Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].C[O-].[Na+]>C(O)C>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1)([O-:16])=[O:15]
Reactant: Sc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1Sc1ncc[nH]1
Yield: 75 %

Procedure:
A mixture of 5.0 g (0.05 mole) of 2-mercaptoimidazole. 7.9 g (0.05 mole) of 2-chloronitrobenzene, 6.5 g (0.12 mole) of sodium methoxide and 150 ml of ethanol was stirred and refluxed for 5 hours. An additional 0.8 g of 2-chloronitrobenzene, was added and refluxing continued for 5 more hours. The mixture was filtered hot and the filtrates concentrated. The residue was partitioned with water and dichloromethane. The undissolved solid was collected by filtration to give 8.3 g of product. The dichloromethane was dried and concentrated. The residue was recrystallized from dichloromethane to give an additional 1.2 g of product. The total yield was 87% and the product was obtained as yellow rods, mp 178°-181° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:11][C:12]1[C:17]([O:18][CH2:4][C:3]2[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=2[F:10])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: Cc1ccc(O)c(N)n1
Reactant: Fc1cccc(F)c1CBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(OCc2c(F)cccc2F)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
A mixture of 2,6-difluorobenzyl bromide (25 g, 0.12 1 mol) and 2-amino-3-hydroxy-6methylpyridine (13.6 g, 0.11 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (10 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product (25.8 g, 94%), m.p. 121°-123° C.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]([CH3:22])=[CH:9][C:8]=1[NH:23][C:24](=[O:28])[CH:25]=NO.C([O-])(O)=[O:30].[Na+]>>[CH3:22][C:10]1[C:11]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:12][C:7]([CH3:6])=[C:8]2[C:9]=1[C:25](=[O:30])[C:24](=[O:28])[NH:23]2
Reactant: O=C([O-])O
Reactant: Cc1cc(OCCN2CCOCC2)c(C)cc1NC(=O)C=NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc(OCCN2CCOCC2)c(C)c2c1NC(=O)C2=O
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To concentrated H2SO4 (3.5 mL) at 60° C. was added N-[2,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-hydroxyimino-acetamide (1.4 g, 4.36 mmol) in portions with stirring. After the addition was finished, the mixture was heated to 75° C. and kept at this temperature for 15 min. A dark-purple solution was formed and poured upon cracked ice. Then solid NaHCO3 is added and pH was adjusted to 8.0. The mixture was extracted with CH2Cl2, dried (Na2SO4), and crystallized from CH2Cl2-hexane to give 4,7-Dimethyl-5-(2-morpholin-4-yl-ethoxy)-1H-indole-2,3-dione as brown solid 1.15 g, 87%).
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].C(=O)(O)[O-].[Na+].[F:24][C:25]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:26]=1[C:27]([NH:29][NH2:30])=[O:28]>C(Cl)(Cl)Cl>[NH2:16][C:5](=[N:30][NH:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:25]=1[F:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Reactant: NNC(=O)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1ccc(F)cc1F
Yield: 41.5 %

Procedure:
A suspension of 15.3 g (0.058 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 125 ml chloroform was treated with 58.1 ml 1N aqueous sodium hydoxide. 18 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 10.0 g (0.058 mol) 2,4-difluorobenzoic acid hydrazide in 110 ml chloroform over night at 50° C. The resulting precipitate was filtered off and dried. A yield of 8.50 g (42%) 2,4-difluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white solid. MS m/e (%): 354 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[N:13]1([C:18]2[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:20][CH:19]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>CO>[N:13]1([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:33][CH:34]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Cc1cccc(OCC2CO2)c1
Reactant: c1ccc(CNCCOc2ccc(-n3ccnc3)cc2)cc1
Solvent: CO
Product: Cc1cccc(OCC(O)CN(CCOc2ccc(-n3ccnc3)cc2)Cc2ccccc2)c1
Temperature: 50 °C

Procedure:
To a solution of 2.75 g (17 mmol) 2,3-epoxypropyl 3-methylphenyl ether in 50 mL methanol add 4.4 g (15 mmol) 2-[4-(1H-imidazol-1-yl)phenoxy]-N-(phenylmethyl)ethanamine and heat to 50° C. for 24 h. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1). At the completion of the reaction, evaporate the solvents. The resulting oil is chromatographed on a silica gel column using 2% methanol in methylene chloride to provide the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl>[C:26]([O:29][CH2:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][CH2:22]1)=[O:32])(=[O:28])[CH3:27]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C)[Si](OCC1CCNCC1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5 g of the crude product from Example 20A are suspended in 24 ml of dichloromethane and cooled to 0° C. 1.88 g (13.79 mmol) of acetoxyacetyl chloride and 5.9 ml (42.42 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 8 h. After addition of 25 ml of dichloromethane the mixture is washed once with 10 ml of water and once with 10 ml of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 20:1→1:1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].C(=O)(O)[O-].[Na+]>ClCCl>[C:24]([NH:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1)(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(OC)c(C(=O)OC)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a 1-liter three-necked round-bottom flask equipped with overhead stirrer, temperature control and addition funnel was added methyl 4-amino-5-chloro-2-methoxybenzoate (44.2 g, 200 mmol), dichloromethane (500 mL) and diisopropylethylamine (104.5 mL, 600 mmol). The resulting mixture was stirred at room temperature until the ingredients dissolved and then the mixture was cooled to 0° C. Acryloyl chloride (16.25 mL, 200 mmol) was then added dropwise while maintaining the internal reaction mixture temperature below 10° C. The total time for addition was about 30 min. The reaction mixture was then slowly warmed from 0° C. to room temperature over a period of about 2 hours. Aqueous saturated sodium bicarbonate solution (200 mL) and dichloromethane (200 mL) were then added and this mixture was stirred for 15 min. and then the layers were separated. The dichloromethane layer was washed with 1 M hydrochloric acid (200 mL) and then concentrated under reduced pressure to about one-third its original volume resulting in a thick slurry. The slurry was filtered and the filter cake was washed with dichloromethane (100 mL) and dried to provide the title compound as an off-white solid (36 g, 67% yield, >98% purity by HPLC).
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[N:8]2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16]>FC(F)(F)C(O)=O>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([N+:15]([O-:17])=[O:16])=[C:9]([CH3:13])[N:8]2[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)n(C2CCCCC2)n1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])c(=O)n(C2CCCCC2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To trifluoroacetic acid (1940 mL) cooled to −15° C. was added 2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (535 g, 2231 mmol) and the reaction mixture was cooled to 0° C. Nitric acid 90% (211 mL, 4461 mmol) was added dropwise over 90 minutes maintaining the temperature below 15° C. and the reaction mixture was stirred for 30 minutes at 10° C. The resulting mixture was slowly poured into ice water (8 L) and stirred for 30 minutes. The solid was collected by filtration and washed with water (2×2 L), saturated sodium bicarbonate solution (1×2 L), water (2×2 L), TBME (3×2 L) and heptane (2×2 L). The isolated solid was dried in the vacuum oven to afford the title compound;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:21][C:20]=1[CH2:19][O:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of acetic acid 3-hydroxyphenyl ester (5.0 g, 32.86 mmol) and potassium carbonate (6.8 g, 49.3 mmol) in DMF (40 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (6.8 g, 32.86 mmol) at RT. The reaction mixture is stirred for 3 h at RT followed by 24 h at 70° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 20% ethyl acetate in hexane to yield acetic acid-3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl ester as a clear oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:13]=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][S:18][C:14]2[CH:13]=[C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1ccc(CCSc2cccc(N)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(CCSc2cccc(NS(=O)(=O)c3ccccc3)c2)cc1
Reaction time: 3 h
Yield: 82.1 %

Procedure:
Benzenesulfonyl chloride (0.62 g; 3.5 mmol) was added to a cold solution (ice:water temperature) of amino-3-[2-(4-cyanophenyl)ethylthio]benzene (0.80 g; 3.15 mmol; from step (ii) above) in a mixture of pyridine (1 mL) and CH2Cl2 (20 mL) over 10 minutes. After 3 hours stirring, 2M aqueous HCl was added and the solution extracted with CH2Cl2. The organic layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2; Et2O:hexane (1:1)) to give 1.02 g (82%) of the sub-title compound.
Reaction SMILES: [Zn](CC)CC.F[C:7](F)(F)[C:8]([OH:10])=O.C(I)I.[Br:16][C:17]1[CH:22]=[C:21]([CH:23]=C)[CH:20]=[C:19](OCOC)[CH:18]=1>CCCCCCC.C(Cl)Cl>[Br:16][C:17]1[CH:22]=[C:8]([OH:10])[CH:7]=[C:19]([CH:20]2[CH2:21][CH2:23]2)[CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C=Cc1cc(Br)cc(OCOC)c1
Agent: CC[Zn]CC
Solvent: ICI
Solvent: CCCCCCC
Solvent: ClCCl
Product: Oc1cc(Br)cc(C2CC2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 30.9 %

Procedure:
To anhydrous CH2Cl2 (10 mL) was added ZnEt2 (12.34 of a 1.0 M in heptane, 12.34 mmol) under nitrogen. The solution was cooled to 0° C., and a solution of trifluoroacetic acid (0.95 mL, 12.34 mmol) in anhydrous CH2Cl2 (4 mL) was added very slowly. After stirring the reaction mixture for 20 m, a solution of CH2I2 (0.99 mL, 12.34 mmol) in CH2Cl2 (4 mL) was added. After an additional 20 m stirring, a solution of the 1-bromo-3-methoxymethoxy-5-vinyl-benzene (1.20 g, 4.94 mmol) in CH2Cl2 (6 mL) was added, and the reaction was allowed to warm to RT. After 1.5 h, the reaction was quenched with saturated aqueous NH4Cl (30 mL) and hexanes (50 mL), and the layers were separated. The aqueous layer was extracted with Et2O (2×40 mL), and the combined organic layers were washed with H2O (30 mL), brine (30 mL), and dried with anhydrous MgSO4. The solvents were evaporated, and the remaining oil was partially purified by flash chromatography on silica gel (0% to 5% EtOAc/hexanes). The partially purified material was placed in i-PrOH (10 mL), and 2 mL of 1.0 M HCl was added. The mixture was aged at 50° C. for 14 h, cooled to RT, and added to H2O (25 mL). The aqueous mixture was extracted with Et2O (3×40 mL), and the combined organics were washed with brine (30 mL), and dried over anhydrous MgSO4. The solvents were evaporated, and the remaining oil was purified by flash chromatography on silica gel (0% to 10% EtOAc/hexanes) to afford 325 mg (31%) of 3-bromo-5-cyclopropyl-phenol (114).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:30][CH3:31])[N:19]=[C:20]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:21]=2)[N:16]([CH3:32])[CH:15]=1.[Cl-].[NH4+].C(O)C.O>O1CCCC1.C(OCC)(=O)C.[Fe]>[F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:30][CH3:31])[N:19]=[C:20]([CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:21]=2)[N:16]([CH3:32])[CH:15]=1
Reactant: COc1nc(CN2CCOCC2)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1nc(CN2CCOCC2)cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 98.2 %

Procedure:
A mixture of Example 182C (58 mg, 0.114 mmol), ammonium chloride (6.08 mg, 0.114 mmol), iron (50.8 mg, 0.909 mmol), in 4 mL tetrahydrofuran and 4 mL ethanol and 2 mL water was heated at reflux for 3 hours. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrated was concentrated to give the title compound (54 mg, 0.112 mmol, 99% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>>[CH2:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12])[CH3:19]
Reactant: O=c1ccc2ccc(Br)cc2[nH]1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCn1c(=O)ccc2ccc(Br)cc21
Yield: 94 %

Procedure:
The compound was obtained according to procedure H starting from 7-bromoquinolin-2(1H)-one (commercial; 561 mg, 2.5 mmol) and ethyl acrylate (0.27 mL, 2.5 mmol, 1 eq.). The crude orange oil (0.76 g; 94% yield) was used as such in the next step.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22](OC)=[O:23])=[CH:18][C:17]=1[CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1.CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][C:17]=1[CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(CO)cc2CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
LAH (1.0 M solution in THF) (0.55 mL, 0.55 mmol) was added to a solution of 66.64A (0.098 g, 0.27 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 1 hour and then it was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO4. After removing solvent, 66.64B was obtained as a colorless oil in 100% yield.
Reaction SMILES: O.[CH2:2]([N:5]([CH:9]=[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH2:11]1)[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4].C>Cl>[CH2:2]([N:5]([CH:9]=[C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH2:19]1)[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4]
Reactant: CCCN(C=C1C=CC(C(=O)OC)=CC1)CCC
Agent: Cl
Solvent: O
Product: CCCN(C=C1C=CC(C(=O)O)=CC1)CCC
Yield: 79.5 %

Procedure:
9 cm3 of distilled water are added to an oily suspension of 2.4 g of methyl 4-(N,N-di-n-propylaminomethylene)benzoate in 9 cm3 of concentrated hydrochloric acid (36% minimum), at a temperature close to 20° C. The reaction mixture is heated under reflux for 24 hours and then supplemented with 3S charcoal, and filtered while hot on a sintered glass. The filtrate is concentrated to dryness under reduced pressure (about 1 kPa) at a temperature close to 40° C. The white solid thus obtained is filtered on sintered glass, rinsed with 3 times 10 cm3 of acetonitrile, 10 cm3 of diisopropyl ether, air-dried and then dried under reduced pressure (about 0.2 kPa) at a temperature close to 50° C. 1.8 g of 4-(N,N-di-n-propylaminomethylene)benzoic acid (monohydrochloride) are thus obtained in the form of white crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2.CN(C)C=O.O>C(Cl)Cl>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCNc1ncnc2nc[nH]c12
Reactant: c1ccc(OCC2CO2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OC(CNCCNc1ncnc2nc[nH]c12)COc1ccccc1

Procedure:
4.5 g. Phenyl glycidyl ether and 14.2 g. 6-(2-aminoethylamino)-purine are stirred in 100 ml. dimethylformamide for 10 hours at 50° C. The reaction mixture is taken up in methylene chloride, shaken out with water, dried and purified chromatographically on a silica gel column in the manner described in Example 25. The product obtained by evaporation of the pure fractions is recrystallized from ethanol. There are obtained 2.3 g. (23% of theory) of the desired product in the form of colorless crystals; m.p. 169°-170° C., with bubble formation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O-:29])(=[S:28])[CH3:27].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:10][S:28][C:26](=[O:29])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To 1.00 g of toluene-4-sulfonic acid (S)-2-tert-butoxycarbonylamino-4-methyl-pentyl ester in 10 ml DMF were added 308 mg of potassium thioacetate. After 24 h at room temperature, the reaction was poured unto water, the pH was then adjusted to 9 and the mixture was extracted with ethyl acetate twice. The combined organic phases were washed with brine until neutral, dried over sodium sulphate and concentrated in vacuo. 0.67 g (90%) of Thioacetic acid S—((S)-2-tert-butoxycarbonylamino-4-methyl-pentyl)ester were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[O:15]=[C:16]1[CH2:19][CH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:15])[CH2:17][CH:18]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:19]2)=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Br
Reactant: CC(C)(C)OC(=O)C1CC(=O)C1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC(O)(c2ccc(Br)c(F)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 1-bromo-2-fluoro-4-iodobenzene (58 g, 192.76 mmol, 1.00 equiv) in tetrahydrofuran (600 mL), followed by the addition of i-PrMgCl (96.3 mL, 1.00 equiv) dropwise with stirring at 0° C. over 30 min. The mixture was stirred at 0° C. for 3 h. To this was added tert-butyl 3-oxocyclobutane-1-carboxylate (32.7 g, 192.12 mmol, 1.00 equiv) dropwise with stirring at −78° C. over 10 min. The mixture was stirred at −78 degree C. for 1 h and overnight at room temperature. The reaction was then quenched by the addition of 200 mL of saturated aqueous NH4Cl at 0° C. and extracted with 3×500 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 62 g (crude) of tert-butyl 3-(4-bromo-3-fluorophenyl)-3-hydroxycyclobutane-1-carboxylate as a yellow oil.
Reaction SMILES: C(=O)([O-])O.[K+].[CH3:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C:10]1[C:11]([C:17]3[C:18](=[O:24])[CH2:19][CH:20]=[CH:21][C:22]=3[N:23]=1)=[N:12]2>>[CH3:6][C:7]1[CH:8]=[C:13]2[C:14]([CH2:9][C:10]3[C:11]([C:17]4[C:18](=[O:24])[CH2:19][CH:20]=[CH:21][C:22]=4[N:23]=3)=[N:12]2)=[CH:15][CH:16]=1
Reactant: Cc1cccc2c1CC1=NC3=C(C(=O)CC=C3)C1=N2
Agent: O=C([O-])O
Agent: [K+]
Product: Cc1ccc2c(c1)N=C1C(=NC3=C1C(=O)CC=C3)C2
Temperature: 120 °C
Yield: 83 %

Procedure:
The resulting compound 5.0 g (0.02 mmol) was mixed with polyphosphoric acid 176 g and heated at 120° C. for 2 hours. After heating, the reaction mixture was poured into ice water. The resulting solution was neutralized with an aqueous solution saturated with potassium hydrogencarbonate and deposited crystals were collected by filtration to obtain a mixture of 1-methyl-6,11-dihydroindolo[3,2-b]-quinoline-6-one and 3-methyl-6,11-dihydroindolo[3,2-b]-quinoline-6-one (4.1 g (yield: 83%)).