Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>C1(C)C=CC=CC=1>[N:26]1([C:22]2[CH2:23][CH2:24][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCCC2)CC1
Reaction time: 2 h

Procedure:
Catalytic amounts of p-toluenesulfonic acid (0.47 g, 0.27 mmol) were added to a solution of N-Boc-4-piperidone (5 g, 25.12 mmol) and pyrrolidine (1.96 g, 27.63 mmol) in toluene (100 ml), and the mixture was stirred for 2 hours under reflux with a water separator. The resulting solution was concentrated to dryness in vacuo and the resulting residue was used directly in the following stage.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:15])([O-])=O.C(O)C.[OH-].[Na+]>O>[NH2:1][C:4]1[C:5]([CH3:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(C)ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)c(C)c2c(C)ccnc12
Temperature: 25 °C

Procedure:
A mixture of 6-nitro-4,5,8-trimethylquinoline (0.60 g), tin(ll)chloride dihydrate (3.13 g), and ethanol (40 mL) is heated for 3 hours at 60°-65° C. and then cooled to room temperature. 10% Aqueous sodium hydroxide (24 mL) and water (48 mL) are added, and the mixture is extracted three times with chloroform. The combined organic layers are washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated to afford a crude product. The crude product is purified by flash chromatography using 25% ethyl acetate in hexane as eluent, providing 6-amino-4,5,8-trimethylquinoline.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu](I)I>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:34]#[C:33][CH2:32][CH2:31][OH:35])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring solution of methyl 4-bromobenzoate (13.4 g, 0.62 mmol) in diethyl amine (200 mL) was added palladium chloride (0.55 g, 3.06 mmol), and triphenylphosphine (0.16 g, 0.62 mmol). The solution was degassed and copper iodide (0.12 g, 0.62 mmol) and 3-butyn-1-ol (4.34 g, 62 mmol) were added. The reaction mixture continued to stir at room temperature overnight. Over the next two days, an additional 0.5 mol % palladium chloride, 1.0 mol % triphenylphosphine, and 12 mol % 3-butyn-1-ol were added. Once the reaction was complete according to LCMS, the reaction mixture was concentrated and the crude material was taken up in a slurry of silica gel and ethyl acetate. The organic solvent was removed and the remaining dried silica gel was packed in a fritted funnel. Extensive washes with a hexane:ethyl acetate mixture (1:4) followed by ethyl acetate (100%) washes yielded the desired 4-(4-hydroxy-but-1-ynyl)-benzoic acid methyl ester (11.9 g, 0.58 mmol) as the desired product (94% yield). 1H (CDCl3, 600 MHz): δ 7.95 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 3.9 (s, 3H), 3.83 (2H, t, J=6.6 Hz), 2.71 (2H, t, J=6.0 Hz).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1([CH2:16]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:13]1([CH2:16][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:15][CH2:14]1
Reactant: OCC1CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1CC1
Temperature: 6 °C
Reaction time: 15 h
Yield: 172.6 %

Procedure:
To a stirring solution/suspension comprised of N-hydroxyphthalimide (Aldrich, 57.15 g, 339.8 mmol), cyclopropanemethanol (Aldrich, 25.10 g, 341.1 mmol), and triphenylphosphine (“DEAD,” Aldrich, 91.0 g, 344 mmol) in 1.00 L of tetrahydrofuran under a nitrogen atmosphere and cooled to 6° C. (internal mixture temperature) with an ice-water bath was added diethyl azodicarboxylate (Aldrich, 56 ml, 356 mmol) dropwise over 20 minutes via addition funnel. The reaction mixture temperature was kept below 20° C. during the addition. Following addition of the DEAD, the cold bath was removed and the reaction mixture was stirred for 15 hours. The mixture was concentrated to a paste under reduced pressure. Chloroform (ca. 300 ml) was added and the mixture swirled to loosen all solids. Vacuum filtration removed the insolubles. The filtrate was likewise filtered to remove white precipitate that formed and to give a clear filtrate. Concentration under reduced pressure afforded a clear oil. Flash filtration through silica gel (100% chloroform) gave filtrates containing unseparated product. These filtrates were combined and concentrated under reduced pressure to afford 127.4 g of a clear oil. The oil was dissolved in absolute ethanol (400 ml) and the solution was refrigerated for two hours. A white crystalline solid had precipitated and was subsequently collected by vacuum filtration. The product was dried in the vacuum oven (60° C.) to afford 42.66 g (58%) of the desired material; m.p. 71–77° C.; 1H-NMR (400 MHz; CDCl3 signal offset to δ 6.96) δ 7.54–7.43 (m, 4H), 3.74 (d, 2H, J=7.6 Hz), 1.02–0.95 (m, 1H), 0.34–0.30 (m, 1H), 0.04–0.00 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[NH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:9].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1C=CC=CC=1>[CH3:14][C:13]([CH3:16])([O:12][C:10]([NH:8][NH:9][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:11])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CNNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Triethylamine (13.94 ml., 0.1 mol.) was added to a solution of hydrazine carboxylic acid, 1,1-dimethylethyl ester (13.216 g., 0.1 mole) in benzene (100 ml.), followed by the addition of ethyl bromoacetate (11.09 ml., 0.1 mol.). The reaction mixture was refluxed (oil bath, 95°-100° C.) for 14 hours, after which triethylamine (1.4 ml., 0.01 mol.) was added followed by ethyl bromoacetate (1.1 ml., 0.01 mole). After refluxing for an additional 8 hours, triethylamine (2 ml., 0.015 mol.) and ethyl bromoacetate (1.4 ml., 0.013 mole) were added. The mixture was allowed to reflux for another 14 hours (total 36 hours). After cooling to room temperature, the reaction mixture was filtered and the solid triethylamine, hydrochloride salt was washed with ethyl acetate/hexane (1:1). The combined filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried (sodium sulfate) and filtered. The filtrate was concentrated in vacuo to afford 19.38 g. of crude product as a yellow syrup which was used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: Nc1ccc(I)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a solution of 2-fluoro-4-iodoaniline (5.0 g, 21 mmol) in pyridine (30 mL) at 0° C. was added methanesulfonyl chloride (2.5 mL, 32 mmol) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, and concentrated. Purification by chromatography (SiO2, 33% EtOAc/Hexanes) afforded the title compound (5.0 g, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.71 (dd, J=9.9, 1.9 Hz, 1H), 7.56 (ddd, J=8.4, 1.9, 1.0 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 3.03 (s, 3H); MS (ESI; M−H) m/z 314.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>ClCCl.CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Reaction time: 0.5 h

Procedure:
3-Methylisoquinoline (2.14 g, 14.9 mmol) was added portionwise to ice-cooled concentrated H2SO4 (10 ml) keeping the internal temperature below 10° C. A nitrating mixture of concentrated H2SO4 (2 ml) and fuming nitric acid (2 ml) was then added dropwise keeping the internal temperature below 15° C. After stirring for 30 minutes, TLC indicated reaction was complete. The acid was neutralized by adding the mixture to an excess of 4N aqueous NaOH (180 ml) with ice-cooling. The mixture was extracted with dichloromethane (2×150 ml), then dried (Na2SO4) and evaporated to give the crude product (2.69 g) as a yellow solid. Flash column chromatography using as eluant 5% methanol in dichloromethane gave a pure sample of the title compound (660 mg) and a sample (1.95 g) containing ca. 10% of the 8-nitro isomer.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Product: O=Cc1cccc(OCc2ccccc2)c1

Procedure:
General procedure K was used to convert 3-hydroxybenzaldehyde (8.2 mmols) and benzyl bromide (12.3 mmols) to 1 (8.2 mmols, quant.)1H NMR (500 MHz, CDCl3) δ 9.98 (s, 1H), 7.51-7.44 (m, 4H), 7.44-7.39 (m, 1H), 7.38-7.33 (m, 1H), 7.26 (ddd, J=1.8, 3.5, 4.2, 1H), 5.13 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 192.08, 159.29, 137.81, 136.29, 130.13, 128.68, 128.22, 127.56, 123.70, 122.20, 113.22, 77.31, 77.06, 76.80, 70.20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:11][NH2:12]>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH2:10])=[N:12][NH:11][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c2ncc(Br)cc12

Procedure:
Compound 3 (307 mg, 1.4 mmol) was dissolved in EtOH (10 mL) in a microwave tube, to which 5 equivalent of NH2NH2 was added, and the reaction mixture was put on Microwave irradiation for 10 min at 170° C. Evaporated the solvent to obtain the title compound 4 in quantitative yield.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH3:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][CH:16]=1>CCOC(C)=O.CCCCCC>[CH3:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][C:16]=1[S:6]([Cl:10])(=[O:8])=[O:7]
Reactant: Cc1ccc(C)o1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(S(=O)(=O)Cl)c(C)o1
Temperature: 60 °C
Yield: 22.3 %

Procedure:
DMF (2.2 ml, 28 mmol) and sulfuryl chloride (1.9 ml, 24 mmol) were stirred at 0° C. for 30 minutes and then the 2,5-dimethylfuran (1.5 ml, 14 mmol) was slowly added. The reaction mixture was heated to 60° C. for 30 minutes, then cooled to ambient temperature and poured into ice water (200 ml). The aqueous layer was extracted with EtOAc (100 ml) and then the organic layer was dried (MgSO4) filtered and concentrated to collect 0.69 g of a brown liquid. Flash chromatography (5% EtOAc/hexane) provided 0.607 g (22% yield) of a yellow liquid.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC(N)=O)c2cccc(Cl)c2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-amino-2-oxoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (902 mg, 2.36 mmol) in anhydrous toluene (30 mL) at 0° C. was added Red-Al® (65% solution in toluene, 1.4 mL, 7.07 mmol) slowly over 10 min. After the addition, the solution was stirred overnight at room temperature. The reaction was cooled to 0° C. and quenched with Na2SO4.10 H2O. The resulting mixture was stirred for 2-3 h, filtered through Celite®, and washed with THF (200 mL). The filtrate was dried and concentrated to give crude product (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (776 mg, 89%). MS ESI+ve m/z 369 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O-:11].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:11][CH3:10]
Reactant: C[O-]
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Solvent: CO
Product: COCc1ccccc1Br
Yield: 87 %

Procedure:
685 g (2.74 mol) of o-bromobenzyl bromide are refluxed together with 2.74 mol of a 30% strength sodium methylate solution in methanol for 15 hours. The mixture is cooled and then concentrated, the residue is taken up in ethyl acetate, and the solution is washed with water. The organic phase is dried over sodium sulfate and then concentrated. 478.2 g (87%) of product are obtained as a colorless liquid.
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NO
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 1 h

Procedure:
Hydroxylamine free base (50% aqueous solution, 2.0 g, 30.3 mmol) is added dropwise to diethyl maleate (4.41 g, 25.6 mmol) and stirred for 60 minutes to give diethyl N-hydroxyaspartate. Toluene (25.02 g) and p-toluenesulfonic acid (0.05 g, 0.26 mmol) are added to the reaction mixture and refluxed for 4.5 hours to afford diethyl 2-aminomaleate. The reaction mixture is cooled to room temperature and added acetic acid (7.0 g) and 2-ethylacrolein (2.13 g, 25, 0 mmol). The reaction mixture is stirred at 80°-90° C. for 24 hours. It is concentrated under reduced pressure and analyzed by GLC using an external standard. The analysis showed the yield of diethyl 5-ethylpyridine-2,3-dicarboxylate is about 35%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C(O)C>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ccc(F)c(F)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(F)c1
Yield: 71.6 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile, 250 ml ethanol and 2.55 ml (25.8 mmol) 3,4-difluoroaniline was heated to reflux under N2. Removed heat at 3½ hours and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids and air dried. Washed with water and dried in vacuo. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 5.02 g of yellow solid: mass spectrum (electrospray m/e): M+H=327.1.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH2:9][CH3:10])[NH:4][N:3]=1.CN(C)[CH:13]=[C:14]([CH3:27])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=O>>[CH2:9]([C:5]1[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[CH:13][C:14]([CH3:27])=[C:15]([C:17]3[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:21][CH:22]=3)[N:3]2[N:4]=1)[CH3:10]
Reactant: CC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: CCc1[nH]nc(N)c1C#N
Product: CCc1nn2c(-c3cccc(C(F)(F)F)c3)c(C)cnc2c1C#N

Procedure:
As for Example 1, 3-amino-5-ethylpyrazole-4-carbonitrile is reacted with 3-dimethylamino-2-methyl-3'-(trifluoromethyl) acrylophenone to give the product as crystals, m.p. 163°-164° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:8][CH2:7]1.CN([CH:17]=[O:18])C>>[CH:6]1([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:17]=[O:18])[CH2:8][CH2:7]1
Reactant: c1ccn(C2CC2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44.46 ml of POCl3 was added to a stirred solution of 1-cyclopropyl-1H-pyrrole (46.46 g) in 37 ml of DMF with cooling with ice, then the mixture was stirred at room temperature overnight. The mixture was poured into 336 ml of 5N NaOHaq with cooling with ice, and the mixture was made basic with an additional 5N NaOHaq. The mixture was extracted with CH2Cl2 and the organic extract was dried over Na2SO4, concentrated, and the residue was purified on SiO2 column chromatography (n-hexane-EtOAc system) to give 38.91 g of 1-cyclopropyl-1H-pyrrol-2-carbaldehyde as a colorless oil.
Reaction SMILES: I[C:2]1[C:10]([N+]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[OH:23][CH2:24][CH:25]=[CH:26]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.[Pd+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:23][CH2:24][CH:25]=[CH:26][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:15][C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5](=[O:14])[NH:6]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: OCC=CB(O)O
Agent: [Pd+]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc[nH]c1C=C1C(=O)Nc2cccc(C=CCO)c21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 2 supra) in dimethoxyethane (5 mL) was added 3-hydroxy-1-propenyl-boronic acid (from Example 66 above) (42 mg, 0.418 mmol), tetrakis(triphenylphosphine) palladium(1) (39 mg, 0.034 mmol) (Aldrich) and 2M Na2CO3 solution in H2O (0.34 mL). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 1,3-dihydro-4-(3-hydroxy-propenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one as a yellow solid. (Yield 22 mg, 53%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:12][CH:11]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
1,2,4-Triazole (7.5 g, 0.109 mol) was dissolved in dimethylformamide (50 mL) and stirred under a nitrogen atmosphere in an ice bath at 10° C. while partially ground pellets of sodium hydroxide (17.5 g, 0.438 mol) were added in one portion causing an exotherm to about 25° C. A solution of 4-methoxybenzyl chloride (15 mL, 0.111 mol) in DMF was added dropwise over five minutes at 25° C. After stirring at room temperature for four hours, ethyl acetate and water were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed four times with water and once with brine and dried over magnesium sulfate. The mixture was filtered and the filtrate solvent evaporated in vacuo to afford the title product as an oil in 69% yield; 14.15 g; 1H NMR (CDCl3) δ 8.00 (s, 1), 7.93 (s, 1), 7.19 (d, 2), 6.88 (d, 2), 5.23 (s, 2), 3.78 (s, 3). mass spectrum: m/z 109 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1I.[C:16]1([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:9]=1)=[O:15]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1-c1ccccc1
Temperature: 90 °C
Yield: 99.5 %

Procedure:
A mixture of 2-Iodo-5-methanesulfonyl-benzoic acid methyl ester (1.20 g, 3.53 mmol), Phenyltri-n-butyltin (1.27 ml, 3.88 mmol), Tris(dibenzylideneacetone) dipalladium(0) (226 mg, 0.25 mmol), Triphenylarsine (108 mg, 0.35 mmol) and Copper iodide (309 mg, 1.62 mmol) in N,N-Dimethylformamide (30 ml) was heated at 90° C. for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was chromatographed over SiO2 (ethyl acetate/heptane gradient) to provide the title compound (1.02 g, 99%) as an off-white crystalline solid. MS (ISP): 291.0 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:21][CH3:22])[CH3:19])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: CNOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.5 %

Procedure:
A solution of 4-chloro-2-phenylamino-benzoic acid (10.1 g, 41.0 mmol) in N,N-dimethylformamide (200 mL) at 25° C. was treated with O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (31.2 g, 82.0 mmol), N,O-dimethyl hydroxylamine hydrochloride (7.94 g, 82.0 mmol), and N,N-diisopropylethylamine (45.0 g, 350 mmol). The resulting mixture was stirred at 25° C. for 24 h. At this time, the reaction mixture was diluted with ethyl acetate (600 mL) and washed with water (4×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica gel, 100-200 mesh, ethyl acetate/hexanes 10-25%) afforded 4-chloro-N-methoxy-N-methyl-2-phenylamino-benzamide (6.62 g, 56.4%) as a yellow solid. 1H NMR (DMSO-d6) δ ppm 7.93 (s, 1H), 7.20-7.39 (m, 3H), 7.02-7.17 (m, 3H), 6.88-6.99 (m, 2H), 3.50 (s, 3H), 3.20 (s, 3H); MS m/e calcd for C15H15ClN2O2 [(M+H)+] 291.0. Found 291.0; [(M−C2H6NO)+] 230.0. Found 230.0.