Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[S:11][C:12]=1[S:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:14].[C:33]([O:36]CC)(=[O:35])[CH3:34].Cl.[C:40]([O:43]CC)(=[O:42])[CH3:41]>C(O)C>[C:40]([OH:43])(=[O:42])/[CH:41]=[CH:34]/[C:33]([OH:36])=[O:35].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH2:23][NH:24][CH3:25])[S:11][C:12]=1[S:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:14]
Reactant: COc1cccc(S(=O)c2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Product: CNCc1cc(-c2ccccc2F)c(S(=O)c2cccc(OC)c2)s1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 4 h

Procedure:
tert-Butyl ({4-(2-fluorophenyl)-5-[(3-methoxyphenyl)sulfinyl]-2-thienyl}methyl)methylcarbamate (231 mg) was dissolved in ethyl acetate (3 mL) and ethanol (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added at room temperature. After stirring for 4 hr, the reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:9) to give a free base of the title compound (155 mg) as a pale-yellow oil. To a solution of fumaric acid (50 mg) in ethanol (10 mL) was added a solution of the obtained free base in ethyl acetate (5 mL), and the solvent was evaporated under reduced pressure. The obtained crude crystals were recrystallized from a mixed solvent of ethyl acetate and 2-propanol to give the title compound as a white powder (yield 118 mg, yield 50%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Li])[CH2:15]CC.[Cl-].[NH4+].[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:22](=[O:21])[CH2:23][CH2:24][CH:25]1[CH2:15][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(CCC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
In a separate flask a solution of (S)-4-benzyl-2-oxazolidinone (7.75 g, 43.8 mmol) in anhydrous tetrahydrofuran (75 mL) was cooled to −78° C. under a nitrogen atmosphere. A solution of n-butyllithium (2.5 M in hexanes, 17.5 mL, 43.8 mmol) was added dropwise. The reaction was stirred at −78° C. for 15 minutes. A solution of the acid chloride in anhydrous tetrahydrofuran (40 mL) was then added. The reaction mixture was stirred at −78° C. for 20 minutes then allowed to warm to room temperature over 1 h. A saturated aqueous solution of ammonium chloride (80 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to yield the title compound (8.88 g, 74%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.08-0.15 (m, 2H), 0.42-0.52 (m, 2H), 0.73-0.89 (m, 1H), 1.55-1.67 (m, 2H), 2.73-2.85 (m, 1H), 2.97-3.18 (m, 2H), 3.27-3.37 (m, 1H), 4.14-4.26 (m, 2H), 4.65-4.75 (m, 1H), 7.19-7.40 (m, 5H). LCMS (m/z) 274.1 [M+H], Tr=2.82 min.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:12]([O:14][C:15](=[O:27])[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH3:13].C(N(CC)CC)C>CN(C=O)C.O>[CH2:12]([O:14][C:15](=[O:27])[CH2:16][N:17]([CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[CH3:13]
Reactant: CCOC(=O)CNCCCN1CCOCC1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CN(CCCN1CCOCC1)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (11.2 g, 32.3 mmol) and (3-morpholin-4-yl-propylamino)acetic acid ethyl ester (7.44 g, 32.3 mmol) in DMF (200 mL) was treated with triethylamine (9.5 mL, 68 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (400 mL) and then extracted with EtOAc (5×250 mL). The combined organic layers were washed with H2O (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (11.8 g, 87%) as a yellow oil: MS (ESI) m/e 415 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]3=[N:18][S:19](=[O:23])(=[O:22])[CH2:20][CH2:21][N:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:17]3=[N:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21][N:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1C
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Platinum(IV) oxide (25 mg) was added to a solution of 9-[4-(3,4-dimethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (93.8 mg) in THF (dry) (10 mL) and MeOH (10 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (71.8 mg) as colorless crystals.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:10]([C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:30]([CH3:37])[CH:29]=1)([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([CH3:27])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>>[CH2:8]([C:10]([C:28]1[S:32][C:31]([S:33]([NH:36][CH2:6][C:5]([OH:4])=[O:7])(=[O:35])=[O:34])=[C:30]([CH3:37])[CH:29]=1)([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:24])([CH3:25])[CH3:23])=[C:15]([CH3:27])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Reactant: COC(C)=O
Agent: [Li+]
Agent: [OH-]
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NCC(=O)O)s1

Procedure:
Using LiOH hydrolysis as described in Example 136, (5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester gives the title compound (quant).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:3]=12.[CH3:19][O:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22]>C1(C)C=CC=CC=1>[F:25][C:24]([F:27])([F:26])[S:21]([O-:23])(=[O:22])=[O:20].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([CH3:19])=[C:4]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:3]=12
Reactant: Clc1c2ccccc2nc2c1sc1ccccc12
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[n+]1c2ccccc2c(Cl)c2sc3ccccc3c21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 38 %

Procedure:
To a solution of 11-chlorobenzothieno[3,2b]quinoline from Example 60 (0.16 g; 0.06 mmol) in 12 mL of toluene was added MeOTf (0.081 mL, 120 mol %) and the reaction mixture was stirred at rt for 20 h. The resulting crystalline yellow product was filtered, triturated with EtOAc for 24 h, filtered and dried, providing the title compound (38%), mp 187-189° C.; 1H NMR (DMSO-d6) δ 9.00 (d, 1H, J=8.4), 8.97 (d, 1H, J=8.2), 8.67 (d, 1H, J=8.4), 8.51 (d, 1H, J=8.4), 8.21-7.89 (m, 4H); 13C NMR (DMSO-d6) δ 148.34, 143.68, 143.11, 139.34, 135.72, 133.95, 130.59, 130.08, 128.35, 127.10, 125.12, 124.89, 119.88, 42.79; MS (+FAB, m/z) 284 (M+) MS (-FAB, m/z) 149.
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7]1([CH3:16])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:9](=[O:10])[CH2:8]1.[CH2:17]([OH:20])[CH2:18]O.O.[C:22]1(C)C=CC=CC=1>>[CH3:6][C:7]1([CH3:16])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:9]2([O:20][CH2:17][CH2:18][CH2:22][O:10]2)[CH2:8]1
Reactant: OCCO
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: O
Product: CC1(C)CC2(CC(C)(C)N1)OCCCO2
Reaction time: 3 h

Procedure:
Use of Phosphoric Acid 77 g of triacetonamine were initially charged in 240 g of toluene together with 47 g of ethylene glycol. Subsequently, sufficient phosphoric acid (63 g) was added that the reaction mixture showed an acidic pH (≦2) when tested with a moistened indicator paper. The reaction mixture was heated to reflux temperature and water of reaction formed was removed on a water separator. After approx. 3 hours, there was less than 10% of the desired product according to the gas chromatogram. Instead, a plurality of secondary components had formed which were not investigated further.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.[OH2:21]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:9])(=[O:18])=[O:21])=[CH:6][CH:7]=1
Reactant: CSc1ccc(Cl)nn1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
3-Chloro-6-(methylthio)pyridazine (90 mg, 0.50 mmol) synthesized in Example (118b) was dissolved in methylene chloride (10 mL), and m-chloroperbenzoic acid (220 mg, 1.00 mmol) was added, followed by stirring at 0° C. for 30 minutes under nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and extraction was carried out twice with methylene chloride (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-100%) to afford the desired compound (77 mg, yield 71%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]([O:33]C)=[O:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.CO>O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]([OH:33])=[O:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Yield: 94.9 %

Procedure:
A mixture of methyl {[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate (0.250 g, 0.559 mmol), prepared in the previous step, and 1N NaOH (0.84 mL, 0.84 mmol) in 1:1:1 THF:MeOH:water (30 mL) was stirred at ambient temperature for 10 minutes. The volatiles were removed under reduced pressure (without the application of heat). The residue was partitioned between 0.1N HCl and EtOAc. The layers were separated and the aqueous layer was extracted one time with EtOAc. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound as a pale-yellow solid (0.23 g, 95%), mp 171–172° C. Elemental Analysis for C29H23NO3.0.17 H2O Calc'd: C, 79.79; H, 5.39; N, 3.21. Found: C, 79.88; H, 5.37; N, 2.96.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-]S([O-])(=O)=O.[Mg+2]>>[C:9]1([N:8]=[C:4]([CH2:3][C:2](=[O:7])[CH3:1])[CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(=O)CC(C)=Nc1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
500 g of 2,4-pentanedione, 600 g of aniline, and 1000 g of MgSO4 were mixed together at 100° C., and the mixed solution was stirred for 12 hours at 100° C. Then, the solid portion was precipitated, and the liquid portion was recrystallized upon addition of n-pentane to get 605 g of yellow 2-phenylimino-4-pentanone solid (70% yield). From the NMR analysis, the structure was confirmed; 1H-NMR(CDCl3) δ1.98(s, CH3), 2.10(s, CH3), 5.18(s, ═CH), 7.20(m, Ph), 12.6(brs, NH).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[N:4][N:3]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[CH3:10]
Reactant: Cc1nnc(C=O)s1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1nnc(C)s1

Procedure:
prepared by reaction of 5-methyl-[1,3,4]thiadiazole-2-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[CH2:29]([O:36][C:37]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[O:50][CH3:51])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([O:36][C:37]1[C:45]([C:46]([F:47])([F:48])[F:49])=[CH:44][C:40]([C:41]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:42])=[CH:39][C:38]=1[O:50][CH3:51])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(C(=O)Cl)cc(C(F)(F)F)c1OCc1ccccc1
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CSc3ccccc32)cc(C(F)(F)F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and diisopropylethylamine (0.63 mL) and 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl chloride (657 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (578 mg) as a yellow oily substance.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][N:5]([CH2:43][C:44]([O:46]C)=[O:45])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:9]=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:7]=1.[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:9]=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:7]=1)[CH2:43][C:44]([OH:46])=[O:45])([OH:48])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccc3ccccc3n2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccc3ccccc3n2)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 69.7 %

Procedure:
A solution of 1.5 g (2.26 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycine methyl ester and 2.0 ml (12 mmol) of 6N NaOH in 80 ml of methanol was stirred at reflux for 4 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was removed byfiltration. Recrystallization from THF-acetone gave 1.0 g (70% yield, mp 172°-174°) of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycine.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].[N+](=[CH:66][C:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:68])=[N-]>ClCCl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:66][C:67]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[O:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (500 mg) and rhodium acetate (5 mg, 2 mol %) in dichloromethane (4 ml) was added α-diazoacetophenone (159 mg, 2 eq.) in dichloromethane (2 ml) dropwise. The reaction mixture was stirred for 15 minutes after the addition and then filtered through a silica gel pad washing with ethyl acetate. The filtrate was concentrated and purified by column chromatography on silica gel eluting with 60% hexane:40% ethyl acetate to give the desired product (188 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O)(=O)C>C(O)C.[Fe]>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccccc1-n1cccc1
Yield: 92.2 %

Procedure:
To a solution of 2-(1-pyrrolyl)nitrobenzene (1.11 g) in ethanol (30 ml) were added iron powder (1.65 g) and acetic acid (3.54 g) and the mixture was refluxed for 1 hour. The reaction mixture was filtered through a bed of celite and the. filtrate was concentrated in vacuo. The residue was diluted with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution and the mixture was filtered through a bed of celite again. The organic layer was separated and washed with water and brine. The solution was dried over sodium sulfate and the solvent was evaporated in vacuo to give 2-(1-pyrrolyl)phenylamine (860 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.CCN=C=NCCCN(C)C.Cl.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:44]([O:51][C:52](=[O:56])[CH2:53][CH2:54][NH2:55])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([NH:8][C@H:9]([C:17]([NH:55][CH2:54][CH2:53][C:52]([O:51][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:56])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Reaction time: 0.67 h

Procedure:
Boc-L-phenylalanine (1.32 g, 5.00 mmol) was dissolved in dichloromethane (50 mL) and treated with HoBt.H2O (1.53 g, 2.00 mmol) followed by WSCDI (water soluble carbodiimide) (1.00 g, 5.24 mmol). After stirring for 40 minutes, β-alanine benzyl ester tosylate (1.85 g, 5.27 mmol) was added, followed by DIPEA (diisopropylethylamine) (1.29 g, 10 mmol). Stirring was continued overnight, then the solvent removed. The residue was dissolved in ethyl acetate (30 mL) and washed with water, 10% sodium bicarbonate solution, then 10% citric acid solution. The organic layer was dried (MgSO4) and evaporated to a white solid--a single component by TLC, 1.74 g, 82% of (32). NMR (CDCl3) δ 1.41 (9H, s), 2.47 (2H, m), 3.01 (2H, m), 3.45 (2H, m), 4.25 (1H, br.q), 5.00 (1H, br.s), 5.07 (2H, s), 6.21 (1H, br.t), 7.15-7.38 (10H, m).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.[CH:13]1[C:18]([CH:19]=O)=[CH:17][C:16]2[O:21][CH2:22][O:23][C:15]=2[CH:14]=1.Cl.CO>O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[C:7](=[CH:19][C:18]3[CH:13]=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=c1ccoc2cc(O)ccc12
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccc3c(c2)OCO3)COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
After 7-hydroxy-4(4H)-benzopyranone 1.0 g and piperonal 1.0 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for two hours and cooled to room temperature, and water 200 ml was added. The mixture was allowed to stand for one hour and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.266 g.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH:9]([NH2:10])[CH:8]([OH:11])[CH:7]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[NH:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[O:37][CH:36]3[O:38]C(C)(C)[O:40][CH:35]3[CH:34]3[O:43]C(C)(C)[O:45][CH:33]23)[O:6]1)=[O:4].FC(F)(F)C(O)=O.O>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([C@@H:5]1[C@@H:9]([NH2:10])[C@@H:8]([OH:11])[C@H:7]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[NH:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[CH:33]([OH:45])[CH:34]([OH:43])[CH:35]([OH:40])[CH:36]([OH:38])[O:37]2)[O:6]1)=[O:4]
Reactant: CNC(=O)C1OC(n2cnc3c(NCc4cc(Cl)ccc4OCC4OC5OC(C)(C)OC5C5OC(C)(C)OC45)ncnc32)C(O)C1N
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC4OC(O)C(O)C(O)C4O)ncnc32)[C@H](O)[C@@H]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
To a solution of 3-amino-5-{6-[5-chloro-2-(2,2,7,7-tetramethyltetrahydro-bis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5-ylmethoxy) benzylamino]purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (59 mg, 0.09 mmol) in chloroform (7 mL) was added trifluoroacetic acid (0.7 mL). This reaction was stirred under anhydrous conditions at room temperature for 2 h. After this time period water was added (10 mL) and the reaction was stirred at room temperature for 5 days. The solvent was removed with a rotary evaporator and the resulting solid was then triturated with Et2O to afford the title compound as a beige powder (60 mg). Mp 212.0-218.0° C. C24H30ClN7O9. MW 596.00. MS 596.1 (M+H)+.