Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]2[CH2:14][C@H:13]3[NH:15][C@@H:9]2[CH2:10][CH2:11][CH2:12]3)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[NH:15][C@H:9]2[CH2:10][CH2:11][CH2:12]3)=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@H]2C[C@@H]3CCC[C@H]2N3)cn1
Solvent: ClC(Cl)Cl
Product: Fc1ccc([C@@H]2C[C@H]3CCC[C@@H]2N3)cn1
Reaction time: 0.47 h
Yield: 43 %

Procedure:
Resolution of racemates is done by semi-preparative chiral HPLC such as e.g. with a 250×20 mm, 5 μL, CHIRALPAK® IA column. 5.2 g (25.2 mmol) of (+/−)-exo-6-(6-fluoro-pyridine-3-yl)-8-aza-bicyclo-[3.2.1]octane-8-carboxylic acid benzyl ester (III) are dissolved in 42 ml of a mobile solvent (MeCN/0.1% diethylamine). The injection volume is 1 ml. Separation was done under isocratic conditions with a flow of 20 ml/min. Detection is performed by means of a UV detector at a wavelength of 280 nm. The retention time of the (+)-enantiomer (VI) is approx. 8-13 min, that of the (−)-enantiomer (V) approx. 19-38 min. Both enantiomers are separately collected, after chiral HPLC the mobile solvent is removed by means of the rotary evaporator. The enantiomeric purity is determined by analytic chiral HPLC by means of a 250×4.6 mm, 5 μL, CHIRALPAK® IA column. 1 mg of the respective enantiomer is dissolved in 1 ml of a mobile solvent (MeOH/0.1% TEA). The injection volume is 10 μL. Separation was done under isocratic conditions with a flow of 1 ml/min. Detection is done at 280 nm. The retention time of the (+)-enantiomer (VI) is 11.5 min, that of the (−)-enantiomer (V) 17.5 min. 2.24 g (10.86 mmol, 43%, >99% ee, [α]D20 (CHCl3, c=0.5)=−30.9°) of (−)-(1R,5S,6S)-6-(6-fluoro-pyridine-3-yl)-8-aza-bicyclo[3.2.1]octane (V) and 2.2 g (10.67 mmol, 42%, >99% ee, [α]D20 (CHCl3, c=0.5)=)+29.0° of (+)-(1S,5R,6R)-6-(6-fluoro-pyridine-3-yl)-8-aza-bicyclo[3.2.1]octane (VI), respectively, is isolated as a colorless solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][C:16](=[O:31])[N:17]([CH2:19][C:20]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:21]=1[S:27][CH:28]([CH3:30])[CH3:29])[CH3:18])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl.O>[C:5]1([O:4][C:2](=[O:3])[NH:26][C:24]2[CH:23]=[CH:22][C:21]([S:27][CH:28]([CH3:30])[CH3:29])=[C:20]([CH2:19][N:17]([C:16]([O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:31])[CH3:18])[CH:25]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)Sc1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Sc1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Phenyl chloroformate (0.204 mL, 1.62 mmol) was added dropwise to a solution of 16E (0.48 g, 1.55 mmol) in pyridine (0.193 mL, 2.38 mmol) and DCM (3.5 mL) at 0° C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient from 0 to 50% ethyl acetate in hexanes) to give 16F (0.609 g, 91%) as a white foam.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([CH2:13][NH:14][CH3:15])=[CH:5][CH:4]=[C:3]3[CH2:2]1.[NH2:16][C:17]1[N:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.[ClH:58]>CN(C=O)C.O>[ClH:58].[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([CH2:13][N:14]([CH3:15])[C:25](=[O:27])/[CH:24]=[CH:23]/[C:20]2[CH:21]=[N:22][C:17]([NH2:16])=[CH:18][CH:19]=2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CNCc1ccc2c3c(cccc13)CC2
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc2c3c(cccc13)CC2)C(=O)/C=C/c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of acenaphthen-5-ylmethyl-methylamine (216 mg, 1.1 mmol), (E)-3-(6-amino-pyridin-3-yl)acrylic acid (164 mg, 1 mmol), HOBt (148 mg, 1.1 mmol) and diisopropylethylamine (0.8 mL, 4.4 mmol) in DMF (20 mL) was added EDC hydrochloride (210 mg, 1.1 mmol). The mixture was stirred overnight at room temperature. Water (100 mL) was added and the solution stirred for 1 hour. The precipitate was collected by filtration. The yellow solid was preabsorded onto silica gel and purified by column chromatography (95:5 CH2Cl2/MeOH). The residue was dissolved into methylene chloride followed by addition of 1M HCl/ether. The precipitate was collected by filtration to afford (E)-N-acenaphthen-5-ylmethyl-3-(6-amino-pyridin-3-yl)-N-methyl-acrylamide hydrochloride (120 mg, 32%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 8.44-8.28 (m, 3H), 7.84-7.72 (m, 1H), 7.59-7.12 (m, 6H), 7.07-6.92 (m, 1H), 5.15-5.02 (2×s, 2H), 3.35-3.15 (bs, 2H), 3.18 (s, 4H), 3.07-2.90 (2×s, 3H); ESI MS m/z 344 [C22H21N3O+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:15]([NH2:18])[CH2:16][CH3:17].C(N(CC)CC)C>C(#N)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([NH:18][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-Nitrophenyl)methanesulfonyl chloride (0.6 g, 2.55 mmol) was dissolved in acetonitrile (10 mL), then to this solution was added propylamine (0.247 ml, 3 mmol) and triethylamine (1 mL) and the reaction mixture was vigorously stirred for 3 h at room temperature. The obtained mixture was diluted with cold water (30 ml), which led to the formation of a precipitate that was filtered off, washed with water (2×10 mL) and dried. Yield of (3-nitrophenyl)-N-propylmethanesulfonamide 0.63 g (95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]([NH:17][C:13]1[CH:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[CH:16]=[CH:15][CH:14]=1)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)c1cccc(-c2cccc(N)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cccc(NC(=O)CNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a mixture of 3′-amino-[1,1′-biphenyl]-3-carboxylic methyl ester (1.14 g) and N-(tert-butoxycarbonyl)glycine (0.879 g) in methylene chloride (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20 g). The mixture was stirred for 3 h at room temperature, then washed twice with 1 N aqueous HCl, twice with saturated aqueous sodium bicarbonate and once with brine. The mixture was dried over sodium sulfate, filtered and concentrated to give a foam. Purification by silica gel chromatography eluting with 7:3 hexane/ethyl acetate gave 1.6 g of the title compound as a colorless oil. Electrospray MS (positive ion): (M+Na) 407.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([N:30]3[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]4([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]4=[O:15])[CH2:32][CH2:31]3)[C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: CC(C)CC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Product: CC(C)CC1(CCCCN2CCN(c3cccc4c3OCCO4)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-isobutyl-1,3-dihydro-2H-indol-2-one and 4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2[CH2:1][NH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Solvent: O
Product: NCc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Methylamine (available as a 40% solution in water, 24 mL, 0.28 mol) was added to a solution of 6-benzyloxy-4-chloro-3-nitroquinoline (15.0 g, 48.5 mmol), prepared as described in Parts A-D of Example 2, in distilled water (300 mL), and the reaction was stirred at 100° C. for 1.5 hours. The reaction was allowed to cool to ambient temperature and stirred for four hours. A precipitate formed, which was isolated by filtration and washed with distilled water (3×60 mL). The solid was combined with material from another run and recrystallized from 2-propanol. The crystals were isolated by filtration, washed twice with cold hexanes, and dried for three days under high vacuum to provide 24.10 g of (6-benzyloxy-3-nitroquinolin-4-yl)methylamine as yellow crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:19]1[O:29][C:28]2[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][C:21]=2[O:20]1>>[O:29]1[C:28]2[CH:27]=[CH:26][C:23]([CH2:24][N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:8]=4[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]5)[CH2:2][CH2:3]3)=[CH:22][C:21]=2[O:20][CH2:19]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: ClCc1ccc2c(c1)OCO2
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc5c(c4)OCO5)CC3)cccc2n1
Yield: 50 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3,4-methylenedioxybenzyl chloride (63.1 mg; 0.37 mmol) to obtain 37.5 mg. (50% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.92 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.04 (m, 2H), 6.85 (m, 3H), 6.65 (s, 2H), 6.0 (s, 2H), 3.47 (s, 2H), 2.99 (d, J=12.0 Hz, 2H), 2.85 (m, 4H), 2.24 (t, J=11.2 Hz, 2H).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[N:3][CH:2]=[N:1][CH:9]=4)[N:5]=[CH:6]3)=[CH:12][CH:13]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ncc2[nH]cnc2n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(-n2cnc3ncncc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from purine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:30]=2[F:29])[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: O=C(Cl)c1cccc(F)c1F
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4F)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 2,3-difluorobenzoyl chloride gave the title compound.
Reaction SMILES: C(B(CC)CC)C.[OH:8][CH:9]([CH2:15][C:16](=[O:25])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[BH4-].[Na+].C(Cl)(=O)C>C1COCC1.CO>[OH:8][CH:9]([CH2:15][CH:16]([OH:25])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(O)CC(=O)CC(=O)OC(C)(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of THF (2.2 ml), methanol (4.4 ml) and triethylborane (1M in THF) (8.52 ml) was stirred at room temperature for one hour in an argon atmosphere. A solution of 1-ethyl 6-tert.-butyl 2-hydroxy-4-oxoadipate (1.85 g, 7.1 mmol) in THF (2 ml) was dropwise added to the above boran solution at room temperature. After stirring at room temperature for 2 hours and cooling the mixture to -78° C., sodium borohydride (229 mg, 6.1 mmol) was added in one portion, followed by stirring at -78° C. for 2 hours. After dropwise adding acetyl chloride (0.26 ml) to the reaction solution at -78° C., the solution was stirred for additional 30 minutes at room temperature. After evaporating methanol off under reduced pressure, methanol (30 ml) was added to the mixture and again methanol was evaporated off under reduced pressure. After adding methylene chloride (20 ml) and water (20 ml), pH of the mixture was adjusted to 6 with 1N hydrochloric acid, and mixture was separated. The aqueous layer was extracted with methylene chloride twice (each 50 ml), and organic layers were combined and washed with water (30 ml). After drying the organic solution over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=5:1) to give pure 1-ethyl 6-tert.-butyl 2,4-dihydroxyadipate (1.76 g, 6.73 mmol). Yield, 95 %.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][S:23][C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[NH:26][CH:27]=[N:28]5)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Sc1ncnc2nc[nH]c12
Product: CCN1c2ncc(CSc3ncnc4nc[nH]c34)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 67 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 148°-151° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 6-mercaptopurine. The yield was 67% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[CH2:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][CH:7]=1>S(=O)(=O)(O)O>[OH:14][C:9]1[CH:10]=[C:11]([CH3:12])[C:5]2[C:4](=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:8]=1
Reactant: CC(=O)CC(=O)Nc1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(O)nc2cc(Br)ccc12
Yield: 84.3 %

Procedure:
6.65 g (26.00 mM) of N-(3-bromophenyl)-3-oxobutyramide was heated in 30 mL of conc. sulfuric acid to 120° C. (oil bath temperature) for 1.5 h. The reaction mixture was then poured into ice, whereby precipitate was formed. This was filtered and washed repeatedly with water. After drying, it was recrystallised in 95% ethanol, providing 5.21 g (84%) of the product as a white solid: mp 275°-276° C.;
Reaction SMILES: [NH:1]([C:7](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:8])[CH:2](O)[C:3]([OH:5])=[O:4].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26][CH:25]=1.[F:36][C:37]([F:49])([F:48])[S:38]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>>[F:36][C:37]([F:49])([F:48])[C:3]([OH:5])=[O:4].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][N:1]2[CH2:2][C:3](=[O:4])[N:45]([C:44]3[CH:46]=[CH:47][C:41]([S:38]([C:37]([F:48])([F:36])[F:49])(=[O:39])=[O:40])=[CH:42][CH:43]=3)[C:7]2=[O:8])=[CH:26][CH:25]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(NC(O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: O=C(O)C(F)(F)F
Product: O=C1CN(Cc2ccnc3ccccc23)C(=O)N1c1ccc(S(=O)(=O)C(F)(F)F)cc1
Yield: 35.5 %

Procedure:
The compound is prepared from 4 mmol of resin, 12 mmol of N-Fmoc-Gly(OH), 20 mmol of 4-quinolinecarboxaldehyde, and 10 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 1 g of expected product is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([O:25]CCC#N)=[O:24])=[C:5]([O:30][C:31]([F:34])([F:33])[F:32])[CH:4]=1)#[N:2].[OH-].[Na+].C(OCC)C.O>COCCOC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([OH:25])=[O:24])=[C:5]([O:30][C:31]([F:32])([F:33])[F:34])[CH:4]=1)#[N:2]
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOCC
Solvent: O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1400 mg (2.96 mmol) of the compound from Example 36A are dissolved in 35 ml of 1,2-dimethoxyethane/water (2.5:1 v/v), 5.93 ml (5.93 mmol) of 1 N sodium hydroxide solution are added, and the mixture is stirred at room temperature for 2 h. The reaction mixture is then mixed with 50 ml of diethyl ether and 50 ml of water. The aqueous phase is separated off and adjusted to a pH of 4-5 with 1 N hydrochloric acid. The resulting suspension is then stirred for 1 h. The resulting precipitate is filtered off and washed with water and a little diethyl ether. Drying in vacuo results in 850 mg (68% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[I-].[Na+].O1CCCC1.[CH2:23]([NH2:25])[CH3:24]>CC(C)=O.C(Cl)Cl>[CH2:23]([NH:25][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1])[CH3:24]
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: CCN
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCNCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (500 mg, 1.47 mmol) in acetone (7.3 ml) was treated with sodium iodide (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of ethylamine (11 ml, 22.0 mmol). The resulting mixture was stirred for about 17 hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was diluted with methylene chloride, and washed with 25 mM phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]([CH2:14]O)=[CH:12][C:11]2[CH:10]=[C:9]3[O:16][CH2:17][O:18][C:8]3=[CH:7][C:6]=2[N:5]=1)[CH3:2].S(Cl)([Cl:21])=O>C(Cl)Cl>[ClH:21].[Cl:21][CH2:14][C:13]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]2[CH:7]=[C:8]3[O:18][CH2:17][O:16][C:9]3=[CH:10][C:11]=2[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: CCNc1nc2cc3c(cc2cc1CO)OCO3
Solvent: ClCCl
Product: CCNc1nc2cc3c(cc2cc1CCl)OCO3
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of (6-(ethylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methanol RBO 40002 (901 mg, 3.66 mmol) in CH2Cl2 (30 mL) in a round-bottomed flask equipped with a magnetic stirrer was added thionyl chloride (2.65 mL, 36.6 mmol). The mixture was stirring for 3 h at RT, evaporated under vacuum at 45° C. and coevaporated twice with CH2Cl2 (to remove SOCl2) to afford 7-(chloromethyl)-N-ethyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride RBO 40004 as a yellow solid (1.01 g, 92% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:18]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:18][C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[NH:3][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
To a solution (20 mL) of ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (1.0 g) in N,N-dimethylformamide was added N-chlorosuccinimide (874 mg) at 0° C. The reaction mixture was stirred at room temperature for 4 hr, 6% aqueous sodium hydrogencarbonate solution was added, 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 silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as colorless crystals (yield 509 mg, 44%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH2:24])[NH:17][C:16]3[C:15]4[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=4[C:13]4[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=4[C:11]2=3)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH2:24])[NH:17][C:16]3[C:15]4[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=4[C:13]4[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=4[C:11]2=3)=[CH:6][CH:5]=1
Reactant: Nc1cccc2c1N(c1ccc([N+](=O)[O-])cc1)c1c(c3ccccc3c3ccccc13)N2
Solvent: C1CCOC1
Product: Nc1ccc(N2c3c(N)cccc3Nc3c2c2ccccc2c2ccccc32)cc1

Procedure:
4.5 g (10.8 mmol) of N-4-nitrophenyl-10-aminodibenzo(A,C)phenazine was dissolved in 200 ml of tetrahydrofuran, and the reaction container was purged with nitrogen. Thereafter, 4.6 g of 5% Pd/C (hydrous) was added, followed by sufficient purging with nitrogen again. This system was purged with hydrogen, followed by reaction at room temperature for 10 hours. After completion of the reaction, the system was filtered, and the resulting filtration residue was further washed with tetrahydrofuran and purified with a column to obtain the intended product.