Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[OH-].[NH4+:35].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:35][C:20]1[C:19]2[N:28]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[C:18]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(=O)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
mCPBA (2.11 g, 8.57 mmol) was added to a solution of 1-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-2-one (1.96 g, 6.59 mmol) in chloroform (30 mL) at room temperature. The reaction mixture was stirred for 1 hour, then was cooled to 0° C. Concentrated ammonium hydroxide (10 mL) and p-toluenesulfonyl chloride (1.38 g, 7.25 mmol) were added. The mixture was stirred at 0° C. for 1 hour, then was filtered. The filtrate was diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (25 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to yield a brown solid. The solid was purified by chromatography on a HORIZON High-Performance Flash Chromatography (HPFC) instrument (available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 0-35% of a solution comprised of 80% CHCl3, 18% MeOH, and 2% conc. NH4OH (CMA) in chloroform) to afford a tan solid that was recrystallized from chloroform/hexanes. The crystals were isolated by filtration and dried in a vacuum oven at 80° C. to afford 0.718 g of 1-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-2-one as pale pink needles, mp 187-188° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[F:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)[CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:29][CH:26]1[CH2:25][CH2:24][CH:23]([CH2:22][N:19]2[CH2:20][CH2:21][C@@H:17]([F:16])[CH2:18]2)[CH2:28][CH2:27]1
Reactant: NC1CCC(CN2CC[C@@H](F)C2)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN2CC[C@@H](F)C2)CC1
Yield: 30.1 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (240 mg, 1.0 mmol) was reacted with 4-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclohexanamine (100 mg, 0.5 mmol) to afford the product (61 mg, 15%) as a brown solid: ESI MS m/z 405 [M+H]+.
Reaction SMILES: C([NH:8][CH:9]1[CH2:23][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]2[CH:10]1[CH3:24])C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:23][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:15][CH:11]2[CH:10]1[CH3:24]
Reactant: CC1C(NCc2ccccc2)CC2CN(C(=O)OC(C)(C)C)CC21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Product: CC1C(N)CC2CN(C(=O)OC(C)(C)C)CC21
Yield: 107.4 %

Procedure:
A mixture of tert-butyl 5-(benzylamino)-4-methylhexahydrocyclopenta-[c]pyrrole-2(1H)-carboxylate (13.2 g, 39.9 mmol) and 20% palladium hydroxide on carbon (4.21 g, 5.99 mmol) was stirred under 30 psi hydrogen for 5 h. The mixture was filtered through a celite pad to remove the solid catalyst. The filter cake was rinsed with methanol. The filtrate was concentrated to give crude tert-butyl 5-amino-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (10.3 g) as an approximately 3:1:1 mixture of three isomers. The material was taken to the next step without further purification. MS (ES+) m/z: 241.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O)#[CH:2].[CH3:17]CN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29](C)[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14]1[N:26]([CH3:17])[C:27]2[C:28](=[O:40])[NH:29][C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=2[N:33]=1)#[CH:2]
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: C#Cc1ccc2cncc(CC(=O)O)c2c1
Solvent: CN(C)C=O
Product: C#Cc1ccc2cncc(Cc3nc4c(c(=O)[nH]c(=O)n4CC(C)C)n3C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(6-Ethynyl-isoquinolin-4-yl)-acetic acid (58 mg, 0.28 mmol) is dissolved in DMF (1 ml) and O-(7-azabenzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphatc (0.125 g, 0.33 mmol) and Hunig's base (0.180 ml, 1.03 mmol) are added, followed by a solution of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (58 mg, 0.28 mmol) in DMF (0.7 ml). The reaction is stirred at room temperature for 2 hours. The solvent is evaporated and the residue purified by flash column chromatography (30:1 dichloromethane-methanol elution). The intermediate is dissolved in methanol (2 ml) and water (2.75 ml) added, followed by 4M aqueous sodium hydroxide (0.25 ml). The reaction is heated at 40° C. for 2 hours, then stirred for 16 hours at ambient temperature. The solvent is evaporated and the crude product purified by flash column chromatography (30:1 dichloromethane-methanol elution) to afford 8-(6-ethynyl-isoquinolin-4-ylmethyl)-3-isobutyl-methyl-3,7dihydro-purine-2,6-dione, [MH]+ 388.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19]([OH:23])(=O)[CH2:20][CH3:21]>>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][O:15][C:19](=[O:23])[CH2:20][CH3:21])[C@@H:10]([O:11][C:16](=[O:17])[CH2:3][CH3:2])[C@H:8]2[O:9][C:8](=[O:9])[CH2:10][CH3:12])[CH:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: CCC(=O)O
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Product: CCC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=O)c2N)[C@H](OC(=O)CC)[C@@H]1OC(=O)CC

Procedure:
A method for producing N2 -phenyl-2,6-diaminonebularine, which comprises reacting 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide with a reactive derivative of propionic acid to yield 5-amino-1-(2,3,5,-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carboxamide, dehydrating 5-amino-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carboxamide to yield 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole, treating 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole with aqueous ammonia or alkali metal alkoxide to yield 5-amino-1-β-D-ribofuranosyl-4-cyanoimidazole and reacting 5-amino-1-β-D-ribofuranosyl-4-cyanoimidazole with phenylcyanamide in the presence of ammonia to yield N2 -phenyl-2,6-diaminonebularine.
Reaction SMILES: [S:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[N:15]([O-])=O.[Na+].O.[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[Na+]>Cl.O>[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[S:1]([C:8]1[CH:14]=[CH:13][C:11]([N+:12]#[N:15])=[CH:10][CH:9]=1)([C:4]([F:5])([F:6])[F:7])(=[O:3])=[O:2]
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 22.5 g (0.1 mole) of 4-triflylaniline in HCl/H2O (50:50) is cooled in an ice bath to about 10° C., and 6.9 g (1 mole) of sodium nitrite in a minimum amount of water is added slowly to the mixture, while maintaining the temperature below 10° C. The reaction then is warmed to room temperature and stirred for 15 additional minutes. Sodium hexafluorophosphate (16.7 g, 0.1 mole) is added in portions, and the mixture is stirred for 10 minutes more. The solid product is collected by vacuum filtration and dried.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]([C:10]1[CH:11]=[C:12]([OH:24])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=2)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:24][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=2)[CH:19]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=1
Reactant: CC(C)(C)c1cc(O)c2cc(C(C)(C)C)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(OP(=O)(Cl)Cl)c2cc(C(C)(C)C)ccc2c1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.145 mL, 1 equiv) and 3,7-di-tert-butylnaphthalen-1-ol (J. Org. Chem. 1995, 60, 2909-2911, 0.4 g, 1 equiv) were stirred in anhydrous diethyl ether (10 mL). Anhydrous triethylamine was added (0.217 mL, 1 equiv) at −78° C. and stirred for 30 min. The dichloridate is very unstable at room temperature. The progress of the reaction was monitored by 31P NMR. This crude mixture was considered to be a 100% conversion to dichloridate and was used directly.
Reaction SMILES: C(OC(=O)[N:7]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])COCC[Si](C)(C)C)=[O:16])[N:11]=[CH:10][N:9]=1)(C)(C)C.C1CCC(N=C=NC2CCCCC2)CC1.[C:62](O)(=[O:66])[C:63]#[C:64][CH3:65].O>C(Cl)Cl>[Cl:37][C:27]1[C:28]([O:35][CH3:36])=[CH:29][C:30]([O:33][CH3:34])=[C:31]([Cl:32])[C:26]=1[NH:17][C:15](=[O:16])[N:14]([C:12]1[N:11]=[CH:10][N:9]=[C:8]([NH:7][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[NH:45][C:62](=[O:66])[C:63]#[C:64][CH3:65])[CH:13]=1)[CH3:38]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccccc3N)ncn2)c1Cl
Reactant: CC#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC#CC(=O)Nc1ccccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of (2-amino-phenyl)-{6-[3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-ureido]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (50 g, 0.075 mmol) and DCC (42 g, 0.2 mmol) in DCM (50 mL) was added a solution of but-2-ynoic acid (13 g, 0.15 mmol) in DCM (10 mL) at 0° C., and the resulting mixture was stirred at room temperature overnight. Water (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by reverse phase chromatography to obtain the title compound (20 mg, yield: 34%). MS (ESI): 659 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=1)([O-:3])=[O:2].[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 90.7 %

Procedure:
To a solution of 1,3-dinitro-5-(trifluoromethyl)benzene (10 g, 42.4 mmol) in absolute methanol (100 mL) was added sodium methanolate (3.43 g, 63.5 mmol) in absolute methanol (20 mL). The red alcoholic solution was refluxed for 1 h, then concentrated to remove solvent, diluted with ethyl acetate (80 mL) and water (30 mL). Separated organic part was dried over Na2SO4, filtered and concentrated to get the title product (8.5 g) as a red solid
Reaction SMILES: [C:1]([O:13]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>C1COCC1>[C:16]1([C:1]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C=CCCCCCCCCC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCCCCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a solution of 10.6 g of ethyl undecylenate in 100 mL of THF at 0° C. was added, over 1 hr, 40 mL of 3M phenyl magnesium bromide. The mixture was warmed to room temperature and stirred for 75 hrs. Methanol, 10 mL, was added to quench the excess Grinard reagent and the solvent was distilled in vacuo. The residue was shaken with diethyl ether and dilute hydrochloric acid. The ether layer was washed with water and saturated sodium hydrogen carbonate, dried, and concentrated in vacuo to give 18.3 g of crude product, which was then chromatographed on silica gel with chloroform as the eluent, to give 13.7 g of 1,1-diphenyl-10-undecen-1-ol which is characterized by:
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N:12]2[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:8][C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:3](=[O:4])[C:2]([Cl:7])([Cl:6])[Cl:1])[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N:12]2[CH3:21]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cn2c3ccccc3n(C)c2n1
Solvent: Cc1ccccc1C
Product: Cc1nc2n(C)c3ccccc3n2c1C(=O)C(Cl)(Cl)Cl

Procedure:
Pour 5.45 g (30 mmol) of freshly distilled trichloroacetyl chloride dropwise into a boiling solution of 2,9-dimethylimidazo[1,2-a]benzimidazole (3.7 g; 20 mmol)--obtained as described in Khim. Geterotsikl Soedin, 86, (7), 918-925--in 50 ml of xylene, with vigorous stirring, over a period of 20 to 30 minutes. The mixture is then heated at reflux for two hours until the product which has initially precipitated is completely dissolved. Cool and filter. Concentrate the mother liquors and add petroleum ether. Combine with the precipitate obtained earlier and repeat the operation. The combined precipitates are treated with an aqueous solution of sodium hydrogen carbonate and then recrystallised from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14]([C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:42])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:44]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([CH3:44])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14]([C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:42])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N(C)c1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C

Procedure:
Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (0.5 g, 0.8 mmol) were dissolved in 1 ml dimethylformamide 0.1 g sodium carbonate was added under stirring at room temperature. Methyl iodide (70 μl, 0.16 g, 1.1 mmol) was added dropwise under vigorous stirring at room temperature by a syringe. The reaction mixture was stirred at room temperature overnight. Water was added to the stirred suspension, and the mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate twice (2×20 ml). The organic layer was dried over sodium sulfate. After drying of the organic layer, the solvent was evaporated under reduced pressure at 46° C. The brownish remaining crude product was used for the further synthesis without purification.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1Br)[N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:21]=[C:20]2[NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39]>O.O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][C:25]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:21]=[C:20]3[NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3)c(-c3ccccc3)cc12
Yield: 141.6 %

Procedure:
1.12 g of phenylboronic acid, 1.55 g of sodium carbonate in 40 cm3 of water and 463 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5,6-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 70, in 150 cm3 of dioxane, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 100 cm3 of ethyl acetate and with 100 cm3 of water and is then filtered through a sinter funnel packed with Celite. The organic phase is separated out after settling of the phases has taken place and washed with 75 cm3 of saturated sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2 kPa; 50° C.) to give 2.6 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and then dried (90 Pa; 45° C.) to give 1.4 g of N-[5,6-diphenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>>[CH2:36]([NH:38][C:39]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:40])[CH3:37]
Reactant: CCN=C=O
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: CCNC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(OC)cc(N5CCN(C)CC5)c4o3)cc2)CC1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available ethyl isocyanate (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=549 by positive ion CI.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:39][NH2:40])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:39][NH:40][C:24](=[O:26])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(OC)c(Br)c1
Yield: 53.9 %

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol) and 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.581 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 ml, 5.6 mmol) was stirred in dichloromethane (45 mL) at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, followed by saturated NaCl. The organic layer was dried over Na2SO4 and then evaporated to dryness which gave, initially, a glassy gum, but which then appeared to crystallize. The residue was taken up in a small amount of MeOH and sonicated for a while. A crystalline white solid formed and was collected and dried to afforded N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (804 mg, 53.9%) as a white solid. LC-MS m/z 601.3 (M+H)+, 0.77 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+].C(O)(=O)C>O>[CH2:8]([N:7]1[C:2]([NH2:1])=[C:3]([N:20]=[O:21])[C:4](=[O:19])[N:5]([CH2:16][CH2:17][CH3:18])[C:6]1=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
2.0 g (7.7 mmol) of 6-amino-1-benzyl-3-propyluracil are heated to 80° C. in 15 ml of water and mixed with a solution of 0.55 g of sodium nitrite in 3 ml of water. After the addition of 1 ml of glacial acetic acid a red solid is precipitated. The pH is adjusted to 4 and the suspension is stirred for a further 30 minutes at 80° C. After cooling, the crystals are filtered under suction and washed with water. 1.9 g of the title compound are obtained in the form of reddish-violet crystals (86% of theory), m.p. 208°-212° C./decomposition.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1Br.C([Li])CCC.[I:22]I.C(O)(=O)C>O1CCCC1>[I:22][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[CH:3]=[O:2]
Reactant: COc1cc(Br)c(C(OC)OC)cc1OC
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(I)c(C=O)cc1OC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
2-Bromo-4,5-dimethoxybenzaldehyde dimethylacetal (59 g) is dissolved in tetrahydrofuran and thereto is added 2.5M n-butyllithium (89 ml) under cooling at -70° C. The reaction mixture is kept below -50° C. for 30 minutes and thereto is added dropwise a solution of iodine (51.4 g) in tetrahydrofuran below -50° C. The mixture is kept at the same temperature for 15 minutes and thereto are added aqueous acetic acid to adjust the pH of the solution at 2. The mixture is allowed to stand at room temperature overnight, and the solvent is distilled off from the reaction mixture. The residue is dissolved in ethyl acetate. The solution is washed and dried, and the solvent is distilled off. The residue is crystallized from ethyl acetate to give 2-iodo-4,5-dimethoxybenzaldehyde (43 g). M.p. 139°-141° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]1=[O:41]>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]1=[O:41]
Reactant: CC(C)(N)CCCn1c(=O)[nH]c2ccccc21
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Product: CC(C)(CCCn1c(=O)[nH]c2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
Prepared according to general method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(4-amino-4-methyl-pentyl)-1,3-dihydro-benzimidazol-2-one. Yield: 192 mg (44%); mass spectroscopy: [M+H]+=441.