Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([CH2:21][C:22](=[O:24])[NH2:23])[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26][C:27](=O)[C:28]([C:30]1[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][C:34]([CH3:43])([CH3:42])[CH2:33][N:32]3[CH:31]=1)=O>>[C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([C:21]4[C:22](=[O:24])[NH:23][C:27](=[O:26])[C:28]=4[C:30]4[C:40]5=[C:41]6[C:36](=[CH:37][CH:38]=[CH:39]5)[CH2:35][C:34]([CH3:42])([CH3:43])[CH2:33][N:32]6[CH:31]=4)[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(C)(C)C2
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(CC(N)=O)ccc(c32)CN1
Product: CC1(C)Cc2cccc3c(C4=C(c5ccc6c7c5ccn7CC(C(=O)OC(C)(C)C)NC6)C(=O)NC4=O)cn(c23)C1

Procedure:
Beginning with 7-Carbamoylmethyl-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester and (5,5-Dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH:1]1([NH:6][C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]([C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCCC1)CO2
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(F)c2c1C[C@@H](N(C1CCCC1)C1CCC1)CO2
Reaction time: 144 h
Yield: 48.8 %

Procedure:
To a solution of (R)-3-(N-cyclopentylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (0.9 g, 3.4 mmol), HOAc (0.22 g, 3.6 mmol) and cyclobutanone (2g, 30 mmol) in methanol (25 mL), were NaCNBH3 (1 g, 16 mmol) added in portions at room temperature. After stirring for four days GC indicated 37% product. pH was adjusted to 5 (HOAc) and additional (1 g, 15 mmol) cyclobutanone was added. After stirring for further 6 days, GC indicated 64% conversion. The solvent was evaporated and the residue worked up by extraction. Flash chromatography (EtOAc/P-ether, 1+1), gave 0.53 g (53% yield) of the title compound as a colourless oil. GC/MS (70 eV) M=319 (3%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[C:12]([Cl:13])=[C:11]([F:14])[CH:10]=[CH:9][CH:8]=1>ClCCl>[Cl:6][C:7]1[C:12]([Cl:13])=[C:11]([F:14])[CH:10]=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Chlorosulphonic acid (12.1 mL) was added dropwise to a solution of 2,3-dichloro-4-fluorobenzene (5.0 g) in dichloromethane (12 mL) at −40° C. The solution was allowed to slowly warm to room temperature and was stirred for 3 days. The solution was poured onto crushed ice/water, extracted into dichloromethane and concentrated under reduced pressure. Purified by silica gel chromatography eluting with dichloromethane/iso-hexane mixtures. Yield 4.2 g
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>>[CH:15]1([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:39]3[CH:40]=[CH:41][C:36]([CH:33]([CH3:35])[CH3:34])=[CH:37][CH:38]=3)=[C:24]([CH3:30])[CH:23]=2)[C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2cc(C)c(Br)c(C)c2)C2CCCCC2)cc1
Product: Cc1cc(OC(c2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)cc(C)c1-c1ccc(C(C)C)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[(4-bromo-3,5-dimethyl-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. MS: 526.2 [M−H]−.
Reaction SMILES: [CH:1]([C@H:4]1[C@H:7]([CH2:8][CH2:9][OH:10])[NH:6][C:5]1=[O:11])([CH3:3])[CH3:2].C(Cl)Cl.[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH:1]([CH:4]1[CH:7]([CH2:8][CH2:9][O:10][C:15](=[O:17])[CH3:16])[NH:6][C:5]1=[O:11])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)[C@@H]1C(=O)N[C@H]1CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCC1NC(=O)C1C(C)C
Reaction time: 0.25 h

Procedure:
Trans-3-isopropyl-4-(2-hydroxyethyl)-2-azetidinone from Step B, is dissolved in 10 ml. CH2Cl2 and cooled to 0° C. Pyridine 0.75 ml is added and then 0.392 ml of acetyl chloride is added dropwise. The mixture is stirred at 0° for 15 min and then at 25° C. for another 15 minutes. The reaction mixture is evaporated to dryness. The residue is chromatographed on silica gel using 50% EtOAc/C6H6 as eluant to give 0.652 g 3-isopropyl-4-(2-acetoxyethyl)-azetidinone.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[F:1][C:2]1[CH:29]=[C:28]([CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH:18]=3)[S:13][C:6]=12)[NH2:30]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)nn4)sc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)nn4)sc23)c(F)c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a solution of 360 (150 mg, 0.329 mmol) in MeOH (10 mL) was added ammonium chloride (35.3 mg, 2 eq, 0.660 mmol) in water (1 mL) and zinc powder (86 mg, 4 eq, 1.320 mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to RT then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound 361 (98 mg, 70% yield) that was used in the next step with no additional purification. MS (m/z): 425.5 (M+H)
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:14]([N:21]1[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[C:24](=O)[O:23]C1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[C:24]=1[OH:23])=[O:4])[CH3:7]
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2sccc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ccsc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Yield: 67 %

Procedure:
Diethyl malonate (2.14 mL, 0.014 mol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil, 0.66 g, 0.017 mol) in 50 mL anhydrous DMF stirred at 0° C. under argon. The solution was stirred for 15 minutes. Solid 1-benzyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (58) (3.58 g, 0.014 mol) was added, and the solution was heated at 110° C. for 2 hours. The solvent was then removed under vacuum, and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with dil. HCl to precipitate the product, which was collected by vacuum filtration to give 3.09 g (68%) of 7-benzyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester. MP 146° C. 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.25 (s, 2H), 7.24-7.36 (m, 7H), 13.21 (b, 1H) ppm; EIMS m/z 330 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][C:23](O)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].ClC(OCC(C)C)=O>O1CCCC1>[OH:24][CH2:23][CH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCO
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 93.8 %

Procedure:
Diisopropylethylamine (575 μl) was added to a solution of 2-[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]acetic acid (688 mg) in tetrahydrofuran (15 ml, and the mixture was cooled to −20° C. Isobutyl chloroformate (428 μl) was added thereto, and the mixture was stirred at −20° C. for 45 minutes. The resulting solid was filtered off, and the solid was washed with tetrahydrofuran. Sodium borohydride (227 mg) was added to the filtrate, and the mixture was stirred at room temperature for 5 minutes. Then, methanol (5 ml) was added thereto, and the mixture was stirred at room temperature for 5 minutes. Ethyl acetate and water were added to the reaction solution to separate the aqueous and organic layers. The aqueous layer was subjected to extraction with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain tert-butyl (2S)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (606 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11](#[N:13])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[C:11]#[N:13]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC#N
Solvent: Cc1ccccc1
Product: N#CC(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
Orthochlorobenzoyl chloride (17.5 g, 0.1 mol), cuprous cyanide (11.65 g, 0.13 mol), and acetonitrile (8 mL) were refluxed in toluene (15 mL) for 3 hours, and were cooled to room temperature. Then, insoluble substances were removed through filtration, and the residue was washed with toluene. Solvent in the resulting filtrate was evaporated under reduced pressure, and the residue was distilled to obtain orthochlorophenyloxoacetonitrile (12.3 g, 75% yield).
Reaction SMILES: Cl.C([N:4]([C:10]1[N:15]=[C:14]([CH2:16][O:17]/[N:18]=[C:19](\[C:26]2[N:30]([CH3:31])[N:29]=[N:28][N:27]=2)/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH2:5]([NH:4][C:10]1[N:15]=[C:14]([CH2:16][O:17]/[N:18]=[C:19](\[C:26]2[N:30]([CH3:31])[N:29]=[N:28][N:27]=2)/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCN(C=O)c1cccc(CO/N=C(/c2ccccc2)c2nnnn2C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCCNc1cccc(CO/N=C(/c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.5 ml of 3 M hydrochloric acid were added to 5 ml of an ethyl acetate solution of the (Z)-(1-methyl-1H-tetrazol-5-yl) phenylmethanone-O-(6-(N-formyl-N-n-pentylamino)pyridin-2-ylmethyl) oxime obtained in Example 1 followed by stirring for 5 hours at room temperature. The pH of the reaction liquid was adjusted to pH 7 by adding aqueous sodium carbonate solution thereto. After extracting with ethyl acetate, the product was washed with water and dried with anhydrous magnesium sulfate followed by distilling off the solvent. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=2/1 (v/v)) to obtain 0.14 g of (Z)-(6-n-pentylaminopyridin-2-yl)methoxyimino-(1-methyl-1H-tetrazol-5-yl)phenylmethane (compound no. 1-6 in the previous tables).
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19][C:20](=[O:39])[O:21][CH2:22][C:23]1([CH2:27][C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CCCCCC>[O:13]=[C:3]([NH:4][C@@H:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6])[C:2]([C@@H:14]([NH:19][C:20](=[O:39])[O:21][CH2:22][C:23]1([CH2:27][C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1]
Reactant: CCCC[C@H](NC(=O)OCC1(Cc2nc(-c3ccccc3)cs2)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)OCC1(Cc2nc(-c3ccccc3)cs2)CCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
To a solution of 0.2 g (0.364 mmol) of {1-[(4-phenyl-1,3-thiazol-2-yl)methyl]cyclobutyl}methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate in 3 mL of dichloromethane cooled to −60° C. was added 0.079 mL (0.91 mmol) of oxalyl chloride and—0.129 mL (1.82 mmol) od dimethylsulfoxide, followed by the addition of 0.204 mL (1.45 mmol) of triethylamine. After stirring for 15 min, the reaction was warmed to room temperature and applied directly to a silica gel column using ethyl acetate:hexane (3:7) as the eluent to afford 0.19 g (96%) of {1-[(4-phenyl-1,3-thiazol-2-yl)methyl]cyclobutyl}methyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (d, J=8 Hz, 1H), 7.98 (m, 3H), 7.64 (d, J=8 Hz, 1H), 7.25-7.23 (m, 8 H), 4.96-5.01 (m, 1H), 4.80 (m, 1H), 4.01 (s, 2H), 3.30 (s, 2H), 2.12-1.64 (m, 10 H), 1.42 (d, J=7 Hz, 3H), 1.29-1.21 (m, 2H), 0.82 (t, J=7 Hz, 3H). LC-MS m/z 548 (M+H).
Reaction SMILES: [NH:1]([C:23](OCC1C=CC=CC=1)=[O:24])[C@H:2]([C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:33]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C@H:34](C(O)=O)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CO.CN(C)C=O.[C].[Pd].O>[NH:33]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C@H:34]([C:23]([NH:1][C@H:2]([C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:24])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.3 %

Procedure:
Compound 1a (9.69 g, 21.9 mmol) was dissolved in 200 mL of methanol, to which 500 mg of 10% palladium carbon was then added, followed by stirring at room temperature for one day under an atmosphere of hydrogen. The catalyst was filtered off from the reaction mixture, followed by concentration under reduced pressure. This residue, Cbz-Phe (6.92 g, 23.1 mmol), HOBT (3.71 g, 24.2 mmol), and NMM (2.66 mL, 24.2 mmol) were dissolved in 50 mL of dimethylformamide (DMF), to which EDC (4.64 g, 24.2 mmol) was then added under stirring and cooling with ice, followed by stirring at room temperature for one day. Water was added to the reaction solution, which was then washed with a 10% citric acid aqueous solution, a saturated sodium bicarbonate solution, and water before drying. The resultant residue was purified using silica gel column chromatography (elution solvent: chloroform:methanol=90:10) to provide 12.8 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:21]([C:22]3[N:27]=[N:26][C:25]([C:28]([NH2:30])=O)=[CH:24][CH:23]=3)[C:20]3[CH:31]=[CH:32][CH:33]=[CH:34][C:19]=3[N:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:21]([C:22]3[N:27]=[N:26][C:25]([C:28]#[N:30])=[CH:24][CH:23]=3)[C:20]3[CH:31]=[CH:32][CH:33]=[CH:34][C:19]=3[N:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C(N)=O)nn2)c1OC1CCCC1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C#N)nn2)c1OC1CCCC1
Reaction time: 1 h

Procedure:
The final compound was prepared by adding triethylamne (80.0 mg, 0.78 mmol) to a stirred solution of Step 2 product (121 mg, 0.263 mmol) dissolved in dry DCM (5 ml) follwed by addition of triflouroacetic anhydride (84 mg, 0.395 mmol) at 0° C., under nitrogen atmosphere and the reaction mixture stirred for 1 h. The reaction mixture was then extracted with CHCl3 and the combined organic layers washed with water, brine, dried (Na2SO4), filtered and concentrated under vaccum. The crude product was purified by silica gel column chromatography using 2% acetone in chloroform to give 79 mg of the product of off-white solid; IR (KBr) 2959, 2243, 1573, 1455, 1263, 743 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 1.62-1.68 (m, 4H), 1.78-1.89 (m, 4H), 3.86 (s, 3H), 4.89 (br s, 1H), 6.90 (d, J=7.8 Hz, 1H), 7.03 (t, J=7.8 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.23-7.28 (m, 1H), 7.35-7.44 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.87 (d, J=9.3 Hz, 2H), 8.06 (d, J=9.0 Hz, 1H), 8.19 (d, J=15.9 Hz,1H); APCI-MS (m/z) 438.21 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:19]=1)=[O:17].O[Li].O>>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:20]2[CH:19]=[C:18]([C:16]([NH:15][C:3]3[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][C:2]=3[F:1])=[O:17])[C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:33][CH:32]=1
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3ccc(F)cc3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3ccc(F)cc3)cc3ccccc23)c1

Procedure:
Compound 17c was synthesized from 16c (0.5 mmol) and LiOH.H2O (5 mmol) using the procedure according to Method E described above.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1

Procedure:
Using the general method of Example 1, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.76 mmol) was reacted with benzoyl chloride (0.25 g, 1.76 mmol) to provide N1-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 203-206° C. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.47 (broad s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.32 (q, J=6.0 Hz, 2H), 2.95 (q, J=7.0 Hz, 2H), 1.87 (quintet, J=7.0 Hz, 2H), 1.70 (quintet, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H);
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1([CH3:43])[O:30][CH:29]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][O:27]1.[N+](C1C=CC(C=CC2C=CC=CC=2)=CC=1)([O-])=O>O.CN(C)C=O>[CH3:25][C:26]1([CH3:43])[O:30][CH:29]([CH2:31][C:2]2[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)[CH2:28][O:27]1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(C=Cc2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)cc2)O1

Procedure:
A mixture of 120.5 g of 4-hydroxy-4'-nitrostilbene, 69 g of anhydrous potassium carbonate, 143 g of 2,2-dimethyl-4-(4-methyl phenyl sulphonyloxymethyl)-1,3-dioxolane, prepared in accordance with the specification of K. Freudenberg and H. Hess in Liebigs Annalen der Chemie Vol. 448 (1926), p. 121, and 1 l of dimethyl formamide (DMF) was boiled for 30 minutes with refluxing. After cooling the reaction mixture was poured, with vigorous stirring, into 5 l of water. The precipitated crystals were filtered off and after-washed with 5 1 of water. The crude product after drying was crystallized from 4 l of acetone. Obtained were 135 g of 4-((2,2-dimethyl)-1,3-dioxa-4-cyclopentyl)methyl)-4'nitrostilbene in the form of yellow acicular crystals having a melting point of 146°-147° C.
Reaction SMILES: Cl[CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:18][C:10]1[N:9]=[C:8]2[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][C:7]2=[CH:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(nc1C)C(Cl)CCCC2
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2c(nc1C)C=CCCC2
Yield: 97.5 %

Procedure:
In an atmosphere of argon, ethyl 9-chloro-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (3.35 g, 12.5 mmol) was dissolved in toluene (12.0 ml), and the solution was mixed with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (2.9 ml, 18.9 mmol) at 0° C. and then heated under reflux for 23 hours. The solvent was evaporated under reduced pressure, and the thus obtained residue was dissolved in ethyl acetate, mixed with water and then extracted with ethyl acetate. The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:2) to obtain the title compound (2.82 g, 97.5%) as pale yellow oil.
Reaction SMILES: Cl.ClC1C=CC=CC=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44](C)([CH3:46])[CH3:45])=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][CH:44]([CH3:46])[CH3:45])=[O:42])[CH2:38]1)[C:27]1[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=1[Cl:25]
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Agent: Cl
Agent: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: [N-]=C=O
Product: CC(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).