Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(I)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CS(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: IC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1nc(Cl)c2ncn(C3CCCCC3)c2n1
Yield: 41 %

Procedure:
2,6-Dichloropurine (1 mmol), powdered potasium carbonate (1 mmol) and cyclohexyliodide (4 mmol) were vigorously stirred in 5 mL DMSO overnight. After evaporation of the solvent the product was extracted (water/diethylether) and purified by column chromatography (silicagel/1% MeOH in CHCl3). Crystallization from methanol gave the product in yield 41%, mp 116-121° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH:33][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][CH:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:28][CH:27]=2
Reactant: CS(=O)(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(NS(C)(=O)=O)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-methanesulfonic acid {1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 470 (MH+); HPLC Rf: 3.23 min.; HPLC purity 93%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>CC(O)=O>[C:1]([NH:4][C:5]1[C:6]([N+:14]([O-:16])=[O:15])=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)CCO2
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
The product obtained in Step 3 (6.0 g, 33.9 mmol) was dissolved in AcOH (100 mL), then HNO3 (1.9 mL, 47.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then poured into ice-water. The water layer was extracted with ethyl acetate. The organic layer was dried, concentrated, purified by column chromatography to obtain a product (7.0 g, 93.3%).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.Cl.[CH3:11][C:12](=[CH2:14])[CH3:13]>>[C:12]([C:5]1[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=1[NH2:7])([CH3:13])([CH3:11])[CH3:14]
Reactant: C=C(C)C
Reactant: Cc1ccc(N)cc1N
Agent: Cl
Product: Cc1cc(C(C)(C)C)c(N)cc1N
Temperature: 180 °C

Procedure:
A 300 cc Hastalloy C pressure vessel equipped with a mechanical stirrer was used for producing t-butyltoluenediamine. Approximately 100 grams of 0.819 moles of 2,4-toluenediamine were charged to the vessel along with 5 grams of 36% aqueous hydrochloric acid. The vessel was sealed and purged with nitrogen, leaving a 33 psig nitrogen blanket. The vessel contents then were heated to 180° C. with continuous stirring. Isobutylene then was introduced into the reactor and 53.4 grams or 0.96 moles was added over 15 minutes. On addition of the isobutylene, the pressure in the reactor increased bo 766 psig. The reaction mixture was maintained at 180° C. for 24 hours with constant stirring. At the end of the 24 hour period the pressure had dropped to 524 psig. The contents were then cooled to 160° C. and stirring discontinued. At that time the reactor was vented and the reaction product analyzed for composition.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=1)([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:6].[OH-].[Na+].Cl>O>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=2)([CH3:6])[CH2:4][C:3]([OH:23])=[O:2])=[CH:8][C:9]=1[CH3:14]
Reactant: COC(=O)CC(C)(c1ccc(O)c(C)c1)c1ccc(O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(C)(CC(=O)O)c2ccc(O)c(C)c2)ccc1O

Procedure:
A suspension of 314 g of 3,3-bis(4'-hydroxy-3'-methyl-phenyl) butanoic acid methyl ester (m.p. 162° C) and 80 g of sodium hydroxide in 1 liter of water was refluxed for 8 hours while stirring. After cooling to 40° -50° C the suspension was acidified with hydrochloric acid and the 3,3-bis(4'-hydroxy-3'-methylphenyl) butanoic acid was extracted with ether. The ether phase was washed several times with water and then the ether was removed in vacuo. The remaining residue was the white crystallized 3,3-bis(4'-hydroxy-3'-methylphenyl)butanoic acid, m.p. 130° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[C:45]([F:53])[CH:44]=1.O>C(#N)C>[F:53][C:45]1[CH:44]=[C:43]([Cl:42])[CH:48]=[CH:47][C:46]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)cc3F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.3 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was added with triethylamine (0.0540 mL, 0.390 mmol) and 4-chloro-2-fluorobenzenesulfonyl chloride (0.0450 g, 0.195 mmol), followed by stirring at room temperature for 12 hours. The reaction mixture was added with water and the solvent was evaporated. The residue was added with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then filtered through a column filled with SCX (positive-ion exchange resin). The SCX was washed with 2 mol/L ammonia-methanol solution and the filtrate was evaporated to obtain 4-(2-fluoro-4-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0116 g, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28]O)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][Br:31])[CH2:10][CH2:11][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CN2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(CN2CCC(CCBr)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 57.7 using 4-(3,4-dichloro-phenyl)-4-2-hydroxy-ethyl-1-(3,4,5-trim ethoxy-benzyl)-pyrrolidine (5 mmol), carbon tetrabromide (6.3 mmol), and triphenylphosphine (7.5 mmol). Purify to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N:12]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl>Cl>[ClH:11].[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][NH2:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)c(C(=O)O)c1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of 5-amino-2-chlorobenzoic acid (10.3 g, 60 mmol) in concentrated HCl at 0° C. is treated with an aqueous solution of NaNO2 (4.8 g, 70 mmol) at a rate to maintain a reaction temperature of <10° C., stirred for 0.5 h at 0° to 10° C., treated with a solution of tin chloride dihydrate (33.9 g, 150 mmol) in aqueous HCl at a rate to maintain a reaction temperature of <10° C., aqueous HCl is added periodically, as needed to facilitate stirring, stirred at 5° C. for an additional 1 h and filtered. The filtercake is recrystallized from water to afford the title product as white crystals, 9.6 g (71% yield), identified by HNMR analysis.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[CH:6]=1)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[CH:6]=1)=[O:4])=[N+:21]=[N-:22]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A solution of 2-bromo-1-[4-(benzyloxy)-3-fluorophenyl]ethanone (J. Med. Chem. 1980, 23, 738-744) (1 g) in dry DMF (2.5 mL) was cooled to 150 and treated portionwise with sodium azide (220 mg). After complete addition the reaction mixture was stirred for a further 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water and the combined aqueous phase back extracted with EtOAc. The combined organic phases were washed with sat. NaHCO3(aq) three times and the combined washes back extracted with EtOAc. The combined organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with hexane-EtOAc (4:1 and 2:1) to give the title compound (810 mg). LCMS RT=3.61 min.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CN(C)C=O.C1C=CC=CC=1>[CH3:3][S:4]([NH:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:6])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)CCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCNS(C)(=O)=O
Temperature: 25 °C

Procedure:
A stirred suspension of sodium hydride (57% in mineral oil) (2.33 g., 0.055 mole) in a solvent mixture of benzene (50 ml.) and dimethylformamide (50 ml.) is treated, over 30 minutes, with methanesulfonamide (4.75 g., 0.055 mole). This mixture is heated on the steam bath for 1.5 hours, then cooled to room temperature. At this temperature is added ethyl 7-bromoheptanoate (13 g., 0.055 mole) and the reaction mixture is heated at 90° C. for 20 hours. The reaction is poured into ater (200 ml.), neutralized with hydrochloric acid and extracted with ethyl acetate (2 × 100 ml.). The ethyl acetate layer is washed with brine, dried over sodium sulfate, then concentrated in vacuo. The yield of ethyl 7-(methanesulfonamido)heptanoate is 7.1 g. (51%) boiling 165°-168°/0.1 mm.
Reaction SMILES: [CH2:1](O)[CH2:2][C:3]#[CH:4].C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C(#N)C.C(OCC)(=O)C>[CH2:1]([N:29]1[CH2:30][CH2:31][CH:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)[CH2:27][CH2:28]1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCO
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a solution (50 ml) of 3-butyn-1-ol (700 mg, 10.0 mmol) and triethylamine (2.05 ml, 15 mmol) in tetrahydrofuran was added methanesulfonyl chloride (1.72 g, 15 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. Ethyl acetate was added to the reaction mixture, and the mixrture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. 4-(4-Chlorophenyl)piperidine hydrochloride (2.30 g, 10.0 mmol), potassium carbonate (1.38 g, 10.0 mmol) and acetonitrile (50 ml) were added to the obtained residue, and the mixture was stirred at 60° C. for 16 hrs. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was washed with ethyl acetate. The aqueous layer was basified with 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.31 g) as a solid.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[S:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([NH2:20])=[N:14][C:15]=2N.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:23]>Cl>[F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[S:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:23])[NH:14][C:13]([NH2:20])=[N:12][C:11]1=2
Reactant: Nc1nc(N)c2ncn(C3S[C@H](CO)[C@@H](O)[C@@H]3F)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Product: Nc1nc2c(ncn2[C@@H]2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
114 mg of the crude anomer mixture of 9-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)-2,6-diaminopurine (beta/alpha=1.55) obtained in Synthesis Example 2 was suspended in 25 ml of tris hydrochloric acid buffer solution (pH=7.0). To this suspension was added 0.43 ml (100 units) of adenosine deaminase, and the mixture was stirred at room temperature for 6 hours. The reaction solution was purified by ODS reverse phase column chromatography to obtain 48 mg (yield 48%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.[N+:14]([C:17]1[CH:18]=[CH:19][C:20](Br)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])([O-:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.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>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])([O-:16])=[O:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COc1cccc(OC)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1c(OC)cccc1OC
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of Example 1A, methyl 5-nitro-2-bromobenzoate (25.8 g, 99.2 mmol), (21.7 g, 119 mmol), cesium carbonate (97.1 g, 298 mmol), and dichlorobis(triphenylphosphine)palladium(II) (3.5 g, 5.0 mmol) in DMF (300 mL) was stirred for 24 hours at 80° C., cooled to 23° C., treated with water (600 mL), and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated, during which a light yellow solid precipitated. The mixture was placed in a freezer (−20° C.) for 2 hours and filtered to provide the desired compound. MS (DCI/NH3) m/z 318 (M+H)+ and 335 (M+NH4)+.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[O:11][C:10]4[CH2:14][CH2:15][CH2:16][CH2:17][C:9]=4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH:1]1[C:13]2[C:12]3[O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)ccc1c3c(oc12)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: c1ccc2c(c1)ccc1c3ccccc3oc21
Temperature: 25 °C
Yield: 60 %

Procedure:
In the atmosphere of argon, 55.5 g of 7,8,9,10-tetrahydrobenzo[b]naphtho[2,1-d]furan, 119 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 1 L of anhydrous 1,4-dioxane were placed in a flask. The resulting mixture was stirred under reflux for 12 hours. After cooling to room temperature, the reaction solution was extracted with toluene, and deposited solids were filtered out. The filtrate was concentrated by means of a rotary evaporator, and residues were purified by silica gel column chromatography, whereby 32.7 g of (yield: 60%) of benzo[b]naphtho[2,1-d]furan was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:7]([C:17]([OH:19])=[O:18])=[C:8]([CH3:16])[NH:9][C:10]=1[CH:11](OC)[O:12]C)=[O:4]>Cl.CC(C)=O.C(OCC)(=O)C>[CH:11]([C:10]1[NH:9][C:8]([CH3:16])=[C:7]([C:17]([OH:19])=[O:18])[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:12]
Reactant: COC(=O)C1=C(C(OC)OC)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C=O)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 79 %

Procedure:
A solution of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (7.50 g) dissolved in a mixture of 6N hydrochloric acid (22.5 ml) and acetone (90 ml) was stirred for 6.5 hours at 20° C. The resulting mixture was evaporated under reduced pressure. The residue obtained was dissolved in ethyl acetate, and washed successively with water, an aqueous sodium bicarbonate and an aqueous sodium chloride. The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue obtained was subjected to column chromatography on silica gel (200 g) and eluted with a mixture of toluene and ethyl acetate (10:1 by volume). The fractions containing the desired compound were collected and evaporated under reduced pressure and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give yellow crystals of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (5.23 g), mp 125° to 125.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([CH3:34])=[CH:4][N:3]=1.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:36][OH:37])[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([CH3:34])=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cnc(F)cc1C(=O)CC(c1ccc(-c2ccc(C(=O)O)cc2)cc1)c1ccccc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cnc(F)cc1C(CC(c1ccc(-c2ccc(C(=O)O)cc2)cc1)c1ccccc1C)=NO

Procedure:
In analogy to example 74, step 7, from 4′-[3-(2-fluoro-5-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (1.7:1) as a colorless oil, MS (ESI+): m/z=469.1924 ([M+H]+).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:6]([NH:8][C:9]1[C:10]([I:31])=[C:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:12]([I:25])=[C:13]([C:23]=1[I:24])[C:14]([NH:16][CH2:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:43](Br)[CH:44]=[CH2:45].Cl>CS(C)=O>[CH2:45]([N:8]([C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:9]1[C:10]([I:31])=[C:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:12]([I:25])=[C:13]([C:23]=1[I:24])[C:14]([NH:16][CH2:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])[CH:44]=[CH2:43]
Reactant: C=CCBr
Reactant: CC(=O)OCCNC(=O)c1c(I)c(COC(C)=O)c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: C=CCN(C(=O)C(COC(C)=O)OC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCCOC(C)=O)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-(2,3-Diacetoxypropionylamino)-3-acetoxymethyl-N-(2-acetoxyethyl)-2,4,6-triiodobenzamide (8.65 g, 10.3 mmol) was dissolved in dimethyl sulfoxide (10 ml) at room temperature. Cesium carbonate (3.88 g, 11.8 mmol) was added and after stirring at room temperature for 15 min, the mixture was cooled in an ice bath. Allyl bromide (2.10 g, 17.3 mmol) was added dropwise and the mixture was then stirred for 17 h at room temperature. The reaction mixture was transferred onto aqueous hydrochloric acid (0.1 M, 300 ml). The formed precepitate was filtered off, redissolved in methylene chloride (150 ml) and washed with water (5×100 ml). The organic phase was dried (Na2SO4), and the solvent evaporated. Yield: 8.73 g (96%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([C:6]([F:9])=[CH:7][CH:8]=1)[NH2:5].Cl[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:18])[C:6]([F:9])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1c(F)ccc(Cl)c1F
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1c(F)ccc(Cl)c1F
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of 3-chloro-2,6-difluoroaniline (430 mg, 2.55 mmol) and TEA (0.5 mL, 3.59 mmol) in THF (5 mL) was added ethyl 2-chloro-2-oxoacetate (0.3 mL, 2.63 mmol). A white precipitate was formed immediately. After 30 min, the reaction mixture was filtered and rinsed with ether. The filtrate was concentrated to yield a crude yellow oil, which was purified by silica gel chromatography to yield the desired product (484 mg, 72%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.42 (br. s., 1H), 7.35 (m, 1H), 6.98 (m, 1H), 4.45 (q, J=7.2 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H). MS (ESI) m/z: 263.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:35].C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CCCCCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Yield: 93.3 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmol) were dissolved in 6 ml dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 127 mg (2 molar equivalents) of octyl chloroformate were respectively added. The reaction mixture was maintained at 20° C. for 3 hours. The solvent was then evaporated under reduce pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95/5 volume ratio) to provide 137 mg (yield=85%) of the desired product (formula below) as an orange powder.
Reaction SMILES: Br.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]1[CH2:12][C:11](=[O:13])[NH:10][N:9]=1.[C:14]([OH:17])(=O)[CH3:15]>>[OH:17][C:14]1[CH:15]=[CH:12][C:8]([N:10]2[C:11](=[O:13])[CH2:12][C:8]([CH2:7][C:3]3[NH:2][CH:6]=[CH:5][N:4]=3)=[N:9]2)=[CH:7][CH:3]=1
Reactant: O=C1CC(Cc2ncc[nH]2)=NN1
Reactant: CC(=O)O
Agent: Br
Product: O=C1CC(Cc2ncc[nH]2)=NN1c1ccc(O)cc1

Procedure:
To a mixture of 1 ml of 47% hydrobromic acid and 1 ml of acetic acid was added 100 mg of 3-(1-imidazolylmethyl)-2-pyrazolin-5-one and stirred under reflux for 4 hours. After removing the solvent by evaporating, the residue was adjusted in pH to 4 by adding water and an aqueous NaHCO3 solution and then extracted with a mixed solvent of chloroform and ethanol (4:1).