Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:43])(=[O:42])[NH:15][C:16](=[O:41])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH3:28])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:15][C:16](=[O:41])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH3:28])=[CH:21][CH:20]=2)(=[O:43])=[O:42])=[CH:10][CH:9]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(N)cc2)cc1)c1ccccc1

Procedure:
Prepared by treating 1y with trifluoroacetic acid (50% in CH2Cl2). Yield (92%); 1H NMR (d6-DMSO) δ 11.71 (br s, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.38–7.07 (m, 13H), 6.83 (d, J=8.1 Hz, 2H), 6.55 (d, J=8.7 Hz, 2H), 6.37 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 1.44 (s, 9H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 507 (M−H−).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19]([O:20]CC)=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:17]=[N:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:28][CH2:29][CH2:30]Cl>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][N:16]([CH2:30][CH2:29][Cl:28])[C:14]=3[N:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C(C)=O)CC3)ncc2c1OCC
Reactant: ClCCCl
Product: CCOC(=O)c1cn(CCCl)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O

Procedure:
A solution of 1.0 g of ethyl 2-(4-acetyl-1-piperazinyl)-5-ethoxypyrido[2,3-d]pyrimidine-6-carboxylate in 10 ml of 1,2-dichloroethane was heated to reflux for 15 hours. After removal of an excess of the reagent by distillation, the resulting solid was taken up in chloroform and the chloroform solution washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to leave a solid which was recrystallized from ethyl acetate to give 0.65 g of the product, m.p. 205° - 206°C.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Cl:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(O)(=O)C>C(OCC)C.C(O)C.O>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:22][C:20]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Route A: To a solution of potassium ethoxide (1.46 g, 17.4 mmol) in diethyl ether (80 mL) and ethanol (10 mL) under an argon atmosphere was added diethyl oxalate (2.4 mL, 17.4 mmol) and the mixture stirred at rt for 0.5 h. A solution of 2-chloro-4-methyl-5-nitropyridine (3.0 g, 17.4 mmol) in diethyl ether (20 mL) was added resulting in the formation of a dark green precipitate. The reaction was stirred at rt for 15 h, cooled to 0° C., filtered and washed with cold diethyl ether to give a dark green solid. The solid was dissolved in water (200 mL) and acidified to pH 4 with acetic acid to give an orange precipitate. The solid was collected by filtration and dried to give the title compound. m/z (ES+)=273 [M+H]+. Route B: To a solution of 2-chloro-4-methyl-5-nitropyridine (1.0 g, 5.8 mmol) in diethyl oxalate (4.23 g, 29 mmol) under an argon atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.95 mL, 6.4 mol). The mixture was stirred at rt for 1.5 h then diluted with t-butyl methyl ether (40 mL), water (30 mL) and acetic acid (1 ml). The organic layer was separated, washed with water, dried (MgSO4) and evaporated to dryness. The resultant damp red solid residue was finally dried under high vacuum at 40-50° C. to give the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([OH:29])([CH3:28])[C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[O:23][CH2:22][CH2:21][N:20]3[C:16](=[N:17][C:18]([C:24]([NH2:26])=[O:25])=[CH:19]3)[C:15]=2[CH:27]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:29][C:8]([CH3:28])([CH2:7][OH:6])[C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[O:23][CH2:22][CH2:21][N:20]3[C:16](=[N:17][C:18]([C:24]([NH2:26])=[O:25])=[CH:19]3)[C:15]=2[CH:27]=1
Reactant: CC(O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2)CO
Yield: 46.3 %

Procedure:
To a solution of compound 9-[4-(tert-Butyl-dimethyl-silanyloxy)-3-hydroxy-3-methyl-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (300 mg, 0.66 mmol) in THF (20 mL) was added TBAF (340 mg, 1.3 mmol) at 0° C. for about 1 h. After washed with water and extracted with EtOAc, the crude product was purified by Pre-HPLC to get the titled compound (100.0 mg, yield 46.5%). LCMS=328.1 [M+H]+; 1H NMR (DMSO-d6, 400 MHz) δ 8.50 (d, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 4.50 (s, 4H), 3.45-3.37 (q, J=10.4 Hz, 2H), 1.39 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1.[H-].[Na+].Br[CH2:20][CH:21]=[CH2:22]>CN(C)C=O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1)[CH:21]=[CH2:20]
Reactant: CCOC(=O)C1CCc2cc(O)ccc2O1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)CCC(C(=O)OCC)O2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a stirred mixture of 40 parts of ethyl 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylate and 360 parts of N,N-dimethylformamide were added portionwise 8.6 parts of a sodium hydride dispersion 50% (foaming). After stirring for 30 minutes, a solution of 21.7 parts of 3-bromo-1-propene in 18 parts of N,N-dimethylformamide was added dropwise. Upon completion, the whole was heated to about 70° C. and stirring was continued for 22 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with 1,1'-oxybisethane. The extract was washed with a sodium chloride solution 10%, dried, filtered and evaporated. The oily residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 33.6 parts (70.2%) of ethyl 3,4-dihydro-6-(2-propenyloxy)-2H-1-benzopyran-2-carboxylate as a residue (intermediate 28).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.C(Cl)Cl.[CH3:14][C:15]([CH3:45])([CH3:44])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[CH:34]=2)[CH:26]=1)[CH2:22][OH:23]>CCCCCC.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:14][C:15]([CH3:45])([CH3:44])[C:16]#[C:17][CH:18]=[CH:19][CH2:20][CH:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[CH:34]=2)[CH:26]=1)[CH:22]=[O:23]
Reactant: CC(C)(C)C#C/C=C/CC(CO)Cc1cccc(/C=C/c2cccc(-c3ccsc3)c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC(C)(C)C#CC=CCC(C=O)Cc1cccc(/C=C/c2cccc(-c3ccsc3)c2)c1
Temperature: -78 °C
Yield: 73.3 %

Procedure:
44 μl of oxalyl chloride is added dropwise to a mixture of 3.6 μl of dimethyl sulfoxide with 2 μl of methylene chloride under a nitrogen atmosphere and under cooling at -78° C. and stirring, and the mixture is stirred at that temperature for 10 minutes. A methylene chloride solution (0.4 ml) of 105 mg of (E,E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-[2-[3-(3-thienyl)phenyl]ethenyl]phenyl]propanol obtained in Example 12 is added dropwise to this solution under cooling at -78° C. and stirring, the mixture is stirred at that temperature for 20 minutes, 200 μl of triethylamine is added, and the mixture is further stirred at -78° C. for 20 minutes. The solvent is distilled off under reduced pressure, the residue is led to two liquid phases using a system of water and ethyl ether, the organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by medium pressure liquid chromatography [column: Lobar column: size A, Lichroprep Si 60F (produced by Merck Co.); eluent: hexane/ethyl acetate=20/1] to obtain 76.6 mg (yield: 73%) of (E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-[2-[3-(3-thienyl)phenyl]ethenyl]phenyl]propionaldehyde as a colorless oily matter.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1)([O-:16])=[O:15].[OH-].[Na+]>CS(C)=O>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][O:1][C:20]2[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCCOc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
183 g (1 mol) 1-(2-hydroxyethoxy)-4-nitro-benzene, 173.3 g (1.1 mols) 4-nitrochlorobenzene and 70 g powdered sodium hydroxide were reacted following the procedure described in Example 1 in 600 ml DMSO.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([CH3:14])[CH2:6][CH2:5]2.CC([O:28]C)(C)C>O>[OH:28][C:7]([CH3:14])([C:15](=[O:16])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:23]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCCCC1)O2
Reactant: COC(C)(C)C
Solvent: O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)N2CCCCC2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 319 mg of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperidin-1-yl)methanone (1.02 mmol) in 5 mL MTBE which was treated with 1.077 g FeCl3.6H2O in 6 mL H2O. The reaction mixture rapidly turned black which faded to a yellow color over the course of the reaction. An additional 2 mL MTBE was added and stirred vigorously for 3 h at room temp. The reaction was quenched with 10 mL H2O and 10 mL MTBE, the layers separated and the organics washed with H2O until colorless. The combined aqueous phases were extracted 2×10 mL MTBE and the combined organics washed with saturated NaCl and dried over Na2SO4. Flash chromatography yielded 335 mg of 2-(3-hydroxy-3-methyl-4-oxo-4-(piperidin-1-yl)butyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione as a dark yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:22]3[S:23][C:19]([CH3:18])=[CH:20][N:21]=3)=[N:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(COc2ccc(Br)nc2)cc1
Reactant: Cc1cncs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(-c3ncc(C)s3)nc2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture was prepared from 2-bromo-5-(4-methoxybenzyloxy)pyridine (2.0 g), 5-methylthiazole (614 mg), Pd(P(t-Bu)3)2 (253 mg), Cs2CO3 (2.02 g) and DMF (10 mL). The system was evacuated and refilled with nitrogen three times. The mixture was stirred at 150° C. under N2 atmosphere for 3 hours. After cooling, insoluble material was removed by filtration over Celite. The resulting solution was added water (100 mL). The precipitate obtained was filtered off and washed with MeOH three times to provide the subtitle compound. MS ESI+: m/z=313 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:34]([NH2:38])[CH2:35][CH2:36][NH2:37]>CN1CCCC1=O>[NH2:37][CH2:36][CH2:35][CH2:34][NH:38][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH2:24][CH2:25]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Reactant: NCCCN
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1NCCCN

Procedure:
A mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), 1,3-propanediamine (177 μL), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave reaction device at 190° C. for 30 minutes. The mixture was subjected to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 5-[(3-aminopropyl)amino]-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (123 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:20]([O:22]C)=[O:21])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:20]([OH:22])=[O:21])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C)c(NCc2cnc(NC(=O)OC(C)(C)C)cn2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1NCc1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
Methyl 3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoate (600 mg, 1.61 mmol) in THF (2 mL) and MeOH (2 mL) was added LiOH—H2O (338 mg, 8.06 mmol) in water (2mL). The reaction mixture was stirred for overnight at room temperature. The organic solvent was removed under reduced pressure and water (4 mL) was added to the reaction mixture. To a reaction mixture was added 1N HCl solution to produce solid. The solid product was filtered and dried with nitrogen gas flow. The title product (460 mg, 79% yield) was used next reaction without further purification. MS m/z: 359 [M+1].
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[NH:14][CH2:15][CH2:16][CH3:17])[C:9]#[N:10].CO[C:20](=O)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[N:32]=[C:31]([F:33])[CH:30]=[CH:29][CH:28]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.C(O)(=O)C.O.CO>[CH2:15]([N:14]1[C:13]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=2[N:5]=[C:20]1[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[N:32]=[C:31]([F:33])[CH:30]=[CH:29][CH:28]=1)[CH2:16][CH3:17]
Reactant: CCCNc1ccc(C#N)cc1N
Reactant: COC(=O)Cn1ccnc1-c1cccc(F)n1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCn1c(Cn2ccnc2-c2cccc(F)n2)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
Trimethylaluminum (0.54 mL of 2.0M in toluene, 1.09mmol) is added dropwise to a solution of 3-Amino-4-propylaminobenzonitrile (152 mg; 0.87 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 1 hr. A solution of [2-(2-Fluoropyridin-6-yl)-imidazol-1-yl]acetic acid methyl ester (102 mg; 0.43 mmol) in dichloromethane (5 mL) is added all at once, and the mixture heated at reflux for 16 hr. The brown solution is cooled to room temperature and treated dropwise with methanol (1 mL) then water (2 mL) and stirred at room temperature for 15 min. Anhydrous sodium sulfate is added until the gel becomes solid, the mixture is diluted with dichloromethane (100 mL) and filtered through celite. The filtrate is concentrated to give a brown oil which is dissolved in acetic acid (7 mL) and heated at 100° for 72 hr. The mixture is cooled to room temperature and concentrated. The residue is dissolved in ethyl acetate (15 mL), washed with saturated aqueous NaHCO3 (1×50 mL), then brine (1×50 mL), dried (MgSO4), and concentrated, and the residue purified by preparative thin layer chromatography to give 1-n-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole as a light brown semi-solid (57 mg).
Reaction SMILES: Cl[C:2]1[CH:24]=C(Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=N[NH:28]1.C(Cl)(=O)C(Cl)=O.NCC1C=CN=CC=1>C(N(CC)CC)C.CN(C)C=O.ClCCl>[O:20]=[C:9]1[C:8]([C:6]([NH:5][CH2:4][C:3]2[CH:2]=[CH:24][N:28]=[CH:22][CH:21]=2)=[O:7])=[CH:13][C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:11][NH:10]1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Agent: NCc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccncc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.15 cm3 of 4-(aminomethyl)pyridine and 0.19 cm3 of triethylamine, 0.14 g of 3-oxo-6-pyridin-4-yl-N-(pyridin-4-ylmethyl)-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 254° C.
Reaction SMILES: [OH:1][NH:2][C:3]([CH2:5][N:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7](=[O:19])[CH2:8][CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[O:4].CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:45](ON)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C>[CH2:45]([O:1][NH:2][C:3]([CH2:5][N:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7](=[O:19])[CH2:8][CH:9]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[O:4])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)CC(CC(=O)N(CC(=O)NO)CC(C)C)C(=O)N(C)C
Reactant: NOCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(CC(=O)N(CC(=O)NOCc1ccccc1)CC(C)C)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.5 %

Procedure:
N4 -(Hydroxycarbamoyl-methyl)-2,N4 -diisobutyl-N1,N1 -dimethyl-succinamide (1.30 g, 0.0041 mol) was dissolved in DMF (10 ml) and treated at 0° C. with NMM (0.56 g, 0.0041 mol) followed by EDC (0.95 g, 0.005 mol) and HOBt (0.67 g, 0.005 mol). The reaction mixture was allowed to stir at 0° C. for 20 minutes and then at ambient temperature for 2 hours before O-benzylhydroxylamine (0.76 g, 0.0062 mol) was added. The reaction mixture was allowed to stir at room temperature for a further 1.5 hours. The solvent was removed under reduced pressure and the resulting crude oil was taken up in ethyl acetate (100 ml). The solution was washed consecutively with saturated aqueous NaHCO3, 1M HCl and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to a crude oil. The crude oil was purified by flash chromatography (silica gel, gradient elution with 5% to 10% methanol in dichloromethane) to give the title compound as a white solid (0.49 g, 29%). 1H NMR: δ (CD3OD), 7.38-7.21 (5H, br m), 4.75 (2H, s), 4.11-3.65 (2H, br m), 3.25 (1H, br m), 3.17-2.97 (2H, br m), 3.07 (3H, s), 2.81 (3H, s), 2.79-2.24 (2H, br m), 1.75 (1H, br m), 1.55-1.25 (3H, br m) and 0.91-0.64 (12H, br m).
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([O-])=[O:7])[N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]1.O1CCOCC1.O.[NH3:23]>O1CCCC1>[C:6]([CH:4]1[CH2:5][S:1][CH2:2][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:7])[NH2:23]
Reactant: CC(C)(C)OC(=O)N1CSCC1C(=O)[O-]
Reactant: N
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CSCC1C(N)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
3-t-Butyl thiazolidine-3,4-dicarboxylate (2.0 g) was dissolved in tetrahydrofuran (10 ml), and N,N′-carbonyl diimidazole (1.4 g) was added thereto with ice-cooling. The mixture was warmed to room temperature and stirred for 6 hours. 1,4-Dioxane (10 ml) was added thereto, and the mixture was added dropwise to 28% ammonia water (40 ml) cooled on an ice bath. The mixture was warmed to room temperature and stirred for 20 hours. The reaction solution was extracted with ethyl acetate (60 ml). The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give t-butyl 4-carbamoylthiazolidine-3-carboxylate (1.6 g, Y.:81%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:12](=[O:14])[CH3:13].C([O-])=O.[Na+].C([O-])(=O)C.[Na+]>O.[Cl-].C([N+](CC)(CC)CC)C.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][C:16]1([CH3:18])[C:2]2[C:3](=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[N:11]([C:12](=[O:14])[CH3:13])[CH2:15]1
Reactant: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Yield: 87.9 %

Procedure:
A solution of N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide (3.1 g, 10.2 mmol), tetraethylammonium chloride hydrate (2.4 g, 149 mmol), sodium formate (1.08 g, 18 mmol), sodium acetate (2.76 g, 34.2 mmol) and palladium acetate (0.32 g, 13.2 mmol) in anhydrous DMF (50 mL) was stirred at 80° C. for 15 h under N2 atmosphere. After cooling, the mixture was filtered through Celite. The Celite was washed with EtOAc and the combined filtrates were washed with sat. NaHCO3. The separated organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide 1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone as a brown solid (2.1 g, 88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]1=2>>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[C:13](=[CH:12][C:4]3[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=3)[C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[CH2:16][CH2:17][C:18]=2[CH:23]=1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: OB(O)c1cccc(O)c1
Product: Oc1cccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using (3-hydroxyphenyl)boronic acid (108 mg, 0.78 mmol) and 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (209 mg, 0.65 mmol) provides the title compound. Mass Spec (EI+) 332.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[CH:8]=[O:9].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([C:2]2[CH:6]=[C:5]([CH3:7])[S:4][C:3]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Br)c(C=O)s1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2ccccc2)c(C=O)s1

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-bromo-5-methylthiophene-2-carbaldehyde and phenylsulfinic acid sodium salt.