Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([NH2:22])=[CH:8][CH:7]=1.[CH2:23]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CO>[CH2:30]([O:4][C:1]1[CH:2]=[CH:36][C:35]([CH:38]=[N:5][C:6]2[C:19]3[C:18](=[O:20])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:21])[C:10]=3[C:9]([N:22]=[CH:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:33][CH:34]=3)=[CH:8][CH:7]=2)=[CH:34][CH:33]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Reactant: CC(=O)O
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Solvent: CO
Product: CCCCCCCCOc1ccc(C=Nc2ccc(N=Cc3ccc(OCCCCCCCC)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Temperature: 0 °C

Procedure:
In a round-bottomed flask fitted with thermometer, reflux condenser and stirrer is placed a mixture of 25 ml. glacial acetic acid and 50 ml methanol and in it is dissolved 2.38 g (0.1 mol) 1,4-diaminoanthraquinone. There is taken added 4.68 g (0.2 mol) p-octyloxybenzaldehyde and the mixture is heated at 90° for one hour. The reaction mixture is cooled to about 20°-25° and poured into ice water. The precipitated product is collected and recrystallized from ethylene glycol monomethyl ether or 1:1 methanol water as small purple needles. The crystallization is repeated twice more to obtain 1,4-bis(p-octyloxybenzylidene amino)anthraquinone m.p. 280° C. (dec) having absorption spectra in visual and infra red ranges as shown in FIGS. 9, 10, and 11 and of sufficient purity for use in guest-host combinations.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:50]=[CH:51][N:52]5[C:65](=[O:66])[N:64]([CH3:67])[N:63]=[C:53]5[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:50]=[CH:51][N:52]5[C:65](=[O:66])[N:64]([CH3:67])[N:63]=[C:53]5[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: Cn1nc2c3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(=O)c3ccn2c1=O
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc2c3oc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)c(=O)c3ccn2c1=O
Yield: 77 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(2-methyl-3,6-dioxo-8-phenyl-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.5 mL), water (3.5 mL) and 1 M HCl (0.1 mL) and chromatographed on a 5 g C18 cartridge {30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (13.5 mg, 77%). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (br s, 3H), 7.86 (d, J=7.2 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.47-7.37 (m, 5H), 7.30 (d, J=8.3 Hz, 2H), 7.00 (d, J=7.2 Hz, 1H), 3.65 (s, 3H), 2.61-2.49 (m, 4H), 2.23-2.12 (m, 1H), 1.85-1.74 (m, 1H). LCMS (Method E): RT=2.95 min, [M+H]+=439.
Reaction SMILES: 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.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:42][CH3:43])=[C:39]([OH:41])[CH:40]=1.[CH3:44][N:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1>C1(C)C=CC=CC=1>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:40]=1)[O:41][CH:48]1[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]1
Reactant: COc1ccc(Br)cc1O
Reactant: CN1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1OC1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a 40 mL screw-cap vial were added triphenylphosphine (1.55 g, 5.91 mmol) and toluene. The solution was stirred a 0° C. for 5 min then a diisopropylazodicarboxylate (1.18 mL, 5.99 mmol) was added drop-wise over 2 min. The solution was allowed to warm to room temperature over 1 h, then a solution of 5-bromo-2-methoxy-phenol (1.01 g, 4.98 mmol) and 1-methyl-piperidin-4-ol (701 mg, 6.08 mmol) in 4 mL of toluene was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was adsorbed onto silica gel and purified by silica gel flash chromatography with a 0-20% MeOH/CH2Cl2 gradient to afford titled compound as a light yellow oil that solidified upon standing (906 mg, 61%). 1H NMR (MeOH-d4) 7.10 (d. J=8.8, 1H), 7.08 (dd. J=8.8, 2.4, 1H), 6.89 (d, J=8.8, 1H), 4.34 (m, 1H), 3.80 (s, 3H), 2.73 (m, 2H), 2.34 (m, 2H), 2.29 (s, 3H), 1.95 (m, 2H), 1.81 (m, 2H). LC/MS (Method B) 1.85 min, [M+1]+ 300/302.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[H-].[Na+].Br[C:13]1[C:14]2[N:15]([C:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[F:32])=[O:24])=[CH:21][N:22]=2)[N:16]=[C:17]([Cl:19])[CH:18]=1.CN(C=O)C>C1COCC1.O>[NH2:8][C:6]1[N:5]=[C:4]([NH:9][C:13]2[C:14]3[N:15]([C:20]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[F:32])=[O:24])=[CH:21][N:22]=3)[N:16]=[C:17]([Cl:19])[CH:18]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1cc(Cl)cc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)cc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of 4-chloropyridine-2,6-diamine (35.2 mg, 0.245 mmol) in THF (0.5 mL) was added 60% NaH (12.26 mg, 0.307 mmol). The mixture was stirred for 10 min. 5A (40 mg, 0.123 mmol) was added, followed by DMF (0.5 mL). The mixture was stirred at room temperature for 1 h. Water was added and the precipitated solid was collected by filtration, and dried to give crude 40A (42 mg, 59%). HPLC Rt=3.131 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=433.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][C@H:19]([CH3:23])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:26])[C@H:19]([CH3:23])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 108d (300 mg, 0.8 mmol) in methanol (8 mL) was added two drops of acetic acid, 30% formaldehyde solution (0.5 mL), and sodium triacetoxyborohydride (354 mg, 1.6 mmol) at room temperature. Then the mixture was stirred at room temperature for 1 h. At the end of reaction, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 108e as a brown solid (280 mg, 90%). LCMS: [M+H]+ 392
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:38]([O:40][C:41]([CH2:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:42])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([N:47]1[CH2:48][CH2:49][CH:44]([CH2:43][C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:45][CH2:46]1)=[O:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Reactant: CCOC(=O)CC1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(C(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred and cooled suspersion of (S)-Nα -t-butoxycarbonyl-Nω -nitroarginine (3.1 g) in anhydrous tetrahydrofuran (THF) (50 ml) is added triethylamine (0.8 g) dropwise over 5 minutes at -20° C. and stirring is continued for a further 10 minutes. To the stirred mixture is then added isobutyl chloroformate (1.1 g) dropwise over 10 minutes at -20° C. and the mixture is stirred for a further 10 minutes. To the stirred mixture is then added 4-(ethoxycarbonylmethyl)piperidine (1.4 g) in THF (20 ml) dropwise over 10 minutes at -20° C. and then after stirring for a further 10 minutes at -20° the mixture is allowed to warm to room temperature with stirring for 1 hour. The reaction mixture is concentrated by evaporation and the residue is diluted with ethyl acetate (100 ml) and the mixture is washed with portions of water (3×15 ml), aqueous 5% NaHCO3 (2×15 ml), aqueous 10% citric acid (2×15 ml), then water (2×15 ml) and dried (MgSO4). Solvent is evaporated to give an oil which is chromatographed on silica gel using ethyl acetate as eluant to yield 1-((S)-Nα -t-butoxycarbonyl-Nω -nitroarginyl)-4-(ethoxycarbonylmethyl)piperidine as a pale yellow oil, Rf (ethanol)=0.16.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH2:8](Br)[CH:9]([CH3:11])[CH3:10].[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CC(C)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CSc1nnc(N)s1
Yield: 38.7 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (2.0 g), isobutyl bromide (2.1 g), and potassium hydroxide (0.8 g) were stirred in methanol (50 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.1 g of the aimed compound.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]([O:12][C:13](=[O:39])[CH2:14][N:15]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][C:25]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:11])([CH3:10])[CH3:9].C(OC(C(NC1C=CC([C:67]2([OH:97])[C:80]3[CH:79]=[C:78]([F:81])[C:77]([O:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH3:88])=[CH:76][C:75]=3[O:74][C:73]3[C:68]2=[CH:69][C:70]([F:96])=[C:71]([O:89][CH2:90][O:91][CH2:92][CH2:93][O:94][CH3:95])[CH:72]=3)=CC=1OCC(O)=O)C(OC(C)(C)C)=O)=O)(C)(C)C.NC1C=CC=CC=1O.N(CC(O)=O)CC(O)=O>>[C:8]([O:12][C:13](=[O:39])[CH2:14][N:15]([C:24]1[CH:29]=[CH:28][C:27]([C:67]2([OH:97])[C:68]3[CH:69]=[C:70]([F:96])[C:71]([O:89][CH2:90][O:91][CH2:92][CH2:93][O:94][CH3:95])=[CH:72][C:73]=3[O:74][C:75]3[C:80]2=[CH:79][C:78]([F:81])=[C:77]([O:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH3:88])[CH:76]=3)=[CH:26][C:25]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccc(Br)cc1OCc1ccccc1
Reactant: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(NC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OCC(=O)O)c1)c1cc(F)c(OCOCCOC)cc1O2
Agent: Nc1ccccc1O
Agent: O=C(O)CNCC(=O)O
Solvent: Oc1ccccc1
Product: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OCc3ccccc3)c1)c1cc(F)c(OCOCCOC)cc1O2
Yield: 69 %

Procedure:
The synthesis of the fluorescein precursor compound 18 is shown in Scheme 5. The xanthene half of 18 was synthesized from the xanthone precursor 7. The latter was prepared via the Friedel-Crafts acylation of 342 with 6. The product was subsequently heated in a sealed tube to furnish the xanthone 8 and the phenol moieties then protected as 2-methoxyethoxymethyl (MEM)43 ethers (9). The aromatic precursor (13) to the “northern” half of compound 18 was prepared in three steps from commercially available o-aminophenol (described above). Compound 13 contains a doubly protected iminodiacetic acid moiety and a benzylated phenol. The latter will ultimately be debenzylated so that it can serve as the attachment site for the peptide. Compound 13 was lithiated at −105° C. and coupled to 9, to furnish adduct 14 in 69% yield. The benzylated phenol in 14 was transformed in three steps to the desired carboxylic acid (18), and then coupled to H2N-Ser(O-tBu)-Phe-[(Arg)Mtr]4-resin (prepared via standard Fmoc solid phase peptide synthesis on the Rink resin). Finally, exposure of the resin-appended fluorophore-peptide to 95% CF3CO2H resulted in the simultaneous cleavage of the peptide from the resin, MEM ether deprotection, and complete aromatization of the tricyclic nucleus via loss of the tertiary hydroxyl moiety to yield 23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I-:9].[Na+].ClOC(C)(C)C>C(#N)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: [I-]
Agent: CC(C)(C)OCl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of 40 mmol of 4-chlorophenol and 52 mmol of sodium iodide in 80 mL of acetonitrile and 16 mL of water at room temperature add 52 mmol of tert-butyl hypochlorite dropwise over a period of 30 minutes. Stir the reaction mixture for 3 hours at ambient temperature. Dilute the reaction mixture with 200 mL of ethyl acetate. Wash the resulting organic solution successively with 5% aqueous sodium thiosulfate solution and brine and dry over anhydrous magnesium sulfate. Remove the solvent and then crystallize from hexanes to yield 51% of (P9) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=1.[CH3:23]N(C=O)C.[C:28]([O:32][C:33]([NH:35][C@H:36]([C:40]([OH:42])=O)[CH:37]([CH3:39])[CH3:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12]([CH2:23][C:40](=[O:42])[C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH:37]([CH3:38])[CH3:39])[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=1
Reactant: CN(C)C=O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1
Temperature: 23 °C
Reaction time: 72 h

Procedure:
To a stir bar equipped flask containing 4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridne (1-5, 0.06 g, 0.19 mmol) under nitrogen was added DMF (10 mL) successively followed by N-(tert-butoxycarbonyl)-L-valine (0.08 g, 0.39 mmol), TEA (0.14 mL, 0.99 mmol), and PyBop (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) (0.20 g, 0.39 mmol). The resulting solution stirred at 23° C. over 72 h. Upon completion, the reaction was diluted with dichloromethane (20 mL) and washed with aqueous sodium chloride (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2, 0-30% EtOAc/hexanes gradient) to give tert-butyl (1S)-3-[4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-3,6-dihydropyridin-1(2H)-yl]-1-isopropyl-2-oxopropylcarbamate (2-1). MS 445.0 found, 445.5 required (MH+−C(CH)3).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][C:18]=1N1CCCCC1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+]>CN(C)C=O.O.O.O.O.O.O.[Co](Cl)Cl>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCCCC3)CS[C@H]12
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
4.76 g (20 mmols) of cobalt(II) chloride hexahydrate are added in several portions, at 0°-5° C., to a solution of 11.7 g (20 mmols) of 7β-phenoxyacetylamino-3-piperidino-3-cephem-4-carboxylic acid benzhydryl ester in 50 ml of dimethyl formamide. The solution turns dark blue. Then 75 ml of glacial acetic acid are added dropwise at 0° C. over 30 minutes. Then 4.08 g (120 mmols) of sodium borohydride are added in 200 mg portions over 1 hour, with vigorous evolution of gas after each addition. When the addition is complete, the reaction mixture is warmed to room temperature and, after the addition of a further 50 ml of glacial acetic acid, stirred for 36 hours at room temperature. The dark red solution is filtered to remove the pink precipitate, the filter residue is washed with methylene chloride, and the filtrate is concentrated in vacuo. The dimethyl formamide is distilled off in a high vacuum. The oily residue is dissolved in methylene chloride and washed three times with 50 ml of water. The methylene chloride solution is filtered over 50 g of silica gel to remove residual cobalt salts and the eluate is concentrated, affording pure 7β-phenoxyacetylamino-3-cephem-4-carboxylic acid benzhydryl ester as a white foam.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=1)[N:10]([CH3:21])[CH2:9][CH2:8]2.[C:22]([Br:25])(=[O:24])[CH3:23]>FC(F)(F)C(O)=O>[BrH:25].[C:22]([O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:3](=[O:2])[CH3:12])=[C:15]([O:20][C:16](=[O:19])[CH3:15])[CH:14]=1)[N:10]([CH3:21])[CH2:9][CH2:8]2)(=[O:24])[CH3:23]
Reactant: CC(=O)Br
Reactant: CN1CCc2cccc(O)c2C1c1ccc(O)c(O)c1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(C2c3c(cccc3OC(C)=O)CCN2C)cc1OC(C)=O

Procedure:
A mixture of 1.0 g of 8-hydroxy-1-(3,4-dihydroxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide prepared as in Example 4 above and 200 ml of trifluoroacetic acid is mixed with 1.3 ml of acetyl bromide. After heating at reflux for 2 hours, the mixture is evaporated to dryness. The residue is purified by recrystallization to give 8-acetoxy-1-(3,4-diacetoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide. Similarly isobutyryloxy, propionyloxy, isovaleryloxy, n-butylryloxy and n-heptanoyloxy derivatives are prepared.
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[C:18]3[N:19]=[CH:20][N:21]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]=3[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=2)C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)=O>[C:23]1([CH2:22][N:21]2[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[N:10]=[C:9]([NH2:8])[C:18]=3[N:19]=[CH:20]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3c(c4c2ncn4Cc2ccccc2)CCCC3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: Nc1nc2c(c3c1ncn3Cc1ccccc1)CCCC2
Yield: 91.6 %

Procedure:
N,N,1-Tris(phenylmethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (4.49 g, 9.8 mmole), palladium hydroxide on carbon (1.0 g, Pearlman's catalyst) and formic acid (20 mL) were combined and heated at reflux for 4 days. During the course of the reaction the formic acid evaporated out of the reaction vessel. The residue was diluted with formic acid (15 mL) and water (20 mL) then filtered through a layer of celite. The filtrate was basified with 28% ammonium hydroxide then extracted with methylene chloride (3×100 mL). The methylene chloride extracts were combined, dried over magnesium sulfate and concentrated to provide 2.5 g of a yellow foam. The foam was loaded onto a 3 cm by 15 cm column of silica gel and eluted with methylene chloride:methanol 90:10. The early fractions were combined and evaporated to provide 0.54 g of N,2-bis(phenylmethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, m.p. 199°-200° C. The later fractions were combined and evaporated to provide 1.58 g of a mixture of 6,7,8,9-tetrahydro-N-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine and 6,7,8,9-tetrahydro-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid. This mixture was loaded onto a 3 cm by 20 cm column of silica gel and eluted with methylene chloride:methanol 90:10. 80 fractions, 6 mL each, were collected. Fractions 18-27 were combined and evaporated to provide 0.48 g of 6,7,8,9-tetrahydro-N-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 168°-170° C. Fractions 40-57 were combined and evaporated to provide 180 mg of the desired product, 6,7,8,9-tetrahydro-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine, as a white solid, m.p. 231°-233° C. (dec). Analysis: Calculated for: C18H19N4 +1/5 CH2Cl2 : % C, 69.95; % H, 6.28; % N, 18.97; Found: % C, 70.44; % H, 6.16; % N, 18.93.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=O)[C:2]1C=CC=CC=1.[NH2:12][C:13]1[C:14]([CH3:23])=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[N:16]2.C(N)C[NH2:26]>CC(C)=O.C1(C)C=CC=CC=1>[NH2:26][CH2:2][CH2:1][NH:9][C:10](=[S:11])[NH:12][C:13]1[C:14]([CH3:23])=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[N:16]2
Reactant: NCCN
Reactant: Cc1c(N)ccc2nccnc12
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Cc1c(NC(=S)NCCN)ccc2nccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a refluxing solution of benzoyl isothiocyanate (1.6 g) in dry acetone (20 mL) is added dropwise a solution of 6-amino-5-methylquinoxaline (1.2 g) in dry acetone (50 mL) over 30 minutes. The mixture is refluxed an additional two hours, cooled to room temperature, and rotary evaporated to a residue. This material is suspended in 10% NaOH solution (50 mL) forming a mixture which is heated at 90° C. for 30 minutes, then cooled to room temperature and adjusted to pH=8 by adding concentrated HCI. The mixture is then cooled in an ice bath and suction filtered. The collected solid thiourea intermediate is dried on a vacuum line (16 h, 0.5 torr), suspended in bromobenzene (50 mL) and heated at reflux for six hours to effect conversion to the isothiocyanate intermediate which is not isolated. The solution is cooled, then added dropwise to a solution of ethylene diamine (5.0 mL) in toluene (10 mL). The resulting mixture is stirred for 16 hours and filtered. The solids are washed with toluene (20 mL) and dried under vacuum to yield 6-(N'-aminoethylthioureido)-5-methylquinoxaline.