Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CO.C[O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[S:18]3)=[CH:11][CH:10]=1)=[O:8]>C(O)(=O)C>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[S:18]3)=[CH:11][CH:10]=1)([OH:8])=[O:6]
Reactant: COC(=O)c1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Yield: 81 %

Procedure:
To a mixture of 15 ml of an aqueous solution of 20% potassium hydroxide and 50 ml of methanol was added 2.2 g of 2-(p-methoxycarbonylphenyl)imidazo[2,1-b]benzothiazole and the mixture was refluxed for 30 minutes. After the reaction was over, 4 ml of acetic acid was added to the reaction mixture and the crystals which had formed were recovered by filtration, washed successively with water, methanol and then ethanol, and dried to provide 1.7 g of 2-(p-carboxyphenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([O:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[N:16]=1.O>CN(C)C(=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[CH:18]=1
Reactant: Clc1cc(Cl)nc(OCc2ccsc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(Oc2cc(Cl)cc(OCc3ccsc3)n2)c1

Procedure:
To a solution of meta-trifluoromethylphenol (0.28 g, 0.0018×1.0 mol) in 10 ml of dry N,N-dimethylacetamide, sodium hydride (0.077 g, (ca.60% in mineral oil), 0.0018×1.1 mol) was added. After the bubbling ceased, a solution of 2,4-dichloro-6-(3-thienylmethyloxy)pyridine (0.46 g, 0.0018 mol) in 10 ml of dry N,N-dimethylacetamide was added dropwise and the resultant solution was stirred for about 7 hours at the temperature of 160° to 170° C. After allowed to cool, water was added to the reaction solution, then the mixture was partitioned by using ethyl acetate. The obtained organic layer was washed with aqueous saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, then the residue was purified successively on silica gel column chromatography and on reversed phase column chromatography (Lobar column, Lichroprep RP-18, 40-63 μm, elution solvent: CH3CN/H2O=7/3(v/v)), whereby the end product was obtained.
Reaction SMILES: [CH3:1][C:2](=[O:10])[CH2:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH:16]=[C:3]([C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[C:2](=[O:10])[CH3:1])[CH3:15]
Reactant: CCCCC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Product: CCCCC(=O)C(=CN(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-octanedione (7.11 g, 0.50 mole) and dimethylformamide dimethylacetal (7.15 g, 0.60 mole) was stirred overnight at room temperature under argon. The resulting red oil was concentrated on the rotary evaporation then distilled on the kugelrohr at -15 mm, 140°-155° C. to yield 8.60 g (87%) of 3-[(dimethylamino)methyleno]-2,4-octanodione.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[N:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[N:23][CH:22]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(OCC)(=O)C>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:27]2[C:25]2[CH:26]=[N:21][CH:22]=[N:23][CH:24]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=Cc1cncnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCC(C)c1ccc(-n2c(-c3cncnc3)nc3ccccc3c2=O)cc1
Temperature: 150 °C
Yield: 38.7 %

Procedure:
2-amino-N-(4-sec-butylphenyl)benzamide (0.544 g, 2.03 mmol) and pyrimidine-5-carbaldehyde (0.241 g, 2.23 mmol), NaHSO3 (0.253 g, 2.44 mmol) and p-TsOH (0.039 g, 0.20 mmol) were dissolved in DMA (20 mL) and heated at 150° C. for 18 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (2×200 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 20% ethyl acetate/heptane to 70% ethyl acetate/heptane, afforded the title compound as a white solid (0.280 g, 39%). 1H-NMR (300 MHz, DMSO-6): δ 9.05 (s, 1H), 8.77 (s, 2H), 8.22-8.25 (m, 1H), 7.92-7.98 (m, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.64-7.69 (m, 1H), 7.31-7.35 (m, 2H), 7.18-7.23 (m, 2H), 2.54-2.61 (m, 1H), 1.37-1.58 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.64 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 357 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:21][CH3:22])([CH3:20])[C:16]([OH:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:21][CH3:22])([CH3:20])[C:16]([O:19][CH3:23])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C)C(O)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCC1(C)C(OC)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
A suspension of 49 mg (0.15 mmol) of 1-tert-butoxycarbonyl-4-(4-ethyl-3-hydroxy-4-methyl-(4H)-pyrazol-5-yl)piperidine (from Step A), 50 mg (0.36 mmol) of potassium carbonate and 0.06 mL (0.96 mmol) of methyliodide in 0.3 mL of acetonitrile was stirred at rt for 17 hours and 85° C. for 7 hours. The reaction was partitioned between 25 mL of EtOAc and 25 mL of brine. After separating phases, the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 4:1 v/v of hexanes/acetone as the eluant to afford the title compound as a colorless film: RF: 0.21 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 0.65 (t, J=7.4, 3H), 1.21 (s, 3H), 1.45 (s, 9H), 1.57–1.66 (m, 2H), 1.73–1.81 (m, 4H), 2.37 (m, 1H), 2.73–2.78 (m, 2H), 3.27 (s, 3H), 4.15–4.20 (m, 2H); 13C-NMR (125 MHz) δ 54.4 (O—CH3).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC1C=CC2C(=CC=CC=2)C=1.BrC1C=CC(C=[O:38])=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCCCCC>[C:14]1([P:7](=[O:38])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
0.50 g (1.91 mmol) of triphenylphosphine, 0.42 g (1.90 mmol) of 2-bromomethylnaphthalene, 0.36 g (1.98 mmol) of p-bromobenzaldehyde, and 0.50 g (3.62 mmol) of K2CO3 were placed in a hardened-steel vial in a glove box under helium. The vial was sealed, and the sample was ball-milled for eight hours. The formed powder was first analyzed by solid state 31P{1H} CP MAS NMR spectroscopy, then loaded on a silica gel chromatography column, and the mixture of (E)- and (Z)-1-(p-bromophenyl)-2-(naphthyl)ethylenes (VII) (E:Z ratio ca. 3.5:1 by 1H NMR in CDCl3) was isolated in 93% yield, (0.54 g ) by eluation with hexane and toluene. Triphenylphosphine oxide was further obtained from the same column in 92% yield (0.53 g) using a hexane-acetone mixture as an eluant. The separation and purification of the E-isomer was performed according to the previously described procedure (Brooks et al., J. Am. Chem. Soc. 121, 5444 (1999)) by the column chromatography on silica gel.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C:33]([CH3:46])([CH3:45])[C:34]([NH:36][C@H:37]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:38](O)=[O:39])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[CH3:46][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:45])[C:34]([NH:36][C@H:37]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:38](=[O:39])[NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24])=[O:35]
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (200 mg) and (R)-2-(2-(tert-butoxycarbonylamino)-2-methylpropanamido)-4-methylpentanoic acid (200 mg) were dissolved in dichloromethane (2 mL), and to the solution was added dropwise a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (107 mg), and triethylamine (42 μL) in dichloromethane (2 mL) over 10 minutes under cooling on ice, followed by stirring at room temperature for 18 hours. The solvent was evaporated, and the thus-recovered residue was dissolved in ethyl acetate. The solution was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (hexane:ethyl acetate (1:1), chloroform:methanol (10:1)), whereby the title compound (342 mg) was yielded.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([C:11]2[NH:16][C:15](=O)[CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)C.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[CH:4]=[O:3])[N:16]=1
Reactant: CCOC(OCC)c1cccc(-c2nccc(=O)[nH]2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=Cc1cccc(-c2nccc(Cl)n2)c1

Procedure:
A 5.3 g portion of 2-(3-diethoxymethylphenyl)- 4(3H)-pyrimidinone and 30 ml of phosphorous oxychloride was heated on a steam bath overnight. The excess phosphorous oxychloride was removed under vacuum and the residue taken up in chloroform and passed through a hydrous magnesium silicate pad. Evaporation of the filtrate left 3.1 g of residue which had two spots by TLC (chloroform-silica gel). Trituration of the residue with ether gave 0.4 g of 3-(4-chloro-2-pyrimidinyl)benzaldehyde, mp 136°-138° C. (the slower moving spot) which was identified by analysis, PMR and IR.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:23])=[CH2:22]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:22][C:21]([CH3:23])=[CH2:20])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)COc1cc(O)cc(C(=O)OC)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (15.0 g, 89.2 mmol), potassium carbonate (24.7 g, 178.4 mmol) and 3-bromo-2-methyl-propene (9.0 mL, 89.2 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.80 g, 39% yield). 1H NMR (400 MHz, CDCl3) δ 7.13-7.22 (m, 2 H) 6.66 (t, J=2.27 Hz, 1 H) 5.81 (s, 1 H) 5.06-5.16 (m, 1 H) 4.93-5.04 (m, 1 H) 4.44 (s, 2 H) 3.91 (s, 3 H) 1.68-1.94 (m, 3 H); LCMS for C12H14O4 m/z 223.10 (M+H)+.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH2:15]>>[CH3:17][Si:16]([CH2:14][CH2:15][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: C=C[Si](C)(C)C
Reactant: c1ccc(Pc2ccccc2)cc1
Product: C[Si](C)(C)CCP(c1ccccc1)c1ccccc1

Procedure:
A magnetically stirred mixture of 46.5 g (0.25 mole) diphenyl phosphine and 25 g (0.25 mole) of vinyl trimethyl silane, in a closed cylindrical quartz tube, was irradiated from about 3 cm distance with two 75 Watt Hanau tube immersion lamps, with a wide spectrum of ultraviolet irradiation, in a 15° C. water bath for 26 hours. A proton magnetic resonance spectrum of a sample of the resulting mixture exhibited no significant peaks in the vinyl region indicating a substantially complete addition.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].N1C=CC=CC=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1>[C:11]([N:3]([CH3:2])[OH:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNO
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
10.0 g of N-methylhydroxylamine hydrochloride was added to 100 ml of tetrahydrofuran. 19.8 g of pyridine was added to the mixture. A solution of 16.8 g of benzoyl chloride in 100 ml of tetrahydrofuran was dropwise added to the mixture under stirring at room temperature over 1 hr. The stirring was continued at room temperature for additional 8 hr. to conduct the reaction. 50 ml of dilute hydrochloric acid was added thereto and then tetrahydrofuran was removed under reduced pressure. After extraction with ethyl acetate, the extract was dehydrated over anhydrous magnesium sulfate. Ethyl acetate was removed under reduced pressure. The resultant crude product was purified according to column chromatography (packing: silica gel, developer: ethyl acetate/hexane) to obtain 8.5 g of N-benzoyl-N-methylhydroxylamine as an oil having a melting point of 20° C. or below. 130 ml of tetrahydrofuran was added to 7.6 g of N-benzoyl-N-methylhydroxylamine and 12.6 g of 4-vinyl-1-naphthalenesulfonyl chloride. A solution of 5.1 g of triethylamine in 20 ml of tetrahydrofuran was dropwise added thereto under stirring over 2 hr. while the mixture was cooled so that the temperature of the solution was below 25° C. After conducting the reaction at 15° to 25° C. for additional 2 hr., the reaction solution was poured into 700 ml of water and the precipitate thus formed was collected by filtration. After recrystallization from acetonitrile, 12.8 g of o-(4-vinyl-1-naphthalenesulfonyl)-N-benzoyl-N-methylhydroxylamine was obtained.
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH2:25][NH2:26]>CO>[CH2:1]([S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:25][NH2:26])=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCSc1ccc(C(=O)OC)cc1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CO
Product: CCCCCCCCSc1ccc(C(=O)NN)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The crude methyl 4-(octylthio)-3-(trifluoromethyl)benzoate was dissolved in 2 mL of MeOH and treated with 2 mL of hydrazine hydrate. The reaction mixture was left to stir at 80° C. for 1 hour, poured into ice-water. The solid was filtered, washed with H2O and dried under vacuum to provide the 4-(octylthio)-3-(trifluoromethyl)benzohydrazide 3a as a yellow solid. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.69 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=349.3; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.13 (d, 1H, J=1.6 Hz), 8.03 (dd, 1H, J=8.2 Hz, J=1.6 Hz), 7.67 (d, 1H, J=8.8 Hz), 4.59 (s, 2H), 3.13 (t, 2H, J=7.2 Hz), 1.61 (pentet, 2H, J=6.8 Hz), 1.44-1.36 (m, 2H), 1.30-1.20 (m, 8H), 0.85 (t, 3H, J=6.8 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CNc2cccc(Br)n2)cc1
Yield: 91.3 %

Procedure:
A solution of 2,6-dibromopyridine (14-1) (37.3 g, 157 mmol), 4-methoxybenzylamine (21.6 g, 157 mmol), and diisopropylethylamine (22.4 g, 173 mmol) in 1,4-dioxane (150 mL) was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (125 mL). The organic layer was washed with water (100 mL) followed by brine (100 mL) and dried (Na2SO4). The organic layer was filtered, concentrated in vacuo, and purified by flash chromatography (silica, 10% to 40% EtOAc/hexanes) affording 42 g of amine 14-2 as a white solid in 91% yield. 1H NMR (300 Mz, CDCl3): δ 8 7.26-7.22 (m, 3H), 6.88-6.86 (m, 2H), 6.75-6.73 (d 1H), 6.27-6.25 (d, 1H), 4.98-4.96 (br s, 1H), 4.39-4.37 (d, 2H), 3.80 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[C:29](I)=[C:28]([O:33][CH3:34])[C:27](=[O:35])[NH:26][C:25]=2[CH:36]=1.[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[C:29](/[CH:39]=[CH:38]/[C:37]([O:41][CH2:42][CH3:43])=[O:40])=[C:28]([O:33][CH3:34])[C:27](=[O:35])[NH:26][C:25]=2[CH:36]=1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.8 %

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium (O) (0.051 g) in toluene (31 mL) was treated with triphenylphosphine (0.058 g). The solution was stirred under argon at room temperature for 15 minutes and then it was treated with 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]-azepine (0.97 g) followed by ethyl acrylate (4.3 mL, 4.0 g). The mixture was then treated with triethylamine (0.37 mL, 0.27 g). The mixture was heated to 104° C. for 1.5 hours and then it was cooled to room temperature. Another portion of tris(dibenzylideneacetone)dipalladium (O) (0.025 g) and more triphenyl phosphine (0.029 g) was added to the mixture. The mixture was then treated with more ethyl acrylate (2.8 mL) and it was heated to 105° C. for 1 hour and then it was cooled to room temperature and concentrated to a brown glass. It was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×20 cm long) using 25% ethyl acetate in hexane to give a pale yellow solid (0.115 g). The solid was recrystallized from ethyl acetate (10 mL) at room temperature to give an off-white solid (0.0712 g); mp 233.8°-234.5° C.; 1H NMR (CDCl3) 7.73 (d, 1, J=16), 6.69 (d, 1, J=16) for trans olefin protons; MS: m/z=336 (M+1). Analysis for C16H14ClNO5 : Calculated: C, 57.24; H, 4.20; N, 4.17; Found C, 57.09; H, 4.16; N, 4.09.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Reactant: NCCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(Nc2nccc(NCCCN3CCOCC3)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine, 3, (0.2 g, 0.84 mmol) in THF (4 mL) is added diisopropylethylamine (0.29 mL, 1.67 mmol) followed by 3-morpholino-propylamine (0.245 mL, 1.67 mmol). The resulting mixture was heated to reflux for 6 hours. Another 2 equivalents of 3-morpholinopropylamine (0.245 mL, 1.67 mmol) is added and the reaction heated to reflux and stirred for 18 hours. The resulting mixture is heated to reflux for 18 hours. The reaction is cooled to room temperature and concentrated in vacuo. The residue is diluted with 5 mL water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is diluted with 5 mL water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. This residue is purified over silica (6% MeOH in CH2Cl2 with 0.7% Et3N) to afford 0.120 g (41% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 1.68-1.75 (m, 2H), 2.34-2.40 (m, 6H), 3.30-3.35 (m, 2H), 3.55-3.58 (m, 4H), 5.97 (d, J=5.7 Hz, 1H), 6.88 (d, J=7.2 Hz, 1H), 7.19-7.28 (m, 2H), 7.59 (d, J=7.2 Hz, 1H), 7.80 (br s, 1H), 8.13 (br s, 1H), 9.19 (br s, 1H). MS (ESI, pos. ion) m/z: 348 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CC(C)=O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:2]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccccn1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
2-Bromo-2′-nitroacetophenone (7.65 g, 31.3 mmol) and 2-aminopyridine (2.95 g, 31.3 mmol) were dissolved in acetone (50 ml) and brought to reflux. After 10 minutes a light yellow/white precipitate forms in addition to strong boiling. Refluxing was continued for 3 hours and cooled to room temperature. The volume was reduced ½ by evaporation and the intermediate solids were collected by filtration and washed with acetone (20 ml) and air dried (7.26 g of intermediate). The intermediate (7.20 g) was dissolved in MeOH (100 ml) with HBr (4 drops, catalytic) and brought to reflux. The reaction was monitored by TLC (10% MeOH in CH2Cl2). After 70 minutes, the reaction mixture was cooled to room temperature, adjusted to pH=12 with 1 M NaOH, and concentrated to remove the methanol. The yellow product was collected by filtration, washed with water and air dried. 5.54 g (74%) of 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine was obtained as a yellow crystalline solid (MS, M++H=240.1).