Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:12]([CH:13]([CH2:18][N+:19]([O-])=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:11][N:10]=[N:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[CH3:16][CH:15]([CH3:17])[CH2:14][CH:13]([C:12]1[NH:8][N:9]=[N:10][N:11]=1)[CH2:18][NH2:19]
Reactant: CC(C)CC(C[N+](=O)[O-])c1nnnn1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)CC(CN)c1nnn[nH]1
Reaction time: 70 h
Yield: 40 %

Procedure:
To a solution of 1-benzyl-5-(3-methyl-1-nitromethyl-butyl)-1H-tetrazole (1.41 g, 4.87 mmol) in MeOH (50 mL) was added 20% Pd/C (0.20 g) and concentrated HCl (0.6 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 70 h, filtered, and concentrated. The residue was dissolved in 5 mL H2O and loaded onto a plug of DOWEX-50WX4-100 ion exchange resin. The column was eluted first with 100 mL H2O, then 50 mL 5% NH4OH (aq), and finally with 50 mL 10% NH4OH aq). The alkaline fractions were concentrated, and the solid obtained was dissolved in the minimum amount of MeOH. The solid was precipitated from MeOH with EtOAc, the solvent was withdrawn with a pipet, and the solid was then triturated with hot EtOAc. The solvent was drawn off with a pipet upon cooling and the remaining solid dried under vacuum to provide 0.33 g (40%) of 4-methyl-2-(1H-tetrazol-5-yl)-pentylamine as a colorless solid, mp>240° C. (dec). 1H NMR (D2O) δ 3.31 (m, 1H, —CHCH2NH2), 3.10 (m, 2H, —CH2NH2), 1.53 (m, 1H, —CHCHHCH—), 1.35 (m, 1H, —CHCHHCH—), 1.03 (m, 1H, CH3CH—), 0.66 (d, J=6.6 Hz, 3H, CH3—), 0.61 (d, J=6.6 Hz, 3H, CH3—). LRMS: m/z 168.0 (M−1). Anal. Calcd for C7H15N5: C, 49.68; H, 8.93; N, 41.38. Found: C, 49.51; H, 8.90; N, 41.20.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([O-])=O>[Pd].O1CCCC1>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]=1[NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Under hydrogen gas atmosphere, a mixture of tert-butyl {2-[(2,6-dinitrophenyl)amino]ethyl}carbamate (8.44 g, 25.9 mmol) and 10% palladium on carbon (50% wet, 1.67 g) in tetrahydrofuran (260 mL) was stirred at room temperature for 4 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound as a brown oil (6.82 g, 25.6 mmol, 99%)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.Br[CH:16]([F:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl.O1CCOCC1>C(#N)C.C(OCC)(=O)C>[F:18][CH2:16][CH2:17][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(F)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC#N
Product: NC1CCN(CCF)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (2.00 g, 10.00 mmol), bromofluoroethane (1.5 g, 12.00 mmol) and potassium carbonate (2.80 g, 20.00 mmol) in acetonitrile (50 mL) was heated at 80° C. for 20 h. Cooled, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The residue was dissolved in DCM (10 mL) and 4N HCl/dioxane (12 mL, 50.00 mmol) was added and the suspension was stirred for 20 h at ambient temperature. The solid was collected by filtration, washed well with ethyl acetate and dried in a vacuum oven to afford 1-(2-fluoro-ethyl)-piperidin-4-ylamine.HCl salt (1.70 g, 93%): 1H NMR (400 MHz, DMSO) δ 8.43 (s, 3H), 5.02-4.90 (m, 1H), 4.89-4.77 (m, 1H), 3.56-3.50 (m, 2H), 3.46 (d, J=3.7 Hz, 1H), 3.38 (d, J=3.8 Hz, 1H), 3.26 (d, J=4.9 Hz, 1H), 3.18-3.02 (m, 2H), 2.20-2.09 (m, 2H), 2.07-1.89 (m, 2H).
Reaction SMILES: COC(=O)[CH2:4][NH:5][CH2:6][C:7]([NH:10][C:11]([O:13]C(C)(C)C)=O)([CH3:9])[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:8][C:7]1([CH3:9])[NH:10][C:11](=[O:13])[CH2:4][NH:5][CH2:6]1
Reactant: COC(=O)CNCC(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCC(=O)N1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A mixture of (2-tert-butoxycarbonylamino-2-methyl-propylamino)-acetic acid methyl ester (compound N; 26.5 g) in DCM (800 mL) was stirred at ambient temperature, TFA (180 mL) was added drop-wise. The mixture was stirred at 30-40° C. for 5 h before it was concentrated in vacuo. The residue was partitioned between dissolved toluene and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residual solid was dissolved in a mixture of ethanol (400 mL) and methanol (90 mL). K2CO3 (207 g) was added and the mixture was refluxed overnight. The mixture was cooled to room temperature. DCM (2500 mL) was added, and the mixture was stirred for 1 hour at ambient temperature. The solid was filtered off, and the filtrate was concentrated in vacuo to afford 6,6-dimethyl-piperazin-2-one (Compound I; 5.85 g) as a white solid sufficiently pure for the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a purple solid (24 mg, 35%). 1H NMR (CDCl3): 8.85-8.83 (m, 1H), 8.57-8.54 (m, 1H), 7.90-7.84 (m, 1H), 7.45-7.41 (m, 1H), 7.39 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.84 (s, 1H), 6.80 (s, 1H), 6.77 (dd, J=2.1, 8.1 Hz, 1H), 6.05 (s, 2H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[N+:32]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])([O-:34])=[O:33]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Yield: 99.6 %

Procedure:
To a solution of p-toluenesulfonic acid salt of L-alanine benzyl ester (7.03 g, 0.02 mol) and triethylamine (4.55 g, 0.045 mol) in methylene chloride (80 ml) was added dropwise a solution of 3-nitrobenzoyl chloride (3.71 g, 0.02 mol) in methylene chloride (20 ml) under ice-cooling and stirring. After the addition was completed, the mixture was stirred for 0.5 hour under the same condition and for 0.5 hour at ambient temperature. The mixture was washed with diluted hydrochloric acid and water twice successively. After drying over MgSO4, the solvent was removed in vacuo to give N-(3-nitrobenzoyl)-L-alanine benzyl ester (6.54 g, 99.6% yield) as a colorless crystal, which was used in a following reaction without further purification. 1H-NMR (CDCl3, δ): 1.56 (3H, d, J=7.2 Hz), 4.86 (1H, q, J=7.2 Hz), 5.24 (2H, dd, J=12.3 Hz, 13.6 Hz), 6.98 (1H, br, d, J=7.0 Hz), 7.37 (5H, s), 7.63 (1H, t, J=8.0 Hz), 8.14 (1H, dd, J=1.2Hz, 8.0 Hz), 8.35 (1H, d, t, J=8.0 Hz, 0.92 Hz), 8.62 (1H, t, J=0.92 Hz); APCI-MS: 329 (M+ +1)
Reaction SMILES: Cl.[C:2]1([CH3:24])[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16]C(=O)OC(C)(C)C.[OH-].[Na+]>C(OCC)(=O)C>[C:2]1([CH3:24])[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH2:16]
Reactant: Cc1cc(C)c(-c2ccncc2NC(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2ccncc2N)c(C)c1
Reaction time: 1 h
Yield: 3.8 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (100 mL) was added to a solution of tert-butyl N-(4-mesityl-3-pyridyl)carbamate (19.5 g, 62 mmol) in ethyl acetate (100 mL) followed by stirring for one hour. The solution was neutralized with a 5N aqueous solution of sodium hydroxide, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give the title compound (500 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7](Cl)=[C:8]([Cl:18])[C:9]2[O:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]=2[CH:17]=1)=O.[O:24]1C2C=CC=CC=2C(C2C(Cl)=C(Cl)C3OC(C(O)=O)CC=3C=2)=[N:25]1.S(=O)(=O)(O)O>C(O)C>[Cl:18][C:8]1[C:7]2[O:24][N:25]=[C:4]([C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[Cl:1])[C:6]=2[CH:17]=[C:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=12
Reactant: O=C(O)C1Cc2cc(-c3noc4ccccc34)c(Cl)c(Cl)c2O1
Reactant: O=C(c1ccccc1Cl)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C(O)C1Cc2cc3c(-c4ccccc4Cl)noc3c(Cl)c2O1

Procedure:
8-Chloro-3-(o-chlorophenyl)-5,6-dihydrofuro[3,2-f]-1,2-benzisoxazole-6-carboxylic acid (4d) was prepared from (3d) using the procedure above; the product contained a significant impurity, presumably the countercyclized 5-(3-benzisoxazolyl)-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid. The mixture was dissolved in 200 ml. absolute ethanol and treated with 0.5 ml. concentrated sulfuric acid overnight. The solution was then evaporated to dryness, redissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and re-evaporated. Chromatography of the ester on silica gel with chloroform and n-hexane in a 3:1 ratio gave a solid, m.p. 136° C., which was determined by detailed mass spectral analysis to be the desired isomer. Hydrolysis at 60° C. in 25 ml. absolute ethanol and 200 ml. aqueous 1M sodium hydroxide for 20 minutes furnished a white precipitate which was distributed between ethyl acetate and 4.0 M aqueous hydrochloric acid, washed with brine, dried over anhydrous magnesium sulfate, and evaporated. Recrystallization from ethyl acetate with n-hexane gave (4 d), m.p. 224°-225° C., in 8.1% yield. Analysis (C16H9Cl2NO4) C,H,N,Cl.
Reaction SMILES: C([O:5][C:6](=[O:11])[CH2:7][C:8](O)=[O:9])(C)(C)C.[CH3:12][NH:13][CH3:14].C1COCC1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.FC(F)(F)C(O)=O>CN(C=O)C.CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:12][N:13]([CH3:14])[C:8](=[O:9])[CH2:7][C:6]([OH:5])=[O:11]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a stirred solution of 3-tert-butoxy-3-oxopropanoic acid (680 mg, 4.25 mmol) and 2M dimethylamine in THF (3.18 mL, 6.37 mmol) in DMF (10 mL) was added diisopropyl-ethylamine (2.224 mL, 12.74 mmol), 4-(dimethylamino)pyridine (DMAP) (104 mg, 0.849 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (2421 mg, 6.37 mmol) and the resulting mixture was stirred at room temperature for 16 h. Water was then added and the resulting mixture was extracted with ethyl acetate (2×50 mL), washed with 1N HCl (20 mL), dried (Na2SO4), filtered and concentrated to give crude product which was dissolved in CH2Cl2 (5.00 mL), treated with trifluoroacetic acid (4.91 mL, 63.7 mmol) and stirred at room temperature for 16 h. The solvent was then removed under reduced pressure to afford the title compound (230 mg, 41% yield) as a light-yellow solid, which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ: 12.1 (1 H, br s), 3.4 (2 H, s), 2.9 (3 H, s), 2.8 (3 H, s). LCMS (M+H)=132.33.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH:21]([NH2:23])[CH3:22])[CH3:20]>C1(C)C=CC=CC=1>[CH3:20][CH:19]1[CH:21]([CH3:22])[N:23]2[C:11](=[O:13])[C:10]3[C:9]([C:1]2([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:18]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CC(N)C(C)N
Solvent: Cc1ccccc1
Product: CC1NC2(c3ccccc3)c3ccccc3C(=O)N2C1C

Procedure:
Condense o-benzoylbenzoic acid (22 g.) and 2,3-diaminobutane in toluene (400 ml.) by the procedure of Example 1 to obtain 2,3-dimethyl-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 162°-4° C. (elemental analysis confirms the empirical formula C18H18N2O) and reduce with lithium aluminum hydride as described in Example 1 to obtain 3,4-dimethyl-1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCS(=O)(=O)c1ccc2oc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCS(=O)(=O)c1ccc2oc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2c1

Procedure:
A mixture of 8.1 mmol of 2-chloro-5-ethanesulfonyl-benzoxazole, 8.3 mmol piperazine-1-carboxylic acid tert-butyl ester and 9.8 mmol of potassium carbonate in 20 ml of acetonitrile was refluxed for 16 hours. The reaction mixture was cooled, concentrated in vacuo and treated with 50 ml water. Extraction with ethyl acetate and recrystallisation from a concentrated ethyl acetate solution yielded the title compound as a brownish solid.
Reaction SMILES: C([O-])(=O)C.C(OC(C)C([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([CH3:22])[CH2:14][C:13]1([CH3:24])[CH3:23])=O)(=O)C.OS(O)(=O)=O.N>C(O)(=O)C.O>[NH2:12][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:16]=1[CH:15]([CH3:22])[CH2:14][C:13]2([CH3:23])[CH3:24]
Reactant: CC(=O)OC(C)C(=O)N1c2ccccc2C(C)CC1(C)C
Agent: CC(=O)[O-]
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(C)(C)c2cccc(N)c21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
The acetate compound prepared in B (ii) (55 g, GC purity 91%, 0.172 moles) was added over 45 minutes to 98% H2SO4 (50 ml) at 25°-60° C. (exotherm). After stirring for a further 30 minutes at 60° C., water (50 ml) containing acetic acid (10 ml) was cautiously added dropwise and the mixture heated at 100° C. for 3 hours. Petrol (60/80 b.p., 100 ml) was added and the mixture basified to pH 9 with 35% aqueous ammonia (150 ml). Separation of the organic layer, drying (MgSO4) and solvent flash gave the desired product (22.6 g, GC purity 92%, yield 69%). NMR analysis using chiral solvating agent [(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol] showed a 70/30 mixture of enantiomers in favour of the (-)-isomer.
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[H-].[Na+].BrC[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1.O>O1CCCC1>[CH3:1][CH:2]([CH2:8][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1)[C:3]([OH:5])=[O:4]
Reactant: BrCc1nc(-c2ccccc2)nc2ccccc12
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Reaction time: 1 h
Yield: 41.3 %

Procedure:
A solution of diethyl methylmalonate (23 g) in anhydrous tetrahydrofuran (100 cc) is added under nitrogen to sodium hydride (4 g, 80% strength in oil) and anhydrous tetrahydrofuran (60 cc). After 1 hour's stirring, a solution of 4-bromomethyl-2-phenylquinazoline (9.9 g) in anhydrous tetrahydrofuran (100 cc) is added, and the mixture is stirred for a further 2 hours at room temperature (approximately 20° C.). Water (100 cc) is added and the mixture is extracted with ethyl acetate (3×100 cc). The organic phase is dried over magnesium sulphate and then evaporated to dryness under reduced pressure. The residue is taken up in concentrated hydrochloric acid (100 cc) and acetic acid (100 cc) and the mixture is brought to 110° C. for 24 hours. After the mixture has cooled, the precipitate is filtered off and washed with water and then ispropyl ether. After being dried, α-methyl-2-phenyl-4-quinazolinepropanoic acid (4 g), m.p. 180° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCCCCC(=O)O
Product: O=C(O)CCCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 98 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and 6-aminohexanoic acid (0.177 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.39 g (97%) 144 as very pale dull orange crystals: mp=140° C.; Rf0.86 (A): Rf0.85 (B): Rf0.75 (D): IR (cm−1): 2875-3125 (OH), 3064 (C═CH), 1775 (C═O), 1706 (bs, C═O), 1624 (C═C), 1544 (N═O), 1437 (C═C), 1398 (C—O), 1348 (N═O), 1069 (C—O), 722 (C═CH); MS m/z (rel intensity) 277 (100), 251 (11), 191 (124).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13]O)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][Br:17])([O-:3])=[O:2]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(CCCO)c1ccccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCBr)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A mixture of 1-(o-nitrophenyl)-4-hydroxy-1-butanone (1.33 g, 6.4 mmol) and CBr4 (2.32 g, 7.0 mmol) in toluene is treated with triphenylphospine (2.50 g, 9.5 mmol), heated at 60° C. with stirring under nitrogen for 24 hours, cooled to room temperature and poured onto water. The resultant aqueous mixture is extracted with ethyl acetate. The extracts are combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give a residue. The residue is purified by flash column chromatography (silica gel; gradient 1:4→1:2 ethyl acetate: hexanes as eluent) to give the title product as a brown oil, 0.90 g, 52% yield, identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]=[S:2]1(=[O:68])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:64][CH2:63][C@@H:62]([C:65]([CH3:67])=[CH2:66])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:61])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:60]=[CH:59][C:36]([C:37]([O:39][C@H:40]5[O:45][C@H:44]([C:46]([O:48]CC6C=CC=CC=6)=[O:47])[C@@H:43]([OH:56])[C@H:42]([OH:57])[C@H:41]5[OH:58])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.C([SiH](C)C)(C)(C)C.C(N(CC)CC)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClC(Cl)C.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:68]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:64][CH2:63][C@@H:62]([C:65]([CH3:67])=[CH2:66])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:61])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20]([C:33]3[CH:60]=[CH:59][C:36]([C:37]([O:39][C@H:40]5[O:45][C@H:44]([C:46]([OH:48])=[O:47])[C@@H:43]([OH:56])[C@H:42]([OH:57])[C@H:41]5[OH:58])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:6][CH2:7]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O[C@H]7O[C@H](C(=O)OCc8ccccc8)[C@@H](O)[C@H](O)[C@H]7O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O[C@H]7O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]7O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of (2S,3S,4S,5R,6R)-benzyl 6-((4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (8 mg, 8.36 mmol), tert-butyldimethylsilane (1.943 mg, 0.017 mmol), palladium acetate (3.75 mg, 0.017 mmol) and triethylamine (5.82 μl, 0.042 mmol) in dichloroethane (1 mL) was heated up at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered and the filtrates were concentrated to provide the residue. To this residue in THF (1.0 mL) was added TBAF (10.93 mg, 0.042 mmol), the reaction mixture was stirred for 1 hours. The reaction mixture was then purified by prep. HPLC to provide the desired product as a colorless oil (4 mg, 52%). LCMS: m/e 867.69 (M+H)+, 2.42 min (method 10). 1H NMR (500 MHz, Acetic) δ 8.06 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 5.96 (d, J=7.9 Hz, 1H), 5.37 (d, J=4.4 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 4.40-4.16 (m, 1H), 4.02-3.76 (m, 3H), 3.46 (d, J=12.3 Hz, 1H), 3.37-3.22 (m, 6H), 3.20-3.11 (m, 3H), 3.07 (br. s., 2H), 3.00-2.82 (m, 1H), 2.37-1.03 (m, 22H), 1.76 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[C:17](=[N:19]/[N:20]=[C:21]([NH2:23])[NH2:22])/[CH3:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.CCO.[CH3:29][N:30]([CH3:42])[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[C:34]2[Cl:41].Cl>O>[ClH:41].[ClH:1].[NH2:22][C:21](=[N:20]/[N:19]=[C:17](/[C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([NH:3][C:34]3[C:33]4[C:38](=[CH:39][CH:40]=[C:31]([N:30]([CH3:42])[CH3:29])[CH:32]=4)[N:37]=[CH:36][CH:35]=3)=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=1)\[CH3:18])[NH2:23]
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(Nc3ccnc4ccc(N(C)C)cc34)cc2)c1

Procedure:
To a solution of triamine F5 (0.22 g, 0.59 mmol) in 1:2 EtOH:H2O (60 mL) were sequentially added 6-dimethylamino-4-chloroquinoline (0.13 g, 0.64 mmol) and c.HCl (0.16 mL, 5.32 mmol), and the resulting solution was refluxed for 20 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid). After this time, solvent was removed under reduced pressure, and the residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. JJ1 (61 mg, 19%) as an amorphous dark brown solid; mp 239-243° C. (powder→glue), 278-282° C. (glue→liquid); 1H NMR (400 MHz, DMSO): δ 14.44 (s, 1H, quinolinyl-N30—H), 11.20 (s, 1H, hydrazonyl-N30—H), 10.58 (s, 1H, ArC(O)NHAr), 10.46 (s, 1H, ArNHAr), 8.35 (d, J=6.71 Hz, 1H, ArH), 8.26 (t, J=1.73 Hz, 1H, ArH), 8.22 (d, J=8.61 Hz, 3H, ArH), 7.95 (m, 2H, ArH), 7.79 (m, 5H, ArH & ═C(NH2)2), 7.69 (d, J=2.52 Hz, 1H, ArH), 7.66 (d, J=8.61 Hz, 2H, ArH), 7.58 (d, J=2.43 Hz, 1H, ArH), 7.43 (t, J=7.98 Hz, 1H, ArH), 6.95 (d, J=6.71 Hz, 1H, ArH), 3.15 (s, 6H, ArN(CH3)2), 2.37 (s, 3H, Ar(CH3)═N—); LCMS (APCl+): 482 (100%); HPLC: 95.8%.