Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:3]=1.OS(O)(=O)=O.NC1C2C(=O)C3C(=C(N)C=C([Cl:51])C=3O)C(=O)C=2C(O)=C(C2C=CC(OC)=CC=2)C=1>O=[Mn]=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:18])[C:10]([Cl:51])=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: COc1ccc(-c2cc(N)c3c(c2O)C(=O)c2c(N)ccc(O)c2C3=O)cc1
Reactant: COc1ccc(-c2cc(N)c3c(c2O)C(=O)c2c(N)cc(Cl)c(O)c2C3=O)cc1
Agent: O=[Mn]=O
Agent: O=S(=O)(O)O
Product: COc1ccc(-c2cc(N)c3c(c2O)C(=O)c2c(N)c(Cl)cc(O)c2C3=O)cc1
Reaction time: 1 h

Procedure:
A mixture of 2.1 g of 4,8-diamino-1,5-dihydroxy-2-p-methoxyphenylanthraquinone (which can be prepared from 1,5-dihydroxy-4,8-dinitroanthraquinone, for method see German Offenlegungsschrift No. 3,007,198), 32 g of 60% H2SO4, and 3 g of active MnO2 is stirred for 1 hour at 20°, the mixture is filtered and 1 g of NaCl is added to the filtrate, which contains the corresponding quinoneimine. After stirring for half an hour, the mixture is poured into ice-water and the product is filtered off. The crude product is chromatographed over silica gel using petroleum ether/ether mixtures. The main product obtained is 4,8-diamino-6-chloro-1,5-dihydroxy-2-p-methoxyphenylanthraquinone, m.p. 310° (decomposition); Rf 0.41 (silica gel; 3:2 ether/petroleum ether). 4,8-diamino-7-chloro-1,5-dihydroxy-2-p-methoxyphenylanthraquinone, Rf 0.45 (silica gel; 3:2 ether/petroleum ether) is also formed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-trans-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (9.48 mmol, 2.05 g) in a biphasic mixture of DCM (10 mL) and saturated sodium bicarbonate (10 mL) at 0° C. was added benzyl chloroformate (2.0 mL) drop-wise and continued stirring at 0-5° C. for 1 h. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with 50% ethyl acetate in hexanes to provide (±)-trans-4-benzyloxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.[NH:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:21]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)[N:22]=2)[CH:20]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc(-c3cc(Cl)ccc3O)nc2-c2cc(Cl)ccc2O)cc1

Procedure:
3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 1.7 g of 4-hydrazinobenzoic acid are boiled under reflux for 2 h in 40 ml of ethanol. The crystals precipitating on cooling are recrystallized from isopropanol. After drying, 4-[3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid remains as colorless crystals of m.p. 275-278 C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[N:24]=[CH:25][NH:26]C=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][C:22]2[N:26]=[CH:25][N:24]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCc1c[nH]cn1)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(CCCc2cn(Cc3ccccc3)cn2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 2.7 %

Procedure:
A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (300 mg, 0.77 mmol) in anhydrous THF (5 ml) was treated with benzyl bromide (144 mg, 0.84 mmol) and DIPEA (147 μl, 0.84 mmol). The mixture was left to stir at rt under nitrogen for 4 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude was purified by a silica SPE column using a 0.5-5% MeOH/DCM gradient. The product fractions were combined and concentrated under high vacuum. The product was dissolved in THF (5 ml) then Pd(PPh3)4 (88 mg, 0.077 mmol) and morpholine (670 μl, 7.67 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. 88 mg of Pd(PPh3)4 (0.077 mmol) was added and the mixture was left to stir at rt under nitrogen for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc (×2). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated. The crude product was purified by MDAP to give the title compound as a white solid (9 mg, 2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cc1onc(-c2ccc(Br)cc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 92 %

Procedure:
As described for Example 49, 3-(4-bromo-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (91 mg, 0.3 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (117 mg, 92%) which was obtained as a light yellow solid. MS: m/e 425.0/426.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([OH:26])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.Cl.[NH:28]1[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:24]([C:16]2[CH:15]=[C:14]([O:13][CH:4]3[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[O:7][CH2:6][CH2:5]3)[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=2)=[O:26])[CH2:31][CH2:30][CH2:29]1
Reactant: C1CNC1
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Agent: Cl
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CCC3)cc2[nH]1

Procedure:
The title compound was prepared as a white solid (132 mg, 79%) from (−)-4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid (150 mg, STEP 1) and azetidine hydrochloride (117 mg, 1.25 mmol) by the same manner in STEP 5 of Example 1.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>>[CH3:22][N:23]([CH3:25])[CH:24]=[C:3]([C:2](=[O:1])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cccc(C#N)c1

Procedure:
Ethyl 3-oxo-3-(3-cyano-phenyl)-propionate (109 mg, 0.5 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (85 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26](Cl)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]2[OH:40])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.O.[NH2:42][NH2:43].C(O)(C)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([NH:42][NH2:43])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]2[OH:40])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: CC(C)O
Solvent: O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Reaction time: 12 h

Procedure:
A mixture comprising N-[(1S,2R,3S,4R)-4-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (1.6 g, 2.82 mmol), and hydrazine monohydrate (14 ml) is stirred at room temperature for 72 h. Then isopropyl alcohol (10 ml) is added and the solvent was decanted off to afford a gummy mixture. It is dissolved in water (10 ml) and stirred for 12 h. The fine solid obtained is filtered, washed with water and dried in vacuo to afford the title product which is used in the next step without further purification. LC-MS (0.1% formic acid, acetonitrile): (MH+ 563).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([OH:21])([C@H:15]([CH2:16]OC(N)=O)[C:6]=2[C:4](=[O:5])[C:3]=1[NH2:24])[C@H:13]1[N:22]([CH3:23])[C@H:12]1[CH2:11]3.N12CCCCC1C=NCCC2>O1CCCC1>[CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([OH:21])([C:15](=[CH2:16])[C:6]=2[C:4](=[O:5])[C:3]=1[NH2:24])[C@H:13]1[N:22]([CH3:23])[C@H:12]1[CH2:11]3
Reactant: CC1=C(N)C(=O)C2=C(C1=O)N1C[C@H]3[C@H](N3C)[C@]1(O)[C@@H]2COC(N)=O
Agent: C1=NCCCN2CCCCC12
Solvent: C1CCOC1
Product: C=C1C2=C(C(=O)C(C)=C(N)C2=O)N2C[C@H]3[C@H](N3C)[C@]12O
Yield: 53.8 %

Procedure:
9-epi-mitomycin D (10 mg) was dissolved in tetrahydrofuran (0.5 ml). To the solution was added 1,5-diazabicyclo[5,4,0]undec-5-ene (20 mg) and the solution was refluxed for 18 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo, and the residue was purified by silica gel column chromatography using a solvent system of chloroform and acetone (3:2 v/v) to give the desired dark green needle crystals (4.4 mg; yield 53.8%) having the following physical characteristics.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:27])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C:16](=[O:17])[CH2:15][C@@H:14]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[O:13]3)[C:6]=2[N:7]=1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[NH2:1][C:2]1[NH:3][C:4](=[O:27])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@@H:16]([OH:17])[CH2:15][C@@H:14]([CH2:18][O:19][Si:20]([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21])[O:13]3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred solution of 5-amino-3-[(2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-oxo-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38e, 1.0 g, 2.43 mmol) in THF (5 mL) was added lithium tri-tert-butoxyaluminum hydride solution (1M in THF, 2.7 mL, 2.7 mmol). After being stirred at room temperature for 2 hours, the resulting solution was quenched by saturated NH4Cl solution and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:10 methanol in DCM) to afford 750 mg crude product of 5-amino-3-[(2R,3S,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-hydroxy-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38f). (Refer to Tetrahedron 1984, 40, 125-135).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd].[H][H]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1CNC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CN2C(=O)CNC2=O)cc1

Procedure:
The 3-(4-nitrobenzyl)hydantoin derivative was dissolved in methanol (about 10 ml per mmol of hydantoin derivative) and hydrogenated with palladium/carbon in a hydrogen atmosphere until reaction was complete. The catalyst was filtered off and the solvent was removed on a rotary evaporator. The 3-(4-aminobenzyl)hydantoin derivative was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[Na+]>Cl>[NH2:1][C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1-n1cncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccnc1-n1cncn1
Temperature: 0 °C
Yield: 35.6 %

Procedure:
To a suspension containing 35.4 g of stannous chloride dihydrate in 100 ml of concentrated hydrochloric acid was added portionwise 10 g of the compound prepared in Example 1 over a 0.25 hour period. After the resulting exotherm (23°-79°) slowed, the suspension was heated at 85°-90° for one hour, then cooled to 0°. The mixture was poured onto excess ice-water (about 700 ml), and the suspension was made strongly basic to litmus by addition of 50% aqueous NaOH to yield a precipitate. After filtering the mixture, the isolated solid was washed with water, suction-dried, then recrystallized from ethyl acetate-hexanes to yield 3 g of the subject compound; m.p. 103°-105°.
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].C(N(CC)CC)C.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.CCCCCC.C(OCC)(=O)C>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(Br)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Bromo-2-methylpropionyl bromide (6.8 mL) was diluted with dichloromethane and added to a solution of triethylamine (7.7 mL) and benzyl alcohol (4.8 mL), while the mixture was cooled in an ice bath and while maintaining an argon atmosphere. The solution was stirred for one hour at 0° C. and then overnight at room temperature. Volatiles were evaporated and the residue was treated with diethylether. The formed salt was removed by filtration and the filtrate was washed with an HCl solution and with water. The ether solution was dried with MgSO4 and concentrated to yield a yellowish liquid. Silica column chromatography using a 2/1 hexane/ethyl acetate mixture as eluent gave a colourless transparent liquid. 1H NMR (400 MHz, CDCl3): δ 7.4 (5H), 5.3 (2H), 2.0 (6H).
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=1)[CH:7]=2)([O-:3])=[O:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=3)[C:7]([C:16]3[CH:15]=[CH:14][CH:6]=[CH:5][C:4]=3[NH2:1])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH2:21])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C1C2=Cc3cc([N+](=O)[O-])ccc3C2=CC=C1[N+](=O)[O-]
Product: Nc1ccccc1C1(c2ccccc2N)c2cc([N+](=O)[O-])ccc2-c2ccc([N+](=O)[O-])cc21

Procedure:
2,7-Bis(diarylamino)-9,9-bis(diarylaminophenyl)fluorene, a compound of this invention, can be synthesized according to the above synthetic route as follows: A mixture of a 2,7-dinitrofluorenone and an aniline is refluxed in the presence of an acid catalyst to give an intermediate 2,7-dinitro-9,9-bis(aminophenyl)fluorene. The two nitro groups are then converted to two amino groups by a reduction reaction with Fe/NH4Cl. Finally, the reduced intermediate is reacted with aryl halides (Ar—X and Ar′—X, stepwise) in the presence of a catalyst such as palladium to produce the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1)[CH2:14][CH3:15].C(C1C=CC(Br)=CC=1)CC.B(OC)(OC)OC.Cl.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)=[CH:18][CH:17]=1)[CH2:14][CH3:15]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCCc1ccc(OB(O)O)cc1
Agent: CCCc1ccc(Br)cc1
Agent: COB(OC)OC
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
50 g of 6-bromo-2-naphthol and 48 g of 4-propylphenylboric acid (synthesized by reacting a Grignard reagent prepared from 4-propylbromobenzene with trimethyl borate, and then subjecting the reaction product to hydrolysis with hydrochloric acid) were dissolved in a mixture of 200 ml of toluene and 100 ml of ethanol. To the solution was then added 200 ml of a 2 N aqueous solution of potassium carbonate. To the reaction mixture was then added 2.6 g of tetrakis(triphenylphophine)palladium (0). The reaction mixture was then heated under reflux for 6 hours. The reaction solution was then allowed to cool to room temperature. The resulting organic phase was then separated. The resulting aqueous phase was then extracted with toluene The material thus extracted and the organic phase ware together washed sequentially with diluted hydrochloric acid, water and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate, The solvent was then distilled off to obtain 47 g of 6-(4-propylphenyl)-2-naphthol in crystal form.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@:6]1([C:26]([OH:28])=[O:27])[C@H:11]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([OH:24])=[O:23]>C(O)C1C=CC=CC=1>[CH2:26]([O:23][C:22]([C@:8]1([F:25])[C@@H:7]2[C@H:9]1[CH2:10][C@@H:11]([S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C@@:6]2([NH2:5])[C:26]([OH:28])=[O:27])=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Solvent: OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 31.3 %

Procedure:
19 μL of thionyl chloride was added to 26 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid suspended in 0.3 mL of benzyl alcohol at ice-cooling, and then the mixture was stirred for 3.5 hours at 50° C. After standing to cool, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (Wako gel 50C18 (Wako Pharmaceutical Industries Ltd.), eluent: water to an aqueous 70% solution of acetonitrile), thereby yielding 5 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-benzyl ester. 2.19-2.43 (3H, m), 2.47-2.63 (1H, m), 2.96-3.12 (1H, m), 3.75 (1H, d, J=13.2 Hz), 3.81 (1H, d, J=13.2 Hz), 5.22 (2H, s), 7.23-7.54 (8H, m)
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:33]([C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Reactant: COc1cccc(C=O)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc(-c2nc3c(N4CCN(Cc5cc(C)on5)CC4)c(Br)cnc3[nH]2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.040 g, 0.10 mmol) and EtOH (3 ml) was added 3-methoxybenzaldehyde (0.022 g, 0.16 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v:v; 3:7) and then a gradient of methanol (0 to 2%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellowish solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.010 g, 21%); 1H-NMR (500 MHz, DMSO-d6) 2.40 (s, 3H, isoxazole 5-CH3), 2.64 (br s, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2 isoxazole), 3.67 (br s, 4H, piperazine N(CH2)2), 3.85 (s, 3H, OCH3), 6.25 (s, 1H, isoxazole 4-H), 7.09 (dd, J=1.9, 8.3 Hz, 1H, PhH), 7.45 (t, J=8.3 Hz, 1H, Ph 5-H), 7.76 (s, 1H, Ph 2-H), 7.79 (d, J=8.3 Hz, PhH), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.50 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:24]=1[C:25]([O:27]C(C)(C)C)=[O:26])=[O:18]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=2)[C:24]=1[C:25]([OH:27])=[O:26])=[O:18]
Reactant: Cn1nc(C(F)(F)F)cc1-c1csc(NC(=O)c2cc3ccccc3o2)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(C(F)(F)F)cc1-c1csc(NC(=O)c2cc3ccccc3o2)c1C(=O)O
Reaction time: 0.75 h
Yield: 18.2 %

Procedure:
Under an atmosphere of argon, trifluoroacetic acid (1.0 mL) was added to a stirred solution of 13 (21 mg, 43 μmol) in dichloromethane (1.0 mL) at room temperature. The reaction was stirred for 45 minutes then concentrated under reduced pressure. The material was washed with dichloromethane to provided 14 (3.4 mg, 18%) as a solid: 1H NMR (500 MHz, d6-DMSO) 513.60 (bs, 1H), 12.55 (bs, 1H), 7.87 (m, 2H), 7.76 (dd, J=8.4, 1.3 Hz, 1H), 7.58 (ddd, J=7.8, 7.8, 1.2 Hz, 1H), 7.42 (ddd, J=7.7, 7.7, 0.7 Hz, 1H), 7.34, (s, 1H), 6.76 (s, 1H), 6.37 (s, 3H); LRESIMS m/z 436 [M+H]+, calcd. for C19H12F3N3O4S1 436.1.