Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N+:12]([O-:14])=[O:13])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([CH3:1])([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:5][CH:6]=1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc(CC(C)(C)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A mixture of 4-(2-methyl-2-nitropropyl)phenol (3.0 g, 15.4 mmol), ethylbromoacetate (2.04 mL, 17.0 mmol) and potassium carbonate (6.4 g, 46.2 mmol) was stirred at room temperature for 18 h. The reaction was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc (3×). The combined organic layers were washed with water (3×), brine, dried (Na2SO4), and concentrated in vacuo to a brown oil. The material was purified by flash chromatography over silica gel eluting with 5% MeOH/CHCl3 to provide 4.22 g (97%) of a clear oil. NMR
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22](Cl)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:25][C@H:26]1[CH2:30][NH:29][C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12>O.O1CCOCC1>[Cl:25][C@H:26]1[CH2:30][N:29]([C:22]([O:21][CH2:20][CH:18]2[C:19]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:16]3[C:17]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:23])[C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12
Reactant: O[C@H]1CO[C@H]2[C@@H]1NC[C@@H]2Cl
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of sodium carbonate (0.49 g, 4.63 mmol) in water (7.5 mL) followed by a solution of 9-fluorenylmethoxycarbonyl chloride (0.55 g, 2.13 mmol) in 1,4-dioxane (2.5 mL) was added dropwise over 15 minutes whilst stirring to a solution of aminoalcohol (69) in 1,4-dioxane (5 mL). The mixture was stirred for 60 minutes then water (50 mL) was added and the product extracted into dichloromethane (3×25 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a colourless oil. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 45:55 gave alcohol (70) (623 mg, 87%) as a white solid. TLC (Rf=0.45, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=16.54 min., HPLC-MS 386.1/388.1 [M+H]+, 408.1/410.1 [M+Na]+; [α]D27.5−51.9° (c=2.31, CHCl3); (proton complex) δC (125 MHz, CDCl3) 47.21/47.41 (Fmoc CH), 53.30/53.43 (FmocNCH2), 57.74/58.36 (CHCl), 66.04/67.42 (Fmoc CH2), 67.87/68.52 (FmocNCH), 74.81/75.09 (OCH2CHOH), 74.92/75.51 (OCH2CHOH), 86.57/87.24 (CHCHCl), 119.80/119.82/120.00/120.64/124.55/124.63/124.90/127.04/127.08/127.40/127.51/127.78/127.80/127.87 and 127.91 (aromatic CH), 141.21/141.29/141.38/143.44/143.70/143.88 and 143.91 (aromatic quaternary), 154.13/154.79 (Fmoc C═O).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[CH3:7]>C(O)C>[N:12]1[CH:13]=[CH:14][C:9]([C:6](=[N:5][NH:4][C:1](=[O:3])[CH3:2])[CH3:7])=[CH:10][CH:11]=1
Reactant: CC(=O)NN
Reactant: CC(=O)c1ccncc1
Solvent: CCO
Product: CC(=O)NN=C(C)c1ccncc1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A mixture of 2.22 gm (0.03 mole) of acetic acid hydrazide, 3.63 gm (0.03 mole) of 4-acetylpyridine and 100 ml of absolute ethanol is refluxed 2 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with water and dried to yield 3.63 gm (69%) of the title compound having a melting point of 178.1° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]=[O:15]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:14][OH:15]
Reactant: COc1ccc2nccc(O)c2c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2ncc(CO)c(O)c2c1
Reaction time: 18 h

Procedure:
4-Hydroxy-6-methoxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide (initially at 40°-50°, then kept at 60° for 18 hours) to give the novel compound 4-hydroxy-3-hydroxymethyl-6-methoxyquinoline, m.p. 327°-334°.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[C:4]([CH3:24])=[CH:3][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCN(C)C4=O)cc3C)CC2)c(C)c1
Yield: 78.2 %

Procedure:
Using (6-bromo-4-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (195 mg) described in Preparation Example 228 and 1-methylimidazolidin-2-one (75 mg) and by the reaction and treatment in the same manner as in Example 511, 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}-3-methylimidazolidin-2-one (160 mg) was obtained. The obtained 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}-3-methylimidazolidin-2-one (160 mg) was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.2 mL) was added, and the precipitate was collected by filtration to give the title compound (98 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:20])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:20])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[CH:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: O=C(Nc1ccncc1)C(=O)c1c[nH]c2ccccc12
Product: O=C(Nc1ccncc1)C(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Yield: 64 %

Procedure:
The N-(pyridin-4-yl)-(indol-3-yl)glyoxylamide obtained according to the 1st Stage (Scheme 2) is reacted with 4-nitrobenzyl chloride according to the “benzylation procedure” (page 5) and the compound N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide obtained is isolated.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:23][CH2:24][CH2:25][OH:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:26][CH2:25][CH2:24][CH2:23][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)[NH:12][C:11]1=[O:16])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(CCCO)(c1ccccc1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CCCOS(C)(=O)=O)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Yield: 65.3 %

Procedure:
A mixture of compound 5-(3,5-dimethylisoxazol-4-yl)-3-(3-hydroxypropyl)-3-phenylindolin-2-one (0.72 g, 2.0 mmol), DIPEA (1.05 mL, 6.0 mmol), MsCl (250 mg, 2.2 mmol) in CH2Cl2 (20 mL) was stirred at 0° C. then gradually raised to RT overnight. The contents were diluted with CH2Cl2, washed with water (2×10 mL), and concentrated. The crude was purified with flash chromatography to afford compound 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (575 mg, 65.3%). 1H NMR (400 MHz, DMSO-d6): δH 10.73 (s, 1H), 7.24-7.38 (m, 7H), 7.02 (d, J=8.0 Hz, 1H), 4.13-4.16 (m, 2H), 3.12 (s, 3H), 2.37 (s, 3H), 2.30-2.34 (m, 2H), 2.20 (s, 3H), 1.30-1.48 (m, 2H). To a stirred solution of 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (440 mg, 1.0 mmol) in dry THF (10 mL) was successively added triethylamine (280 μl, 2.0 mmol) and morpholine (174 mg, 2.0 mmol) at room temperature. The reaction mixture was heated at 80° C. for 15 h and then water (10 mL) was added. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and filtered. After concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH: 95/5) to afford compound (385 mg, 89.3%) as a white solid. 1H NMR (400 MHz, CDCl3): δH 7.88 (s, 1H), 7.28-7.39 (m, 5H), 7.14-7.16 (m, 1H), 7.08 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.76 (m, 4H), 2.45-2.55 (m, 5H), 2.37-2.39 (m, 4H), 2.22-2.29 (m, 5H), 1.54-1.55 (m, 2H). MS (ESI) m/e [M+1]+ 432.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10](=[O:17])[C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10](=[O:17])[C:11]([CH3:15])([CH3:16])[CH2:12][CH2:13][Cl:14]
Reactant: BrBr
Reactant: CC(C)(CCCl)C(=O)CSc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(CCCl)C(=O)C(Br)Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
137 g (0.47 mole) of 1-(4-chlorophenylthio)-5-chloro-3,3-dimethyl-2-pentanone are dissolved in 1,000 ml of chloroform. 75.3 g (0.47 mole) of bromine are added dropwise at room temperature such that the solution is always decolorized. The reaction mixture is then subsequently stirred at room temperature for 1 hour and is concentrated by distilling off the solvent. 172.7 g (99.3% of theory) of 1-bromo-1-(4-chlorophenylthio)-5-chloro-3,3-dimethyl-2-pentanone of refractive index nD20 1.5796 are obtained. ##STR94##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:17])[CH3:16]
Reactant: Cc1ccncc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnccc1C
Yield: 53.3 %

Procedure:
To solution of 3-amino-4-methylpyridine (540.2 mg, 5.0 mmol, 1 equiv) in dichloromethane (20 mL) was added pyridine (0.8 mL, 10.0 mmol, 2 equiv) and acetic anhydride (0.57 mL, 6.0 mmol, 1.2 equiv). The resultant solution was stirred at room temperature for 16 h and concentrated in vacuo to provide a crude residue. The residue was diluted with dichloromethane (200 mL), and washed with saturated sodium bicarbonate aqueous solution (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield 3-acetylamino-4-methylpyridine (400.2 mg) as yellow solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]([CH3:13])[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=1.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]([CH3:13])[C:10](=[O:11])[O:23][C:20]2[CH:21]=[CH:22][C:17]([CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(N(C)C(=O)Cl)n1
Reactant: CC(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1cccc(N(C)C(=O)Oc2ccc(C(C)C)cc2)n1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 2.01 g of N-(6-methoxy-2-pyridyl)-N-methylcarbamoylchloride, 1.36 g of 4-isopropylphenol, and 1.38 g of anhydrous potassium carbonate in 50 ml of methyl ethyl ketone was refluxed for 5 hours. After the reaction mixture was cooled to room temperature, it was poured into cold water and the product was extracted with benzene. The benzene solution, successively washed with water and brine, was dried over anhydrous magnesium sulfate. The residue obtained by the removal of benzene under reduced pressure was chromatographed through silica gel column using benzene as an eluent to give 2.56 g of pure 4-isopropylphenyl N-(6-methoxy-2-pyridyl)-N-methylcarbamate as solid in the yield of 85%. A part of the solid was recrystallized from hexane and crystals having melting point of 64° to 65° C. were obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([Cl:16])[CH:18]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Product: Nc1ccc(Cc2ccccc2)cc1-c1ccc(F)c(Cl)c1

Procedure:
4-benzyl-2-bromo-aniline and 3-chloro-4-fluorobenzene boronic acid were combined to form 4-benzyl-2-(3-chloro-4-fluorophenyl)-aniline,
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Pd]>[NH:1]([C:8]1[N:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2c(cn1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a flask containing 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (10 mg, 0.03 mmol) in EtOAc (2 mL) and EtOH (2 mL) at room temperature was added a drop of TEA, and Pd/C (10 weight % on activated carbon Degussa type E101, 2 mg). The system was purged with H2 and left stirring at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo to provide 2-anilino-7-methyl-1-phenyl-1,6naphthyridin-4(1H)-one (8 mg, 91%): LCMS RT: 1.22 min, MH+: 328.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:13]1[CH:14]=[CH:15][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:44]=[CH:45][C:46]([N:49]5[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]5)=[CH:47][CH:48]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH:9]=2)=[N:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(Br)cnc32)cc1
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: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 28.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 63) (150 mg, 0.276 mmol) was coupled with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 40) (139 mg, 0.359 mmol) using sodium carbonate (82 mg, 0.78 mmol) and Pd(PPh3)4 (10 mg, 0.013 mmol) in DME/water (10/1 ml). This afforded 58 mg (28.7% yield) after purification by column (Silica gel 60/120) using 20% ethyl acetate in hexane as eluent. MS: m/z=725.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1.[CH3:21][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:12])[CH3:21])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(F)cc(C=O)c2n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C

Procedure:
To a solution of 5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (1.53 g, 5.2 mmol) in tetrahydrofuran (32 mL) at −78° C. was added methyl magnesiumbromide (3M in diethyl ether, 3.46 mL, 10.4 mmol). The reaction was allowed to gradually warm in the ice bath (ca. 2 h) to 0° C. The reaction which had been a suspension became a solution. The reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 1.59 g (99%) as an yellow oil. 1H-NMR (CDCl3, 500 MHz) δ 8.05(s, 1H), 7.15(m, 1H), 7.05(m, 1H), 5.68(s, 2H), 5.33(q, J=5 Hz, 1H), 3.63(m, 2H), 1.68 (d, J=10.0 Hz, 3H), 0.93(m, 2H), −0.03(s, 9H); 13C-NMR (CDCl3, 126MHz) δ 58.7 (d, J=960 Hz), 144.4, 137.7, 122.9, 121.9, 113.5, 113.3, 101.6, 101.4, 81.9, 68.0, 67.6, 25.7, 23.3, 17.9, −1.38; Mass spec.: 311.33 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:3]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:3]1
Reactant: Nc1nnc(Br)s1
Reactant: CC1CCN(Cc2cccc(OCCCCN)c2)C1
Product: CC1CCN(Cc2cccc(OCCCCNc3nnc(N)s3)c2)C1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 4-[3-[(3-methylpyrrolidin-1-yl) methyl]-phenoxy]-butanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:33][CH3:34])[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1)[CH3:31]
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Reactant: CCNCC
Product: CCN(CC)c1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Yield: 48 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methane sulfonylamino-benzyl)-acrylamide (27 mg, 0.06 mmol) was reacted with diethylamine (5 eq) to give the title compound (14 mg, 48%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][C:28]([O-])=O.[K+]>CC#N.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:28]4[CH:27]=[CH:18][N:17]=[CH:15][CH:13]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CC(=O)[O-]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3ccncc3)cc1OCC2)c1ccccc1Cl
Temperature: 140 °C

Procedure:
A suspension of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (50 mg, 0.11 mmol) in 1.0 mL MeCN and 1.0 mL 1M KOAc in water in a 10 mL microwave vial was degassed with bubbling nitrogen for approximately 10 min. 4-pyridineboronic acid (16 mg) was added followed by Pd(PPh3)4 (13 mg). The vessel was sealed and heated in a microwave at 140° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue purified by reverse phase HPLC to give 134. 1H NMR (DMSO-d6) δ 8.77 (m, 2H), 8.05 (m, 2H), 7.70-7.53 (m, 7H), 6.65 (br s, 1H), 4.25 (m, 2H), 3.31 (s, 3H), 3.02 (m, 2H). MS: (ESI+) 447.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([N:42]2[C:46]3([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:45](=[O:52])[NH:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:49]3[CH2:48][CH2:47][C:46]4([N:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:43][NH:44][C:45]4=[O:52])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)NCN4c3ccccc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:13][CH3:14].[Cl-:16].[NH2:17][N+:18]1[CH:22]=[CH:21][N:20]([NH2:23])[C:19]=1[CH2:24][CH2:25][CH3:26]>C(O)(=O)C>[Cl-:16].[CH3:1][N:2]([CH3:15])[C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=[N:17][N+:18]2[CH:22]=[CH:21][N:20]([N:23]=[CH:7][C:6]3[CH:9]=[C:10]([O:11][CH3:12])[C:3]([N:2]([CH3:1])[CH3:15])=[C:4]([O:13][CH3:14])[CH:5]=3)[C:19]=2[CH2:24][CH2:25][CH3:26])=[CH:5][C:4]=1[O:13][CH3:14]
Reactant: CCCc1n(N)cc[n+]1N
Reactant: COc1cc(C=O)cc(OC)c1N(C)C
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCCc1n(N=Cc2cc(OC)c(N(C)C)c(OC)c2)cc[n+]1N=Cc1cc(OC)c(N(C)C)c(OC)c1
Reaction time: 16 h

Procedure:
1.43 g (6.8 mmol) of 4-dimethylamino-3,5-dimethoxy-benzaldehyde are added to a solution of 0.60 g (3.4 mmol) of 1,3-diamino-2-propyl-imidazolium chloride in 5 ml of glacial acetic acid. After leaving to stand for 16 hours the product is crystallized out by the addition of ether and then recrystallized from ethanol. There is obtained 1,3-bis[[4-(dimethylamino)-3,5-dimethoxybenzylidene]amino]-2-propylimidazolium chloride of melting point 218°-219°.