Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[S:24]1(=[O:39])(=[O:38])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:29][CH2:30][S:24]3(=[O:39])=[O:38])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNS(=O)(=O)CC1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S(=O)(=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.188 g, 0.50 mmol), tert-butyl 1,2,5-thiadiazepane-5-carboxylate 1,1-dioxide (0.12 g, 0.45 mmol) and Cu2O (0.071 g, 0.50 mmol) in pyridine (3 mL) were heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (0.2 g in water 10 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.2 g in water 10 mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][C@H:24]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:23]3)O1>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[O:4][C:3]([CH2:2][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][C@H:24]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:31])=[O:32])[CH2:23]3)=[CH:7][CH:6]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: FC(F)(F)c1ccc(CBr)o1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3ccc(C(F)(F)F)o3)cc2C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
2-(bromomethyl)-5-(trifluoromethyl)furan (0.123 mmol, 28.2 mg), (S)—N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.123 mmol, 45 mg) and Bromo(N-succinimidyl)bis-(triphenylphosphine)palladium(II) (6.16 μmol, 4.98 mg) were suspended in THF (1 mL) and 2M NaCO3 (0.5 mL) added. The mixture was heated to 100° C. for 10 min. After this time the reaction mixture was irradiated for a further 20 min at 100° C. before standing overnight. The mixture was concentrated to remove THF before partitioning between DCM/H2O. The organic layer was collected and dried using a hydrophobic filter tube. Concentration and purification on basic HPLC gave the title compound (7.5 mg, 0.019 mmol, 15.7%). MS (ESI): m/z [M−H]− 386.3.
Reaction SMILES: C[CH:2]([C:4]1[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])=[N:6][C:7]2[C:12]([CH:13]=1)=[N:11][CH:10]=[CH:9][CH:8]=2)[OH:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:23][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:5]1[C:4]([CH:2]=[O:3])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[N:6]=1)(=[O:21])=[O:22]
Reactant: CC(O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1nc2cccnc2cc1C=O
Reaction time: 8 h

Procedure:
To a solution of crude of methyl (2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)methanol (1 g, 3.18 mmol) in DCM (10 mL) was added pyridinium dichromate (2.4 g, 6.36 mmol) at 25° C. The reaction mixture was stirred for overnight at same temperature. The reaction mixture was filtered through Celite™. The filtrate was concentrated in vacuo to give 2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carbaldehyde: LC-MS (ESI) m/z 313.0 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:14]Br>[Fe].II>[CH3:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(c2ccccc2)CCCCC1
Reactant: BrBr
Agent: [Fe]
Agent: II
Product: CC1(c2ccc(Br)cc2)CCCCC1
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To 20.0 g (115 mmol) of the 1-methylcyclohexylbenzene obtained in the above-mentioned (1) were added 279 mg (5.00 mmol) of iron and 198 mg (0.78 mmol) of iodine, and 17.8 g (111 mmol) of bromine was slowly added dropwise at 0° C. spending 1.5 hours, followed by stirring at the same temperature for 1.5 hours and then at room temperature for 20 hours. The reaction solution was cooled and then quenched with 30 ml of saturated sodium sulfite aqueous solution and extracted three times with 50 ml of hexane. The combined organic layers were washed with 30 ml of sodium sulfite aqueous solution and 30 ml of water and dried with anhydrous sodium sulfate. After filtration of the desiccant, the solvent was recovered under a reduced pressure to obtain 27.9 g of crude bromide. By purifying the thus obtained crude bromide by distillation under a reduced pressure (from 117 to 120° C./2 mmHg), the specified substance was obtained with a yield of 80.3%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>O1CCOCC1.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>[S:18]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:19]1
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)c1cccc(Br)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2ccsc2)c1
Temperature: 100 °C
Yield: 98.3 %

Procedure:
Nitrogen (gas) was bubbled through the solution of methyl 3-bromobenzoate (50 mg, 0.233 mmol), potassium carbonate (96 mg, 0.698 mmol) and 3-thiopheneboronic acid (59.5 mg, 0.465 mmol) in dioxane (2 mL) and Water (0.2 mL) for 5 minutes. tetrakis(triphenylphosphine)palladium(0) (26.9 mg, 0.023 mmol) was added and again nitrogen was bubbled through the solution for 5 minutes. The reaction mixture was heated overnight at 100° C. and concentrated to dryness. Purified by chromatography (20% EtOAc in heptane) gave compound methyl 3-(thiophen-3-yl)benzoate 82 (50 mg, 99%). (m/z)=219 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])([O-])=O>CO.[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:15]([F:16])([F:17])[F:18])[CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCC2)cc1C(F)(F)F
Yield: 97.2 %

Procedure:
A solution of 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (350 mg, 1.34 mmol) in methanol (2 mL) and Pd/C (30 mg, 0.3 mmol) were stirred for 16 h under H2. The reaction mixture was filtered and the solvent evaporated in vacuo to provide 4-(pyrrolidin-1-yl)-2-(trifluoromethyl)aniline (0.3 g, 97%). LC/MS: m/z 231.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J=8.8 Hz, 1H), 6.72 (dd, J=8.8, 2.5 Hz, 1H), 6.53 (d, J=2.7 Hz, 1H), 4.74 (s, 2H), 3.21-3.11 (m, 4H), 2.00-1.93 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=O)[O:10]C2C=CC=CC=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:9]([NH:8][C:6]2[N:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)=[O:10])[CH:43]=[CH:44][CH:45]=1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 31.3 %

Procedure:
A stirred mixture of phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (0.15 g, 0.50 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (0.15 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C. for 15 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford an oil. Purification via preparative silica gel thin-layer chromatography (eluting with a mixture of 8% methanol in dichloromethane containing 0.5% ammonia) followed by recrystallization from diethyl ether afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea (80 mg, 32%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 7.52-7.55 (m, 6H), 7.34-7.42 (m, 3H), 7.18 (m, 1H), 6.92 (m, 1H), 6.30 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 511 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][CH:17]=[C:11]3[CH2:10]2)[CH2:3][CH2:2]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH2:17][CH:11]3[CH2:10]2)[CH2:3][CH2:2]1)=[O:24]
Reactant: O=C(Cl)c1cccs1
Reactant: C1=Cn2cccc2CN1CCC1CCNCC1
Solvent: c1ccncc1
Product: O=C(c1cccs1)N1CCC(CCN2CCN3CCCC3C2)CC1

Procedure:
In the manner of Example 2, 2-(4-piperidylethyl)-pyrrolo[1,2-a]pyrazine and 2-thienylcarbonyl chloride will react in pyridine solution to produce the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23](O)=[O:24].N.O1CCOCC1.F[P-](F)(F)(F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C.C(N(CC)CC)C>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([NH2:40])=[O:24]
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
To a stirred solution of (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid (0.25 g, 0.74 mmol), triethylamine (0.5 mL), ammonia in dioxane (0.5M, 4.5 mL, 2.3 mmol) in acetonitrile (10 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.33 g, 0.9 mmol). The solution was stirred at ambient temperature for 18 h then concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate (50 mL) and washed with 2 M sodium carbonate (2×25 mL) and 1 M hydrochloric acid (2×25 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness. Recrystallization from diethyl ether (25 mL) in a Branson ultrasonic bench top water bath afforded 2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide (0.06 g, 23%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.29-7.21 (m, 2H), 7.10 (d, J=6.5 Hz, 1H), 7.03-6.90 (m, 2H), 6.55 (s, 1H), 6.36 (s, 1H), 4.72 (ABq, 2H), 4.53-4.38 (m, 1H), 4.29 (ABq, 2H), 2.92 (t, J=8.6 Hz, 2H); MS (ES+) m/z 337.1 (M+1), 359.1 (M+23).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:4]=[CH:5][N:6]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24]>C(O)C>[ClH:18].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: NCCON
Reactant: Cc1nccn1CCCC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1nccn1CCCC(=NOCCN)c1ccccc1
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A mixture of 4-(2-methyl-1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.35 g), 3 equivalents of pyddine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for four hrs. The solvent was evaporated toluene was added and evaporated The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 3.1 g (66%) of product, mp 153°-155° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)[C:13](=[O:15])[CH2:12][CH2:11]1)[CH3:2]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCOc1ccccc1C1CCC(=O)N1
Product: CCOc1ccccc1C1CCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2-ethoxyphenyl)pyrrolidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.08 min.; [M+H]+: 379.99 g/mol.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C)C=O>O>[N+:17]([C:14]1[CH:15]=[CH:16][C:9]([N:4]2[CH2:3][C@@H:2]([CH3:1])[N:7]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:6]([CH3:8])[CH2:5]2)=[C:10]([C:11]#[N:12])[CH:13]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1[C@H](C)CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@@H]1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Then, cis-2-(3,5-dimethylpiperazin-1-yl)-5-nitrobenzonitrile (14.3 g), potassium carbonate (4.9 g) and ethyl bromoacetate (6 g) were added to dimethylformamide (35 ml), and the mixture was stirred at 60° C. for 1 h. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give ethyl cis-4-(4-nitro-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate (10.8 g) as an oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)/[N:8]=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: C(=N\C(c1ccccn1)c1ccccn1)\c1ccccn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNC(c2ccccn2)c2ccccn2)nc1
Yield: 88.8 %

Procedure:
To a solution of N-[di(2-pyridinyl)methyl]-N-[(Z)-2-pyridinylmethylidene]amine (1.5 g, 5.5 mmol) in methanol (20 ml) was added NaBH4 (0.45 g, 11.8 mmol) in small portions. After stirring at room temperature for 2 hours HCl (aq) is added until the pH<2. After stirring for 30 min 5 N NaOH (aq) is added until the pH>9. The methanol is removed through evaporation and the aqueous layer is extracted with ethyl acetate (3×30 ml). The combined ethyl acetate layers are washed with brine (30 ml) and dried (Na2SO4). Evaporation of the solvent gave N-[di(2-pyridinyl)methyl]-N-(2-pyridinylmethyl)amine (N3Py) (1.35 g, 89%) as a yellow oil. 1H-NMR (CDCl3, 300 MHz) δ 3.85 (s, 2H), 5.10 (s, 1H), 7.03 (m, 3H), 7.41 (m, 6H), 8.46 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ 53.1 (t), 68.9 (d), 121.8 (d), 122.1 (d), 122.2 (d), 122.3 (d), 136.3 (d), 136.5 (d), 149.2 (d), 159.6 (s), 161.2 (s); MS (CI): m/z 277 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: ClCCCBr
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(OCCCCl)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxybenzophenone (0.99 g), potassium carbonate (3.45 g) and 1-bromo-3-chloropropane (2.5 mL) in N,N-dimethylformamide (7.5 mL) affords 1.4 g of 4-(3-chloropropoxy)benzophenone as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:14][CH3:15])=[O:13])=[C:7]([OH:16])[CH:6]=[CH:5]2.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:14][CH3:15])=[O:13])=[C:7]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[CH:5]2
Reactant: CNC(=O)c1c(O)ccc2cc(Br)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CNC(=O)c1c(O[Si](C)(C)C(C)(C)C)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of 6-bromo-2-hydroxy-N-methyl-1-naphthamide (2.50 g), tert-butyldimethylsilyl chloride (1.61 g), and imidazole (912 mg) in DMP (30 mL) was stirred for 2 h at room temperature. After dilution with water, the resulting mixture was extracted with AcOEt. The organic layer was washed with water and brine followed by concentrating in vacuo. The residue was passed through silica gel plug (hexane:AcOEt=1:1). The elute was concentrated, and the residue was washed with hexane to give the titled compound (3.33 g) as colorless needles.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([OH:31])=O.Cl.[CH3:33][NH:34][OH:35].O>C(Cl)Cl>[OH:35][N:34]([CH3:33])[C:29](=[O:31])[CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CNO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CN(O)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1'-Carbonyl-diimidazole (5.5 g; 34 mmol) is slowly added to a warm solution of 2-[(2,6-dichlorophenyl)-amino]-benzeneacetic acid (6.5 g; 22 mmol) in CH2Cl2 (600 mL) and stirred at room temperature for 2.0 hours when a clear solution is formed. N-Methylhydroxylamine hydrochloride (5.5 g; 66 mmol) is slowly added to the solution and the mixture stirred at room temperature for 48 hours. It is decomposed with water, extracted with CH2Cl2 and dried over Na2SO4. The solvent is evaporated off and the residue flash chromatographed over silica gel (250 g) using 10% EtOH-CH2Cl2 as eluant to give the pure product as white solid which is recrystallized from toluene-CH2Cl2. Yield 2.95 g (41.2%); mp 135°-138° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[CH:6][N:5]2[C:16]=1[CH2:17][C:18]1[CH:37]=[CH:36][C:21]2/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[O:25][CH2:26][C:20]=2[CH:19]=1.O>C1COCC1>[C:10]([C:8]1[CH:7]=[CH:6][N:5]2[C:16]([CH2:17][C:18]3[CH:37]=[CH:36][C:21]4/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=5[O:25][CH2:26][C:20]=4[CH:19]=3)=[C:2]([CH3:1])[N:3]=[C:4]2[CH:9]=1)#[CH:11]
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C)nc4cc(C#C[Si](C)(C)C)ccn34)cc2COc2cc(F)ccc21
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccn2c(Cc3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
[step 2] (E)-2-{8-[(2-methyl-7-trimethylsilylethynylimidazo[1,2-a]pyridin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (340 mg, 0.62 mmol) obtained in step 1 was dissolved in THF (3 ml), 1 mmol/L tetrabutylammonium fluoride THF solution (0.81 ml, 0.81 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane/ethyl acetate=1/2 v/v) to give the title compound (152 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:16](/[C:15]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=2)\[C:17]#[N:18])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc(F)cc(F)c1
Product: COc1ccc(/C(C#N)=C/c2cc(F)cc(F)c2)cc1OC
Yield: 69.8 %

Procedure:
3,5-Difluorobenzaldehyde (1.42 g) and 3,4-dimethoxybenzyl cyanide (1.77 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (2.10 g, yield: 69%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[N+:6]([O-])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CO.[Pd]>[CH2:1]([NH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCNc1c[n+]([O-])ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCNc1cnccc1N

Procedure:
A solution of 3-ethylamino-4-nitro-pyridine 1-oxide (1.5 g, 8.19 mmol), in methanol (30 mL) is hydrogenated over 10% Pd—C (1.5 g) at 50-60 psi for 48 h. The catalyst is removed by filtration through a pad of celite, and the solvent is evaporated under vacuum to afford N3-Ethyl-pyridine-3,4-diamine as an white solid. 1H NMR (300 MHz, CDCl3): δ 7.59 (s, 1H), 7.57 (d, J=2.4 Hz, 1H), 6.56 (d, J=5.4 Hz, 1H), 3.20 (t, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H), m/z 138 [M+1]