Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH:29][C:30]4[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=4)[N:18]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[N:40]1([CH2:45][C:46]2([CH2:49][NH2:50])[CH2:48][CH2:47]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.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>C(Cl)Cl>[N:40]1([CH2:45][C:46]2([CH2:49][NH:50][C:34]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:19]4[N:20]=[C:21]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])[N:22]=[C:17]([NH:16][C:13]5([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:39])=[CH:12][CH:11]=6)[CH2:15][CH2:14]5)[N:18]=4)=[CH:38][CH:37]=3)=[O:35])[CH2:48][CH2:47]2)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)O)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Reactant: NCC1(CN2CCCC2)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: ClCCl
Product: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Yield: 65 %

Procedure:
4-(4-(1-(4-(2-ethoxy-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (330 mg, 0.603 mmol), (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanamine (112 mg, 0.723 mmol), HATU (344 mg, 0.904 mmol), and Hunig's Base (0.526 mL, 3.01 mmol) were stirred in DCM (Volume: 5 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc then 5% DCM/MeOH to give ethyl 2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetate (268 mg). LC-MS (Condition A), MS m/z (M++H) 684.1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([OH:31])[C@H:14]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)(=O)=O)=CC=1.[CH2:32]([NH2:34])[CH3:33]>CO>[F:30][C:26]1[CH:25]=[C:24]([C@H:14]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)[C@H:13]([OH:31])[CH2:12][NH:34][CH2:32][CH3:33])[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2cccc(F)c2)n2ccc3ccccc32)cc1
Reactant: CCN
Solvent: CO
Product: CCNC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Reaction time: 12 h

Procedure:
(2S,3S)-3-(3-fluorophenyl)-2-hydroxy-3-(1H-indol-1-yl)propyl 4-methylbenzenesulfonate (200 mg, 0.456 mmol) was dissolved in a solution of ethylamine in methanol (2.0 M, 10 mL) and stirred for 12 hours in a sealed reaction vessel. All volatiles were removed under reduced pressure, and the liquid residue was dissolved in dichloromethane (15 mL), washed with a saturated aqueous solution of potassium carbonate, dried (anhydrous sodium sulfate), and concentrated. Purification of the liquid residue by Biotage chromatography (FlasH12i, silica, 0-15% MeOH/dichloromethane/0.5% triethylamine) gave (1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(ethylamino)propan-2-ol, which was used to prepare (1S,2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)propan-2-ol hydrochloride as a white powder in an analogous matter to EXAMPLE 144, step 2. Yield: 99 mg (70%). MS (ES) m/z 313.1 ([M+H]+); HRMS: calcd for C19H21FN2O+H+, 313.1716; found (ESI, [M+H]+), 313.1716.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:36]#[CH:37].C(NC(C)C)(C)C>O1CCCC1.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.[Cu]I>[CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31]([C:37]#[C:36][CH2:35][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a degassed solution of the above ester (1 g, 1.705 mmol), N-propargylmorpholine (440 mg, 3.515 mmol) and diisopropylamine (1.12 mL, 7.96 mmol) in anhydrous tetrahydrofuran (27 mL), bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.135 mmol) and copper(I) iodide (27.0 mg, 0.142 mmol) were added. The reaction mixture was stirred at 50° C. overnight under nitrogen. The solvents were evaporated in vacuo and the residue was twice purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5 and then chloroform/ethyl acetate/methanol 80:13:7) yielding methyl (E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:23][C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-nitrobenzhydrazide (2.16 g, 11.92 mmol) in pyridine (40 ml) cooled to 0° C. in an ice bath is added dropwise p-toluoyl chloride (1.94 g, 11.92 mmol). The mixture is allowed to warm to room temperature and stirred for 12 hours. The mixture is quenched with 350 mL of water and stirred for thirty minutes. The precipitate is filtered and dried in a vacuum oven :o yield 1-[(4-methyl)benzoyl]-2-(3-nitrobenzoyl)hydrazine as a pale yellow solid. (2.94 g, 82%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([O-:12])(=[O:11])[CH:9]=[CH2:10]>>[C:1]([O:6][C:4](=[O:5])[CH:3]=[CH2:2])(=[O:7])/[CH:10]=[CH:9]\[C:8]([OH:12])=[O:11]
Reactant: C=CC(=O)[O-]
Reactant: O=C1C=CC(=O)O1
Product: C=CC(=O)OC(=O)/C=C\C(=O)O

Procedure:
U.S. Pat. No. 5,135,984 describes a method for modifying a chlorinated polyolefin with maleic anhydride and an acrylic-modified hydrogenated polybutadiene. This method involves the graft copolymerization of the chlorinated polyolefin with the maleic acid anhydride and acrylate modified hydrogenated polybutadiene by heating the mixture in the presence of a peroxide initiator. This results in an acrylic- and maleic anhydride-modified chlorinated polyolefin.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)N1CCN(NC(=O)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(N(Cc2ccccc2)C(=O)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide (230 mg) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% oil dispersion, 35 mg) in one portion at 0° C. The mixture was stirred at 0° C. for 1 hour then benzyl bromide (0.17 ml) was added to this mixture at 0° C. After stirring at 0° C. for 1.5 hours, water was added and the solvent was evaporated. The residue was taken up in ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and ethyl acetate (1:5) to give crystals. Crystallization from ethyl acetate and n-hexane to give N-(4-acetyl-1-piperazinyl)-N-benzyl-4-fluorobenzamide (260 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:30][CH:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32](Cl)=[O:33]>ClCCl>[Cl:30][CH:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32]([N:17]1[CH2:16][C:15]2[CH:14]=[N:13][C:12]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=4)[N:9]=[CH:10][C:11]=3[C:20]=2[CH2:19][CH2:18]1)=[O:33]
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)C(Cl)c2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (1.536 g, 5.22 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (2.18 mL, 15.66 mmol) followed by 2-chloro-2-phenylacetyl chloride (90%, 1.05 mL, 6.52 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of water (10 mL). The reaction mixture was extracted with dichloromethane (10 mL) and the organic layer washed with brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (SiO2, gradient from 40% EtOAc in hexanes to 50% EtOAc in hexanes) to give the desired product, 2-chloro-1-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone as an off-white solid (1.99 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.43/8.24 (s, 1H, rotamers), 8.15/8.12 (s, 1H, rotamers), 7.52 (m, 2H), 7.40 (m, 3H), 7.17 (m, 2H), 6.83 (m, 2H), 6.53/6.48 (s, 1H, rotamers), 5.56 (s, 2H), 5.02-4.70 (m, 2H), 3.84 (m, 2H), 3.68 (s, 3H), 3.11/2.67 (m, 2H, rotamers); LCMS [M+H]: 447.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[Cl:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=[CH:5][C:6]=1[NH:9][C@@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12]
Reactant: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O

Procedure:
Following the method of Example 6, (S)-2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid and N-chlorosuccinimide in carbon tetrachloride are reacted, yielding (S)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:10](Br)Br.CC[OH:15]>O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:10]=[O:15]
Reactant: N#Cc1ccc(Br)c(C(Br)Br)c1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: N#Cc1ccc(Br)c(C=O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Bromo-3-dibromomethyl-benzonitrile (5.66 g, 16 mmol) was dissolved in EtOH (150 mL) and heated to 60° C. Silver nitrate (6.80 g, 40 mmol), prepared as a solution in H2O (40 mL), was added dropwise, and the reaction was heated to 75° C. and stirred overnight. The organic layer was decanted, concentrated, and filtered, and the residue was partitioned between EtOAc and H2O. The product was extracted with EtOAc, and the combined organic layers were concentrated and purified by silica gel chromatography (0-30% EtOAc in hexanes) to give 4-bromo-3-formyl-benzonitrile.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:11])[CH:3]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][Br:13])=[C:4]([F:11])[CH:3]=1
Reactant: OCc1cc(F)c(Br)cc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(CBr)c(F)cc1Br
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 2 g (8.44 mmol) of 4-bromo-2,5-difluorobenzoic acid (prepared according to the procedure of Ishikawa et al., Kogyo Kagaku Zasshi, pg 972-979, 1970) in 20 mL of tetrahydrofuran was added 40 mL of a 1M solution of borane-tetrahydrofuran complex. The solution was heated under reflux for 64 h, cooled to ambient temperature and 100 mL of methanol was added. The reaction was then heated for a further 2 h, cooled and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 1.6 g of 4-bromo-2,5-difluorobenzyl alcohol. To a solution of 1.3 g (5.6 mmol) of 4-bromo-2,5-difluorobenzyl alcohol in 20 mL of dichloromethane at 0° C. was added 2.27 g (6.7 mmol) of carbon tetrabromide and 1.8 g (6.7 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) to afford 1.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[Cl:11][C:12]([Cl:16])=[C:13]([F:15])[F:14].C(N(CC)CC)C>O>[Cl:11][C:12]1([Cl:16])[CH:7]([C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:8][C:13]1([F:15])[F:14]
Reactant: FC(F)=C(Cl)Cl
Reactant: C=Cc1ccc(OC)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C2CC(F)(F)C2(Cl)Cl)cc1

Procedure:
p-Methoxystyrene (40.8 g., 0.30 mole), 1,1-dichloro-2,2-difluoroethylene (55.8 g., 0.42 mole), and triethylamine (3.0 ml., 0.02 mole) are heated in a sealed tube (25 × 615 mm) at 125°-130° C. for 16 hrs. The cooled mixture is then poured into water, the reaction product extracted with ether, and the extracts washed with water, dried (MgSO4), and evaporated to an oil. Distillation of the oil yields 69.0 g. (86%), b.p. 80°-85° C. (0.1 mm), of the desired intermediate sutiable for use in the next step. Part of the oil was chromatographed (alumina, cyclohexane), and redistilled, b.p. 81° C. (0.02 mm), nD27 1.5207.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccccc4)cc3)sc2c1
Yield: 85.8 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methylbenzothiazole (1.0 g, 4.16 mmol) and benzoyl chloride (0.58 g, 4.16 mmol) in dry THF (10 ml) containing triethylamine (0.46 g, 4.58 mmol) to give the title compound (1.23 g, 86%) as a colourless solid after work-up.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=2)[CH2:17][CH2:16]1.CN1CCCC1=O.N>CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:26]2[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=[C:22]2[NH:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:2]3[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=3)[CH2:16][CH2:17]2)=[CH:29][CH:30]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: N
Solvent: CN1CCCC1=O
Solvent: CO
Product: Nc1nc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of 3.4 parts of 6-chloro-3-nitro-2-pyridinamine, 7.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-amine and 10 parts of 1-methyl-2-pyrrolidinone was stirred and heated for 2 hours at 150° C. The reaction mixture was cooled and taken up in methanol saturated with ammonia. The whole was evaporated and water was added to the residue. The product was extracted three times with 4-methyl-2-pentanone. The combined extracts were dried, filtered and evaporated in vacuo. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 5 parts (50%) of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinyl]ethyl]-3-nitro-2,6-pyridinediamine; mp. 205.7° C. (compound 63).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:16]([OH:18])=O)[CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:19][C:20]1(C)OC(=O)CC(=O)[O:21]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:20](=[O:21])[CH:19]=[C:16]([OH:18])[CH:11]2[CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N[C@@H](CC2CC2)C(=O)O)cc1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C(=O)C=C(O)C2CC2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)-3-cyclopropylalanine (2.05 g), Meldrum's acid (1.35 g) and 4-(N,N-dimethylamino)pyridine (1.56 g) in tetrahydrofuran (40 mL) was added N,N′-carbonyldiimidazole (1.66 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (40 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate-isopropyl ether to give the title compound as pale-yellow crystals (yield: 844 mg, 34%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:22]1[N:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1)#[N:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[N:27][CH:26]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: N#Cc1ccc(C(=O)Cl)cn1
Product: N#Cc1ccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)cn1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 6-cyanopyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-cyanonicotinamide as an off white powder, m.p. 125.0-129.0° C. 1H NMR (300 MHz, DMSO-d6) δ 9.05 (dd, J=2.1, 0.8 Hz, 1H), 8.88 (t, J=5.6 Hz, 1H), 8.31 (dd, J=8.1, 2.1 Hz, 1H), 8.21 (s, 1H), 8.14 (dd, J=8.1, 0.8 Hz, 1H), 8.03 (m, 1H), 7.62 (dd, J=8.3, 1.1 Hz, 1H), 7.42 (m, 1H), 7.20 (m, 1H), 6.59 (broad s, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 1.93 (m, 2H), 1.59 (m, 2H); MS (EI) m/e 385.1648 (385.1651 calcd for C21H19N7O).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[N:26][OH:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[OH:27][N:26]=[C:20]([CH2:19][C:4]1[C:3]2[C:7](=[CH:8][C:9]([Br:11])=[CH:10][C:2]=2[Br:1])[NH:6][CH:5]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: Brc1cc(Br)c2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1c[nH]c2cc(Br)cc(Br)c12)=NO

Procedure:
Mix 4,6-dibromoindole (2.09 g, 7.58 mmol), potassium carbonate (1.57 g, 11.4 mmol) and anhydrous methylene chloride (30 mL). Stir and add a solution of ethyl 3-bromo-2-hydroxyiminopropanoate (1.59 g, 7.58 mmol) in methylene chloride (20 mL). Stir under a nitrogen atmosphere for 48 hours. Take the solution up in ethyl acetate and wash with water (100 mL), saturated sodium hydrogen carbonate (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in in vacuo and purify by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:7][CH2:6]1)[CH2:2][CH:3]=C.O.I([O-])(=O)(=O)=[O:25].[Na+]>CC(O)(C)C>[O:12]=[C:11]1[N:5]([CH2:1][CH2:2][CH:3]=[O:25])[CH2:6][CH2:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:9][CH2:10]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 1 h
Yield: 636.3 %

Procedure:
To a solution of 4-but-3-enyl-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one 0.09 g (0.03 mmol) in tBuOH:water (2 ml 1:1) was added potassium osmate dihydrate 0.001 g (0.001 mmol) and sodium periodate 0.13 g (0.1 mmol). The mixture was stirred for 1 h, then extracted with CH2Cl2, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 1:1→1:0) afforded the title compound 0.06 g (64%) as a brown gum. MS: 315.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CO.Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(C=NO)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
4-Nitrobenzaldehyde (40 g, 264.49 mmol) was added to MeOH (100 ml) followed by hydroxylamine hydrochloride (22.9 g, 330.9 mmol) in H2O (100 ml). The solution was then cooled to 0° C. Sodium carbonate (16.9 g, 159.5 mmol) in H2O (100 ml) was added and the reaction was allowed to stir overnight. The MeOH was removed under vacuum and then H2O (400 ml) was added. The precipitate was filtered and dried under vacuum to yield the product (39.65 g, 238.68 mmol).