Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1[N:20]1[C:29]2[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=2[N:22]=[CH:21]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36]([NH:25][C:24]2[C:23]3[N:22]=[CH:21][N:20]([C:29]=3[N:28]=[CH:27][N:26]=2)[C@@H:13]2[O:14][C@H:15]([CH2:18][O:19][C:36]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:53][CH:52]=3)[C@@H:16]([OH:17])[C@H:12]2[O:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2[C@H](O)[C@@H](CO)O[C@H]2n2cnc3c(N)ncnc32)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)[C@@H](O)[C@H]2OS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
2'-O-Tosyladenosine (Compound A1) (4.21 g, 10 mmol) and 4,4'-dimethoxytrityl chloride (7.45 g, 22 mmol) were added to anhydrous pyridine (50 ml), and stirred at room temperature for 20 hours. After ice cooling, 50% aqueous pyridine was added, the mixture was extracted with chloroform, and the organic layer was washed successively with aqueous sodium bicarbonate and water, and dried over magnesium sulfate. After distillating away the chloroform, the pyridine was removed by co-evaporation with toluene, and the residue was subjected to silica gel column chromatography eluant: toluene-ethyl acetate-triethylamine→(9:1:0.1) toluene-ethyl acetate-triethylamine-methanol (9:1:0.1:0.2)]. Fractions containing the desired substance were combined and concentrated to give Compound A2 (7.74 g, yield 75%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]([CH3:20])[CH2:9][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=1)(=O)=O.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH:8]([CH3:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1CN(Cc2ccccc2)CC=C1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(C2=CCN(Cc3ccccc3)CC2C)c1
Temperature: 100 °C

Procedure:
A mixture of 1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (3 g, 9.0 mmol), [3-(ethoxycarbonyl)phenyl]boronic acid (2.26 g, 11.6 mmol), PdCl2(PPh3)2 (315 mg, 0.44 mmol), and potassium carbonate (2.5 g, 18.0 mmol) in Toluene:EtOH (10:1, 50 mL) were heated to 100° C. for 18 hr. The cooled reaction mixture was partitioned between EtOAC and H2O and the aqueous layer was extrated with EtOAc (4×). The organics were combined, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with a gradient of hexane:EtOAc to yield ethyl 3-(1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate as a clear oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[OH-:8].[K+].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.CN(C=O)C>[CH2:13]([O:8][C:3](=[O:7])[CH:2]([CH3:1])[CH2:6][CH2:5][O:4][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: [OH-]
Reactant: CC1CCOC1=O
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(CCOCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
To a solution of 3-methyldihydrofuran-2-one (2.0 g, 20.0 mmol) in dioxane (15 mL) was added a solution of KOH (1.32 g, 20.0 mmol in 5 mL of water) and the mixture was stirred at RT for 30 min, then at 90° C. for 15 min. After cooling to RT, volatiles were removed under reduced pressure and the residue was azeotroped with toluene and heated at 190° C. affording a white residue. The resulting residue was suspended in DMF (25 mL) and NaH (800 mg, 20 mmol) was added at RT over 5 min. The mixture was stirred at RT for 30 min, then bromomethylbenzene (5.94 mL, 50 mmol) was added over 5 min. Stirring at RT was continued for 18 h then the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. Half of the resulting residue was purified by column chromatography (Si-PCC, gradient 2-30% EtOAc in cyclohexane) affording 4-Benzyloxy-2-methylbutyric acid benzyl ester as a colorless oil (0.738 g, 25%). 1H NMR (CDCl3, 400 MHz): δ 7.38-7.22 (10H, m), 5.08 (2H, s), 4.44 (2H, s), 3.51-3.44 (2H, m), 2.78-2.64 (1H, m), 2.12-1.97 (1H, m), 1.79-1.64 (1H, m), 1.19 (3H, d, J=7.06 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C:18]([OH:20])=[O:19])[C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[OH2:19].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Product: O
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-1acetic acid (3.83 g, 0.013 mole) and 1,1'-carbonyldiimidazole (2.11 g, 0.013 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. Dipropylamine (2.63 g, 0.026 mole) was added and the reaction mixture was heated at reflux for 2 hrs, followed by standing at room temperature over the weekend. The tetrahydrofuran was evaporated to dryness and placed under high vacuum overnight. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water to produce a crystalline product upon refrigeration. The solid was collected by filtration, washed with water, and dried under high vacuum ovenight to give 1.22 g. A recrystallization from isopropyl alcohol-water gave 0.91 g of title compound after drying under high vacuum at 50° C. over the weekend, mp 139°-141° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-:12].[Na+].Cl[CH2:15][CH:16]([OH:19])[CH2:17]Cl>O>[OH:19][CH:16]([CH2:17][O:12][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH2:15][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: OC(CCl)CCl
Reactant: [OH-]
Reactant: COc1cc(C=O)ccc1O
Agent: [Na+]
Solvent: O
Product: COc1cc(C=O)ccc1OCC(O)COc1ccc(C=O)cc1OC
Temperature: 25 °C

Procedure:
Vanillin (91.2 g, 0.60 mol) is dissolved in water (500 mL) containing sodium hydroxide (24.0 g). To this solution is added 1,3-dichloro-2-propanol (38.7 g, 0.30 mol) and the reaction mixture is stirred and heated at reflux for 8 hours. Upon cooling to room temperature the product crystallizes and is collected by filtration, washed with water and dried. The crude product is recrystallized from 2 L ethanol, filtered, washed with ethanol and air dried. The purified product, 4,4'-[(2-hydroxy-1,3-propanediyl)bis(oxy)]bis[3-methoxybenzaldehyde], is obtained as a white solid in a yield of 74.3 g; 68.7% of theory. Mass spectroscopy analysis supports the structure: ##STR23## A mixture of 4,4'-[(2-hydroxy-1,3-propanediyl)bis[3-methoxy-benzaldehyde] (3.60 g, 0.01 m), ethyl cyanoacetate (2.26 g, 0.02 m), ethanol (100 mL), piperidine (10 drops), and acetic acid (5 drops) is heated at reflux for 4 hours and then allowed to cool. The essentially white product is collected by filtration, washed with ethanol, and dried in air (yield--3.5 g). Mass spectrum analysis supports the following structure: ##STR24## The product, diethyl 3,3'-[(2-hydroxy-1,3-propanediyl)bis(oxy)bis(3-methoxy-4,1-phenylene)]bis[2-cyano-2-propenoate], has an absorption maximum (λmax) at 360 nm in methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([NH:14][NH2:15])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:16](OC(=O)C)(=O)[CH3:17].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[O:13][C:16]([CH3:17])=[N:15][N:14]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CCN(C(=O)NN)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2nnc(C)o2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 20.1 %

Procedure:
To a solution of 1-hydrazinocarbonyl-piperidine-4-carboxylic acid ethyl ester (215 mg, 0.999 mmol) in THF (2 ml) was added acetic anhydride (188 μl, 2.00 mmol). After stirring for 5 minutes at rt phosphorus oxychloride (182 μl, 2.00 mmol) was added and the reaction mixture was stirred for 5 days at RT. The reaction mixture was added dropwise onto a 1 M solution of sodium carbonate (10 ml). The mixture was diluted with EtOAc (15 ml). The aq. layer was extracted with EtOAc (15 ml). The organic layers were washed with brine (15 ml) and dried over Na2SO4. A column chromatography (SiO2, EtOAc/Hept 1/1 to Hept/MeOH 9/1) yielded 48 mg (20%) of the title product as a light brown oil. MS m/e: 240.3 [M+H]+
Reaction SMILES: N#N.N[C@H](C(N[C@@H](CC1C=CC=CC=1)[C@H](O)C[C@@]1(C(N)=O)CCCN1C(C)(C)C)=O)CC(=O)N.C(O[C:43]([NH:45][C:46]1[C:47](C(O)=O)=[CH:48][C:49]2[C:54]([CH:55]=1)=CC=CC=2)=O)C1C=CC=CC=1.O[C:60]1[C:68]2N=N[NH:65][C:64]=2[CH:63]=[CH:62][CH:61]=1.C(N1CCOCC1)C>>[CH:64]1([N:65]=[C:43]=[N:45][CH:46]2[CH2:55][CH2:54][CH2:49][CH2:48][CH2:47]2)[CH2:68][CH2:60][CH2:61][CH2:62][CH2:63]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(Nc1cc2ccccc2cc1C(=O)O)OCc1ccccc1
Agent: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O)C(N)=O
Agent: CCN1CCOCC1
Agent: N#N
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
In a manner analogous to that described in Example 27, from 295 mg of N2 -[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide, 214 mg of 3-(benzyloxyformamido)-2-naphthoic acid, 90 mg of hydroxybenzotriazole, 77 mg of N-ethylmorpholine and 151 mgof dicyclohexylcarbodiimide there were obtained, after chromatography on silica gel using System G for the elution, 380 mg of N2 -[3(S)-[[N-[3-(benzyloxyformamido)-2-naphthoyl]-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a white solid from methanol: MS: m/e 751 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26]C(=O)C)=[CH:22][CH:21]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17].C([O-])([O-])=O.[K+].[K+]>CCO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17]
Reactant: CC(=O)Oc1ccc(/C=C/c2cnc(OCCOCCOCCF)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(/C=C/c2cnc(OCCOCCOCCF)c(Br)c2)cc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
Acetate 11d (0.145 g, 0.31 mmol) and K2CO3 (0.064 g, 0.465 mmol) were placed in EtOH/THF (5 mL/5 mL) and the reaction mixture was stirred at r.t. 2 h. After standard workup with EtOAc, the crude product was purified by PTLC to give 11e as a white solid (0.128 g, 97%). 1H NMR δ8.07 (d, 1H, J=2.1 Hz), 7.99 (d, 1H, J=2.1 Hz), 7.35 (d, 2H, J=8.6 Hz), 6.96-6.74 (m, 4H), 5.22 (br s, 1H), 4.69 (t, 1H, J=4.2 Hz), 4.54 (t, 2H, J=4.8 Hz), 4.45 (t, 1H, J=4.2 Hz), 3.94-3.68 (m, 8H). 13C NMR δ 158.5, 156.4, 143.6, 138.2, 129.2, 129.0, 127.9, 120.7, 116.0, 107.6, 84.9, 81.6, 71.1, 71.0, 70.8, 70.4, 69.6, 66.8. HRMS calcd for C19H21BrFNO4 (M+), 425.0638. found, 425.0651.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH:21]([C:24]1[CH:25]=[C:26]([C@@H:30]([NH2:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1)([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:32][C@H:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]([CH3:23])[CH3:22])[CH:25]=4)[CH3:31])=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: O=C(O)c1ccc2c(c1)ncn2Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)ncn3Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1-(4-bromobenzyl)-1H-benzo[d]imidazole-5-carboxylic acid (521 mg, 1.57 mmol), (S)-1-(3-isopropylphenyl)ethanamine (314 mg, 1.88 mmol), HATU (1.19 g, 1.88 mmol) and DIPEA (607 mg, 4.71 mmol) in DMF (15 mL) was stirred at RT overnight. Then the mixture was poured into 20 mL of water, then extracted with EtOAc (10 mL×3). The combined organic layers was washed with water (10 mL) and brine (10 mL) and dried with Na2SO4. After filtration, the filtrate was concentrated under the reduced pressure. The residue was purified with Combiflash (DCM/EtOAc=4/1, silica gel) to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+].CN(C)[CH:29]=[O:30]>>[C:19]1([N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH:29]=[O:30])=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 72 %

Procedure:
4-(Diphenylamino)benzaldehyde can be obtained commercially from a supplier, such as Aldrich, Milwauke, Wis. or Fluka, Buchs SG, Switzerland. It could also be prepared by the following procedure. Dry dimethylformamide (DMF, 4.73 ml, 0.0612 mol) was added to a 25 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. After the flask was kept under nitrogen atmosphere and cooled to 0° C., phosphorus oxychloride (POCl3, 3.8 ml, 0.0408 mol) was added dropwise. The temperature inside the flask was kept below 5° C. during the addition of POCl3. After the addition of POCl3 was completed, the solution was allowed to warm up slowly to room temperature. Then a solution of triphenylamine (5 g, 0.0204 mol, from Aldrich, Milwauke, Wis.) in dry DMF (10 ml) was added dropwise. The reaction mixture was refluxed at 80° C. for 24 hours and then poured into ice water. This solution was neutralized with potassium hydroxide until the pH reached between 6 and 8. The product was extracted with chloroform. The chloroform extract was dried with anhydrous sodium sulfate, filtered, and evaporated off to form the crude product, which was recrystallized from methanol to yield 5.57 g (72%) of 4-(diphenylamino)benzaldehyde. The melting point was found to be 126.5° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 6.57–7.56 (m, 12H, Ar), 7.60–7.98 (m, 2H, Ar), 10.21 (s, 1H, CHO). The IR spectrum of the product was characterized by the following absorption frequencies (KBr, cm−1): ν(C—H) 2743; 2830, ν(C—H in Ar) 3037, ν(C═O) 1689, ν(C═C in Ar) 1585; 1567; 1490, γ(Ar) 825. The mass spectrum of the product was characterized by the following mass peaks (m/z): 274 (100%, M+1).
Reaction SMILES: C([CH:3]([OH:24])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:32]([O:24][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCC(O)CCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution containing ethyl 3-(5-nitro-2-phenyl-1H-indol-1-yl) propan-1-ol (2.2 g; 7.4 mmol) and triethylamine (1.24 ml; 8.9 mmol) in CH2Cl2 (20 ml), acetyl chloride (0.6 ml; 8.9 mmol) was added dropwise; the reaction mixture was left under stirring at room temperature for 2 hours. Then water (20 ml) and NaHCO3 (saturated solution) were added to pH 7. The biphasic solution was transferred into a separating funnel extracted with CH2Cl2 (2×50 ml). The organic phases were combined, washed with brine (2×100 ml) and dried over Na2SO4. The solvent was removed by evaporation under reduced pressure to give 3-(5-nitro-2-phenyl-1H-indol-1-yl)propyl acetate (1.5 g), which was used without any further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:20][CH3:21])[C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=1.[Br:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:25]=1[O:37][CH3:38]>>[Br:23][C:24]1[C:25]([O:37][CH3:38])=[CH:26][C:27]([C:32]2[O:33][C:34]([C:14](=[O:15])[CH:13]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:22])=[CH:12][CH:11]=3)[O:20][CH3:21])=[CH:35][CH:36]=2)=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCCS4(=O)=O)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyethanone was synthesized from 2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide and 2-(4-bromo-3,5-dimethoxyphenyl)furan following the procedure used for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) provided Example 19 as a yellow solid (0.111 g, 37% yield). MS: m/z 550.1 [M+H]+.
Reaction SMILES: [C:1](Cl)(=O)C.[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:40]=[CH:39][CH:38]=[CH:37][C:15]=1[C:16]([NH:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1)=[O:17])([OH:7])=[O:6]>CO>[CH3:1][O:6][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:40]=[CH:39][CH:38]=[CH:37][C:15]=1[C:16]([NH:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1)=[O:17])=[O:7]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of acetyl chloride (1 ml) and methanol (20 ml) was added 1-{4-[2-(2-carboxyphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (350 mg) at 0° C. The solution was stirred for 30 minutes at the same temperature and then stirred for 3 hours at ambient temperature. The solvent was evaporated in vacuo and triturated from dichloromethane to give 1-{4-[2-(2methoxycarbonylphenyl)benzoylamino]benzoyl}-1,2,3,4tetrahydroquinoline (300 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:19][CH2:20][CH:21]([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22]Br)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:11]([O:19][CH2:20][CH:21]([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: O=C(OCC(CBr)OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCC(Cn1ccc2ncnc(Cl)c21)OC(=O)c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), 3-bromopropane-1,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59 g) and N,N-dimethylformamide (6.5 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→40/60) to give the title compound (401 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]5[NH:25][C:24]([C:26]6[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=6)=[N:23][C:21]=5[CH:22]=4)=[N:14][C:12]=3[CH:13]=2)[CH2:4][CH2:3]1.[OH-].[NH4+]>C(O)(C)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]5[NH:25][C:24]([NH:23][C:21]=5[CH:22]=4)=[C:26]4[CH:27]=[CH:28][C:29](=[O:32])[CH:30]=[CH:31]4)[NH:14][C:12]=3[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3[nH]c(-c4ccc5[nH]c(-c6ccc(O)cc6)nc5c4)nc3c2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1

Procedure:
Hoechst 33258 (3.0 g, 5 mmol) was dissolved in a hot mixture of isopropanol-water (24 mL/12 mL) and neutralized with ammonium hydroxide (3 mL). The precipitate was filtered, triturated with Et2O and dried in vacuo to obtain the free base of bisbenzimidazole. A 1.0 M solution of B4NOH in MeOH (0.6 mL, 0.6 mmol) was added to the solution of bisbenzimidazole (1.635 g, 3.85 mmol) in MeOH (30 mL), stirred for 15 min and concentrated to dryness in vacuo. Iodonaphthoquinone 505 (1.485 g, 3.87 mmol) in DMF (30 mL) was added to the teirabutyl ammonium salt and the mixture was stirred for 48 h. The reaction mixture was suspended in H2O, the crude product was filtered, washed with H2O, dried and purified by flash chromatography (MeOH/CHCl3 1:9, 1:5) to afford 514 as a yellow solid (790 mg, 30%). 1H NMR (CDCl3/MeOH-d4) 8.21 (s, 1H), 8.09 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.85-7.95 (m, 2H), 7.48-7.75 (m, 4H), 7.14 (bs, 1H), 7.10-6.98 (m 3H), 4.21 (t, J=6.3 Hz, 2H), 4.08 (t, J=6.2 Hz, 2H), 2.65-2.75 (m, 4H), 2.40 (s, 3H), 1.80-2.15 (m, 4H), 1.60-1.75 (m, 4H). MS (LSIMS, 3-NBA) 725.2 (M++1).