Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:58]=[CH:57][CH:56]=[CH:55][C:14]=1[C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH2:51][C:52]([OH:54])=[O:53])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:59][Si](C=[N+]=[N-])(C)C>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:58]=[CH:57][CH:56]=[CH:55][C:14]=1[C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH2:51][C:52]([O:54][CH3:59])=[O:53])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N(C)C(=O)c2ccc(NC(=O)c3ccccc3OCCCNC(=O)OC(C)(C)C)c(OCC(=O)O)c2)c(OCCCCCC(=O)N2CCN(C)CC2)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-carboxymethoxy-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]-4-methylphenyl]benzamide (128 mg) in methanol (5 ml) was added dropwise trimethylsilyldiazomethane (5 ml, 2.0M n-hexane solution) and stirred at ambient temperature for 30 minutes. The solution was concentrated in vacuo and the residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol:28% aqueous ammonia solution, 50:5:1) to give 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxycarbonylmethoxy-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]-4-methylphenyl]benzamide (85 mg).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][C:10](Cl)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.C(O)C>[C:20]([C:22]1[CH:27]=[C:26]([C:10]2[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][CH:9]=2)[CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cccc(-c2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1
Reaction time: 0.75 h
Yield: 42 %

Procedure:
First, 1.02 g of 2,3-diphenyl-5-chloropyrazine, 0.62 g of 3-cyanophenylboronic acid, 0.15 g of tetrakis triphenylphosphine palladium(0) (abbreviation: Pd(PPh3)4), 10 mL of toluene, 1.5 mL of ethanol, 1.16 g of potassium carbonate, 4.2 mL of water were put in an eggplant-type flask with a reflux pipe, and the atmosphere in the flask was substituted with argon. Then, irradiation with microwave (2.45 GHz, 100 W to 150 W) was performed for 45 minutes to cause a reaction. Water was added to this mixture and dichloromethane was used as an extraction solvent, so that an organic layer was extracted. The obtained organic layer was dried with anhydrous magnesium sulfate. After the drying, the solution was filtrated. After a solvent of this solution was distilled off, the residue obtained by the distillation was purified by silica gel column chromatography which uses a mixture solution of dichloromethane and ethyl acetate as a developing solvent to obtain a white powdered solid in a yield of 42%. Note that the irradiation with a microwave was performed using a microwave synthesis system (Discover, produced by CEM Corporation). A synthesis scheme of Step 1 is shown by the following (a-1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13](C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.Cl.[C:21]([NH:25]N)([CH3:24])([CH3:23])[CH3:22].C(O)C>O>[C:21]([N:25]1[C:4]([C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[Cl:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[N:13]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccccc1Cl
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A mixture of 2.82 g of ethyl 2-(2-chlorobenzoyl)-3-(N,N-dimethylamino)acrylate (a compound described in JP-A 7-101940), 1.25 g of tert-butylhydrazine hydrochloride and 10 ml of ethanol was heated to reflux for 8 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.48 g of ethyl 1-tert-butyl-5-(2-chlorophenyl)-1H-pyrazole-4-carboxylate of the formula:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=2[F:29])[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:29][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=1[CH2:19][C:4]1[CH:3]=[CH:2][N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])[CH:9]=[CH:10][C:5]=12)[NH2:26]
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc([N+](=O)[O-])cc3F)cc(Cl)nc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc(N)cc3F)ccnc21

Procedure:
270 mg (0.62 mmol) of 6-chloro-4-(2-fluoro-4-nitrobenzyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine are dissolved in 2 ml of ethanol. 170 μl (1.24 mmol) of triethylamine and 50 mg of 10% palladium-on-carbon are added. The mixture is hydrogenated at RT and a hydrogen pressure of 1.5 bar for 20 h. The mixture is filtered and concentrated, ethyl acetate is added and the mixture is washed with 1N aqueous sodium hydroxide solution. The organic phase is dried over sodium sulfate and concentrated. The product is reacted further without purification.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:13])[CH2:5][CH2:6][CH:7]=[C:8]([CH2:11][CH3:12])[CH2:9][CH3:10].[OH:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1>>[CH3:13][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:3][CH2:2][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: CCC(=CCCC(C)=CCBr)CC
Product: CCC(=CCCC(C)=CCOc1ccc2c(c1)OCCC2)CC

Procedure:
Following the procedure of Example 1, 1-bromo-3-methyl-7-ethyl-2,6-nonadiene and 7-hydroxy-chromane are reacted to form 7-(3-methyl-7-ethyl-2,6-nonadienyloxy)-chromane, nD20 = 1.5342.
Reaction SMILES: C[N+]1([O-])CCOCC1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[CH:25]([CH3:35])[CH:26]([OH:34])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1)[O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[CH:25]([CH3:35])[C:26]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1)=[O:34])[O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1
Reactant: Cc1cc(C(O)C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)ccn1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
4-Methyl-morpholine-4-oxide (136 mg) and tetrapropylammonium perruthenate (18 mg) were added to a solution of 4-{3-chloro-4-[2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-ethyl]-phenoxy}-benzonitrile (190 mg, 0.5 mmol) in DCM (5 ml) with 3A molecular sieves. The mixture was stirred for 2 h at room temperature, filtered and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 30% EtOAc/heptane) to give the title compound (80 mg) as a light yellow solid. MS (m/e)=377.3 [M+H+].
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[C:9]1([N:15]2[C:19]3[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[S:22][CH2:23][C:18]=3[C:17]([C:28](Cl)=[O:29])=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CN(C)C=O.O1CCOCC1>[C:1]([CH:3]([C:28]([C:17]1[C:18]2[CH2:23][S:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:19]=2[N:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:16]=1)=[O:29])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: N#CCC(N)=O
Reactant: O=C(Cl)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#CC(C(N)=O)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Temperature: 25 °C

Procedure:
2-Cyanoacetamide (1.85 g) is treated with 50% sodium hydride (1.28 g) in dimethylformamide (35 ml) under stirring at room temperature until the effervescence subsides. To this solution 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carbonyl chloride (6.53 g), prepared according to Example 15, dissolved in dioxane (35 ml) is added under stirring at room temperature. The reaction mixture is allowed to react for 2 hours, then is diluted with ice water and acidified to pH 1 with 37% HCl. The gummy precipitate is extracted with ethyl acetate and the organic solution washed with N HCl and then evaporated to dryness in vacuo. The residue is purified over SiO2 column, using chloroform/methanol 80:20 as eluent, to give 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanamide, m.p. >300° C. dec., NMR (DMSO d6) δ ppm: 4.10 (s) (2H, --S--CH2 --), 6.00-7.00 (bs) (2H, CONH2), 6.60-7.80 (m) (9H, phenyl protons), 9.00 (bs) (1H, OH).
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>CCOCCO>[C:12]([NH:20][N:21]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([OH:1])[CH3:11])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1
Reactant: NNC(=O)c1cccnc1
Reactant: CC(O)C(=O)c1ccccc1
Solvent: CCOCCO
Product: CC(O)C(=NNC(=O)c1cccnc1)c1ccccc1
Yield: 68.8 %

Procedure:
A mixture of 15.0 g of 2-hydroxypropiophenone and 13.7 g of nicotinic acid hydrazide is stirred in 100 ml of ethyl cellosolve, initially for 18 hours at 120° C. (with distillation of a small amount of solvent) and then for a further 5 hours at room temperature. The light yellow precipitate produced is isolated by suction filtration and washed with ethanol and then with water. 18.5 g of 2-hydroxypropiophenone nicotinoylhydrazone are obtained after the product has been dried at 40°-50° C. under vacuum. 2.7 g of this product are suspended in 30 ml of dimethylformamide and treated with a solution of 2.8 g of nickel(II) acetate·4H2O in 35 ml of dimethylformamide. The resulting mixture is stirred at 120° C. for 4 hours and the product is then isolated by filtration and subsequently washed with isopropanol and then with water. After the product has been dried under vacuum at 60°-70° C., 2.8 g of a yellow powder of the following formula (or a tautomeric form thereof): ##STR17## as the 1:1 nickel complex are obtained which gives the following microanalysis:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.Br.[C:17](OCC)(=O)C>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]([O:15][CH3:17])=[O:14])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OCCC2C(=O)O
Reactant: CCOC(C)=O
Agent: Br
Product: COC(=O)C1CCOc2cc(O)ccc21
Temperature: 130 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To 7-methoxy-3,4-dihydro-2H-chromene-4-carboxylic acid (0.71 g, 3.41 mmol) was added HBr (0.276 g, 3.41 mmol) and the reaction was heated at 130° C. for 3 hours. The reaction was cooled and concentrated, and the residue was loaded onto a silica gel samplet. The product was eluted using a gradient of 0.5% MeOH/CH2Cl2 containing 0.5% acetic acid to 10% acetic acid/CH2Cl2 containing 0.5% acetic acid. The isolated product was dissolved in MeOH (5 mL) and concentrated sulfuric acid (1 mL) was added and the reaction heated at 75° C. After 2 hours, reaction was cooled, diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 0.5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2, to provide the title compound (0.312 g, 43.9% yield).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:20])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C[C@@H:23]1[C:27]2[NH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:26]=2[C:25](=[O:40])[NH:24]1>>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:20])[C:13]2[C:8](=[C:9]([C:29]3[NH:28][C:27]4[CH2:23][NH:24][C:25](=[O:40])[C:26]=4[CH:30]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: COCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Product: COCCn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)CNC4=O)cccc2c1=O
Yield: 51.3 %

Procedure:
This compound (138 mg, 51% yield) as a brown solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-8-iodo-3-(2-methoxyethyl)quinazolin-4(3H)-one (715) (273 mg, 0.68 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (706) (219 mg, 0.88 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (1H, br.), 7.90 (2H, m), 7.56 (1H, br.), 7.20 (1H, t, J=7.4 Hz), 6.83 (1H, s), 6.50 (1H, s), 4.27 (4H, m), 3.70 (2H, m), 3.35 (3H, s), 1.49 (9H, s). m/z (ESI, +ve) 395.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:23][C:24]([NH2:26])=[O:25].O>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:23][C:24]([NH2:26])=[O:25])=[CH:16][CH:17]=2)[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(O)cc2C1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.16 g of 60% NaH (0.004 mole) and 3.5 ml of anhydrous DMF were stirred at ambient temperature in a stream of nitrogen and 1 g (0.0038 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxy-tetralin in 9 ml of anhydrous DMF and 0.52 g (0.0038 mole) of 2-bromoacetamide in 2.5 ml of anhydrous DMF were added. It was stirred at ambient temperature for 6 hours then the mixture was poured into water. The precipitated product was filtered and the product of the heading was then obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:29]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[N:22]=2)[CH2:16][CH2:15]1)=S.[S]>[Hg]=O.O1CCCC1>[CH2:33]([O:32][CH2:31][CH2:30][N:29]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1[CH2:20][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][C:9]2[NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)[CH2:15][CH2:16]1)[CH3:34]
Reactant: CCOCCn1c(CN2CCN(CCNC(=S)Nc3cnccc3N)CC2)nc2cccnc21
Agent: O=[Hg]
Agent: [S]
Solvent: C1CCOC1
Product: CCOCCn1c(CN2CCN(CCNc3nc4cnccc4[nH]3)CC2)nc2cccnc21
Reaction time: 3 h
Yield: 30 %

Procedure:
A mixture of 16.9 parts of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl) -3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazinyl]ethyl]thiourea, 11.4 parts of mercury(II)oxide, 0.1 parts of sulfur and 135 parts of tetrahydrofuran was stirred for 3 hours at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.73 parts (30.0%) of N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazinyl]ethyl]-1H-imidazo[4,5-c]pyridin-2-amine; mp. 124.5° C. (compound 123).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][CH:21]=O)[CH:15]=[CH:16][C:17]=1[F:18]>>[F:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][CH:21]2[NH:10][CH2:9][CH2:8][N:3]3[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]23)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Cc1cn(CCN)c(C)n1
Reactant: O=CCCc1ccc(F)c(F)c1
Product: Cc1nc(C)n2c1C(CCc1ccc(F)c(F)c1)NCC2

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(3,4-difluoro-phenyl)-propionaldehyde. LC-MS: tR=0.57 min.; [M+H]+=292 g/mol.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11](=[O:23])[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([CH3:16])=[CH:14][N:15]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:1][CH2:16][C:13]1[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11](=[O:23])[C:10]([Cl:9])=[N:15][CH:14]=1
Reactant: CCOC(=O)Cn1c(C)cnc(Cl)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)Cn1c(CBr)cnc(Cl)c1=O
Temperature: 75 °C

Procedure:
N-BROMOSUCCINIMIDE (2.61 G, 14.7 MMOL) WAS ADDED TO A STIRRED SOLUTION OF 3-CHLORO-1-ETHOXYCARBONYLMETHYL-6-METHYLPYRAZINONE (3.38 G, 14.7 MMOL) IN DRY BENZENE (50 ML). BENZOYL PEROXIDE (70%, 30 MG, 0.087 MMOL) WAS ADDED AND THE SOLUTION WAS HEATED TO 75° C. AFTER 16 H THE MIXTURE WAS PARTITIONED BETWEEN METHYLENE CHLORIDE AND 5% SODIUM METABISULFITE. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE RESIDUE WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (30% ETOAC/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>[Pd].CO>[C:30]1([C:13]2[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=[CH:2][C:11]=3[N:12]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCn2c(-c3ccccc3)nc3cnc4ccccc4c32)CC1
Reaction time: 12 h
Yield: 65.9 %

Procedure:
A suspension of 0.80 g of tert-butyl 4-[2-(4-chloro-2-phenyl-1H-imidazo-[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 0.30 g of 5% palladium on carbon in 80 ml of methanol was catalytically hydrogenated at ordinary temperature under atmospheric pressure for 12 hours. Mter the reaction, the catalyst was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using ethyl acetate—n-heptane (1:1 to 4:1) as eluting solvents and washed with diisopropyl ether to give 0.49 g of pale yellow crystals. Recrystallization from diisopropyl ether gave colorless crystals having the melting point of from 138 to 139° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([Li])CCC.CCCCCC.Br[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[N:43]=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]([C:50]3[CH:51]=[CH:52][CH:53]=[C:48]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:42][N:43]=4)[N:49]=3)=[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(-c2csc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Reactant: Brc1cccc(-c2ccccn2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2c(-c3cccc(-c4ccccn4)n3)sc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
After placing 3.5 g of 3,4-diphenylthiophene and 60 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 11 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 4.1 g of a zinc chloride/tetramethylethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 3.8 g of 2-bromo-6-(2-pyridyl)pyridine and 0.52 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, the organic layer was extracted, and the concentrate obtained using an evaporator was purified by recrystallization to obtain 4.5 g of 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene. After placing 3.3 g of the 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene and 80 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 6.2 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 2.4 g of a zinc chloride/tetramethyl-ethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 2.2 g of 2-bromo-6-(2-pyridyl)pyridine and 0.30 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, and the organic layer was extracted. The organic layer was concentrated with an evaporator and purified by column chromatography and recrystallization to obtain 1.1 g of BPPDPT.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:14](=[O:16])[CH3:15])=[CH:10]2)=[CH:5][CH:4]=1.[Cl:19]N1C(=O)CCC1=O.Cl>C(O)(=O)C>[Cl:19][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of 7-trifluoromethyl-2-acetamidonaphthalene (620 mg, 2.45 mmol), N-chlorosuccinimide (326 mg, 2.45 mmol) and 1 M HCl in acetic acid (2.45 mL, 2.45 mmol) in acetic acid (10 mL) is heated at 50° C. under a N2 atmosphere for 1 hour. After cooling to room temperature, the mixture is partitioned between EtOAc and water. The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator to give 1-chloro-7-trifluoromethyl-2-acetamidonaphthalene as an off-white solid.