%. Melting point: 167-169° C. (Ethyl acetate-hexane)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][OH:8].[NH2:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([Cl:17])[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([NH2:9])[CH:15]=[CH:14][C:13]=1[O:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: OCc1cnccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCc2cnccn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.8 %

Procedure:
To a mixture of pyrazin-2-yl-methanol (62 mg, 0.56 mmol), 4-amino-2-chloro-phenol (80.8 mg, 0.56 mmol) and triphenylphosphine (148 mg, 0.56 mmol) in THF (3 ml) was added DIAD (0.11 ml, 0.56 mmol) and the mixture was stirred at rt for 20 h. The mixture was concentrated in vacuo, diluted with 1N HCl (30 ml), washed with EtOAc (3×20 ml) and basified to pH 12 by 1N NaOH. The mixture was extracted with EtOAc (4×40 ml) and the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 16A (43.3 mg, 33% pure)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].I[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)([O-:3])=[O:2]
Reactant: Ic1cnccn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Oc2cnccn2)c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of 3-nitrophenol (0.151 g, 0.733 mmol) in DMSO (5 mL) was added NaH (35 mg of a 60% dispersion, 0.88 mmol) at 0° C. under Ar atmosphere. After stirring for 30 min, 2-iodopyrazine (0.133 mg, 0.953 mmol) was added and mixture heated to 85° C. for 4 h. To the mixture was added satd. NH4Cl solution (25 mL) and the product extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to yield a crude residue which was purified by column chromatography to afford (97 mg, 61% yield) 2-(3-nitrophenoxy)pyrazine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (brs, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.16-8.09 (m, 3H), 7.63 (t, J=8.0 Hz, 1H), 7.57-7.54 (m, 1H); MS (ESI) m/z: 218.0 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:21][OH:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C@H:27]1[O:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:27]([OH:29])[CH2:28][NH:2][C@H:3]([CH2:21][OH:22])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:9][CH:10]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: N[C@H](CO)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Reactant: Clc1cccc([C@@H]2CO2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)NC[C@H](O)c2cccc(Cl)c2)cc1
Yield: 28.2 %

Procedure:
Under nitrogen, a solution of (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]-N′-phenylurea hydrochloride (150 mg), (R)-3-chlorostyrene oxide (56 mg) and N,N-diisopropylethylamine (0.17 ml) in ethanol (5 ml) was refluxed for 28 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give N-[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea (45 mg) as a colorless form.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[C:9]#[CH:10])[CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:18])CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([F:18])[C:9]#[CH:10])[N:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: C#CC(O)c1cccc(Br)n1
Solvent: ClCCl
Product: C#CC(F)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(6-Bromopyridin-2-yl)prop-2-yn-1-ol (1.06 g, 5.00 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. Diethylaminosulfur trifluoride (925 μL, 7.00 mmol) was added dropwise, and the brown solution was stirred at 0° C. for 1 h. The reaction was quenched with saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (0-15% EtOAc/hexanes) afforded the title compound as an orange oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]>CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[O:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(=O)c1ccccc1F
Reactant: Oc1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(=O)c1ccccc1Oc1ccc(F)c(Br)c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A suspension of 3.75 g of 80% pure NaH in 50 ml of dimethyl sulfoxide (DMSO) was admixed with 21.7 g of 3-bromo-4-fluorophenol (cf. DE-A 192 80 27) and then stirred at 20-25° C. for 30 min, and a solution of 22.7 g of methyl 2-(2-fluorophenyl)oxoacetate in 100 ml of DMSO was added dropwise. The reaction mixture was stirred at 20-25° C. for approximately 12 hours, poured into ice-water and then extracted with ethyl acetate. The organic phases were washed with 1 N aqueous sodium hydroxide solution and water and dried, and the solvent was distilled off, giving 35 g of the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[N:22]=[C:21]([C:4]2=[CH:3][CH:2]=1)[N:20]=[C:19]1[C:23]2[C:28]([C:17](=[N:18]1)[N:16]=[C:15]1[C:29]4[C:34]([C:13](=[N:14]1)[N:12]=[C:11]1[C:35]5[C:40]([C:9](=[N:10]1)[N:8]=3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=2.[Cu:41]>C(O)COCCO>[CH:25]1[CH:24]=[C:23]2[C:19]3[N-:18][C:17]([C:28]2=[CH:27][CH:26]=1)=[N:16][C:15]1=[N:14][C:13]([C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:12][C:11]1[N-:10][C:9](=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[CH:39]2)[N:8]=[C:7]1[C:5]2[C:4]([C:21](=[N:22]1)[N:20]=3)=[CH:3][CH:2]=[CH:1][CH:6]=2.[Cu:41]
Reactant: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12
Agent: [Cu]
Solvent: OCCOCCO
Product: c1ccc2c(c1)-c1nc-2nc2[n-]c(nc3nc(nc4[n-]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21

Procedure:
An aliquot (400 parts) of the α-copper phthalocyanine pigment (C-2) obtained in Production Example 11(2) and containing copper monomethylphthalocyanine, common salt (1,600 parts) and diethylene glycol (400 parts) were milled for 6 hours in a kneader while controlling the temperature of the contents at 80 to 100° C. The resulting contents were subjected to treatment with a dilute acid and then to filtration. The thus-collected solids were washed with water, and then dried to obtain a fine β-copper phthalocyanine pigment (C-4) containing copper monomethylphthalocyanine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:41][C:42](=[O:68])/[CH:43]=[CH:44]/[C:45]2[CH:50]=[CH:49][C:48]([O:51][C:52](=[O:67])[C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][C:63]([F:66])([F:65])[F:64])=[CH:55][CH:54]=3)=[CH:47][CH:46]=2)[C:11]([C:14](=[O:40])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:39])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)([OH:13])[OH:12])=[CH:6][CH:5]=1)([O-])=O.CCCCCC.C[N:76](C)C=O>O.[Zn]>[NH2:76][C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=1[CH:10]([CH2:41][C:42](=[O:68])/[CH:43]=[CH:44]/[C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52](=[O:67])[C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][C:63]([F:66])([F:65])[F:64])=[CH:55][CH:54]=2)=[CH:47][CH:46]=1)[C:11]([C:14](=[O:40])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:39])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)([OH:13])[OH:12]
Reactant: CN(C)C=O
Reactant: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)CC(c1ccc([N+](=O)[O-])cc1)C(O)(O)C(=O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: O
Solvent: CCCCCC
Product: Nc1ccc(C(CC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)C(O)(O)C(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1

Procedure:
7.60 g (7.64 mmol) of 2-(4-nitrophenyl)-1,3di[(2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl]propanediol are dissolved in a mixture of 45 ml of N,N-dimethylformamide and 5 ml water. 12.39 g (45.84 mmol) ferric chloride hexahydrate are added. 4.99 g (76.4 mmol) Zinc powder are added portionwise within 40 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 1000 g silica gel using toluene:ethyl acetate 1:1 as eluant and crystallization form ethylacetate:hexane mixture to yield 4.30 g of 2-(2,4-Diaminophenyl)-1,3di[(2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl]propanediol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:20][OH:21])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH2:17][O:18][CH3:19].I[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:21][CH2:20][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH2:17][O:18][CH3:19])=[C:2]([O:1][CH2:23][CH2:24][CH3:25])[CH:3]=[N:4][CH:5]=1
Reactant: CCCI
Reactant: COCOc1cc(OC)ccc1-c1c(O)cncc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cncc(CO)c1-c1ccc(OC)cc1OCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-hydroxy-5-hydroxymethyl-4-(2-methoxymethoxy-4-methoxy-phenyl)-pyridine (550 mg, 1.89 mmol), iodopropane (0.210 ml, 2.15 mmol), potassium carbonate (3 g) in dry DMF (70 ml) was stirred overnight at rt. The mixture was dissolved in water and extracted with a 1:1 hexane:t-butyl methyl ether solution (×3) and washed with brine, dried (Na2SO4), and concentrated to afford the title compound as a greenish oil. (527 mg, 84%)
Reaction SMILES: O.[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=O)(C(O)=O)O.S(=O)(=O)(O)O.S(O)(O)(=O)=O.[CH2:25]([N:27]([CH2:31][CH3:32])[C:28]([NH2:30])=[NH:29])[CH3:26].N>O>[OH:12][C:10]1[CH:9]=[C:4]([CH2:3][C:2]([OH:14])=[O:13])[N:30]=[C:28]([N:27]([CH2:31][CH3:32])[CH2:25][CH3:26])[N:29]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCN(CC)C(=N)N
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CC)c1nc(O)cc(CC(=O)O)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Powdered citric acid monohydrate (42.0 g) was added in small portions over one hour to concentrated sulphuric acid (180 ml) at 0° C and the mixture stirred until a clear solution was obtained. N,N-Diethylguanidine sulphate (32.8 g) was added over 15 minutes and the solution stirred for one hour at the ambient temperature (ca 22°-24° C) and then at 90° C for a further 2 hours. After dilution of the mixture with deionised water (1050 ml), ammonia solution (s.g. 0.880) was added to adjust the pH to 4, and the mixture cooled to 0° C for one hour. The precipitate was collected by filtration, washed with ice-water (20 ml), acetone (100 ml), and with ether (100 ml) to yield 4-hydroxy-2-diethylaminopyrimidin-6-yl acetic acid as a white powder, having a melting point (with decomposition) of 156°-157° C.