Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][C:23]=1[CH3:30]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:30])[CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc([Mg]Br)cc1C
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 18.36 mmol) in 50 mL dry THF at ambient temperature was added (4-methoxy-3-methylphenyl)magnesium bromide (55.1 mL, 0.5 M) was added dropwise under N2, the reaction mixture was stirred at the same temperature for 16 hours. The reaction was quenched with saturated sodium sulfate solution (10 mL) and partitioned between brine (150 mL) and 10% isopropyl alcohol/chloroform (200 mL), and the organic layer was removed to yield the crude product. Purification by flash chromatography (silica: 5-35% ethyl acetate/pentane) gave the title compound as a white solid (6.4 g, 19.21 mmol, >99% yield). HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) retention time=4.131 min.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:6]=1[CH2:25][CH3:26].COC(=O)CC1C2C(=NC=CC=2)NC=1CC.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.FC(F)(F)C1C=CC(CBr)=CC=1>CN(C=O)C.O>[CH2:25]([C:6]1[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][C:3]([OH:27])=[O:2])[CH3:26]
Reactant: CCc1c(CC(=O)OC)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCc1[nH]c2ncccc2c1CC(=O)OC
Agent: FC(F)(F)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
[2-Ethyl-1-(4-trifluoromethyl-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To an ice-cooled stirring solution of (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.37 mmol) in DMF (1 ml) is added BEMP (171 μl, 0.59 mmol). The solution is stirred at room temperature for 40 minutes and then re-cooled. 4-(Trifluoromethyl)benzyl bromide (91 μl, 0.59 mmol) is added and stirring continues while the reaction mixture gradually warmed up to room temperature overnight. The resulting mixture is poured into water (30 ml) and extracted with 1:1 EtOAc/ether. The organic layer is washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM to yield the titled compound as a pale yellow oil. (MH+ 377)
Reaction SMILES: [OH:1][C:2]12[CH2:8][N:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[Li+].CC([N-]C(C)C)C.[CH2:17]([N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])=O>C1COCC1>[N:5]12[CH2:8][C:2]([O:1][C:25](=[O:26])[N:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: OC12CCN(CC1)C2
Reactant: O=C(Cl)N(Cc1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OC12CCN(CC1)C2)N(Cc1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 2 h
Yield: 1.3 %

Procedure:
In a two necked flask under nitrogen, 3 ml of THF and 150 mg (1.33 mmoles) of 4-hydroxy-1-azabicyclo[2.2.1]heptane were placed. The suspension was cooled to −60° C. and 0.7 ml (1.46 mmoles) of LDA was added dropwise. After the addition the temperature was allowed to rise to 0° C. and was kept during two hours. A solution of 295 mg (1.20 mmoles) of benzylphenylcarbamoyl chloride in 2 ml of THF was added in 30 minutes. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 hours. The suspension was filtered and the filtrate concentrated under reduced pressure. The residue was extracted with dichloromethane and water. The organic layer was extracted with 2N HCl and the aqueous layer basified with 8N NaOH and extracted with dichloromethane. The organic layers were dried over anhydrous Na2SO4 and evaporated. The oil obtained (162 mg) was purified by HPLC-MS to obtain 4.86 mg (0.015 mmoles) 1.3% of a pure product as a formate, structure confirmed by 1H-NMR.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].NCCC(O)=O.C(O)(=O)C>O>[CH3:16][C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:24]2[NH:18][C:19](=[O:20])[NH:21][C:22]2=[O:23])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])([CH3:15])[CH3:17]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=C2NC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 50.6 %

Procedure:
A mixture of 3,5-di-t-butyl-4-hydroxybenzaldehyde (7.0 g, 30 mmoles), hydantoin (3.0 9, 30 mmoles), β-alanine (1.4 g, 16 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 48 hours the mixture is stirred into water (300 ml), and the precipitate is filtered off, rinsed with water three times, and dried. Recrystallization from acetonitrile gave the pure product (4.8 g), mp 251°-252° C.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:31]4[CH:32]=[CH:33][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Temperature: 80 °C

Procedure:
To 10 mL of 1,4-dioxane was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (100 mg, 0.31 mmol), 4-formylphenylboronic acid (56 mg, 0.37 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 1M Na2CO3 aqueous solution (1.2 mL, 1.2 mmol). The mixture was heated at 80° C. under N2 for 1 hour, cooled to room temperature and poured into 100 mL of water. The mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as orange/red solid. Yield: 100 mg, 93%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1.C(N(CC)CC)C>C(#N)C>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
6-Chloro-3-nitropyridin-2-amine (0.8 g, 4.64 mmol) was added to a solution of (R)-ethyl piperidine-3-carboxylate (1.0 g, 5.16 mmol) and triethylamine (1.56 g, 15.48 mmol) in acetonitrile (20 mL) at room temperature. The reaction mixture was stirred at 80° C. for 3 h. The mixture was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 10-50% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (1.0 g). MS (ES+) (M+H) 295.22.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5](=[O:25])[NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([C:22]([NH2:24])=[O:23])=[CH:21][C:16]3=[N:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.CC(O[CH:33](N(C)C)[N:34]([CH3:36])[CH3:35])(C)C.CCOCC>CN(C=O)C>[CH3:33][N:34]([CH3:36])/[CH:35]=[N:24]/[C:22]([C:20]1[CH:19]=[CH:18][N:17]2[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][C:5]([NH:4][CH2:3][C:2]([F:1])([F:26])[F:27])=[O:25])[CH:8]=3)=[CH:14][N:15]=[C:16]2[CH:21]=1)=[O:23]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: NC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)/C=N/C(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a stirred solution of 3-[3-[3-(2,2,2-trifluoroethyl)ureido]-phenyl}imidazo[1,2-a]pyridine-7-carboxylic acid amide (20 mg, 0.053 mmol) in dry DMF (0.5 ml) was added Bredereck's reagent (25 μl, 0.12 mmol) and the reaction mixture stirred for 1 h. Et2O was added to the reaction and the resulting precipitate filtered off. The precipitate was redissolved in MeOH, transferred to a flask and the solvent removed in vacuo to afford a pale yellow solid (17 mg). MS: [M+H]+433.
Reaction SMILES: [C:1]1([S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>>[C:1]1([S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)(=[O:25])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(OCCCCS(=O)c3ccccc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 3 from 6-(4-phenylsulfinyl-butoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][CH:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: CCCCCC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Yield: 29.4 %

Procedure:
A mixture of 1,4,5-triphenylimidazol-2-one (6.25 g), dibromohexane (24.4 g) and potassium carbonate (5.53 g) in dry butanone (300 ml) was heated at reflux temperature for 24 hours. The mixture was cooled and the filtrate evaporated to an oil which was chromatographed on silica gel (hexane/ethyl acetate) to give 1,4,5-triphenyl-2-(6-bromohexyloxy)-imidazole (2.8 g, 29%) as a white solid, m.p. 87°-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+](C1C=CC=CC=1)([O-])=O.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>>[Cl:1][C:2]1[C:7]2[N:8]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccnc(Cl)c1N
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Clc1nccc2[nH]c(-c3ccccc3)nc12
Temperature: 175 °C
Reaction time: 0.5 h

Procedure:
A mixture of 100 mg (0.696 mmol) of 2-chloropyridine-3,4-diamine [H. Dvorakova et al., Collect. Czech. Chem. Commun., 58, 629 (1993)], 0.086 mL (0.835 mmol) of benzaldehyde, and 2 mL of nitrobenzene was heated at 175° C. under microwave irradiation for 30 min. The cooled solution was treated with 500 mg of Montmorillonite K 10 clay, and microwave irradiation at 175° C. was continued for an additional 30 min. The cooled mixture was filtered through Celite, and the filter cake was washed with methanol. The combined filtrate and washings were concentrated to dryness. Flash chromatography of the residue on silica gel (0-5% methanol in dichloromethane) yielded the title compound as a foam. LC-MS 230 (M+1).
Reaction SMILES: CO.C[O-].[Na+].[SH:6][CH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11].[CH3:16][C:17]([CH3:35])=[CH:18][CH2:19][C@H:20]1[O:22][C@@:21]1([C@@H:24]1[C@:29]2([O:31][CH2:30]2)[CH2:28][CH2:27][C@@H:26]([OH:32])[C@H:25]1[O:33][CH3:34])[CH3:23]>O>[O:22]1[CH:20]([CH2:19][CH:18]=[C:17]([CH3:35])[CH3:16])[C:21]1([CH:24]1[CH:25]([O:33][CH3:34])[CH:26]([OH:32])[CH2:27][CH2:28][C:29]1([CH2:30][S:6][CH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11])[OH:31])[CH3:23]
Reactant: OCc1ccccc1CS
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1C(O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To an about 14% methanol solution (6 ml) of sodium methoxide were added, under ice-cooling, 2-mercaptomethylbenzylalcohol (655 mg) and fumagillol (1.00 g). The mixture was stirred for one hour at room temperature, to which was added water to suspend the reaction. The product was extracted with ethyl acetate, The extract solution was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent : ethyl acetate - hexane=2:1) to give 2-(1,2-epoxy-1,5-dimethy-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (1.43 g : yield 92%) as a colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH:9]2[NH:26][CH2:25][C:24](=O)[NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][C:10]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CO>C1COCC1.O>[N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][NH:26]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CNC(Cc2ccc([N+](=O)[O-])cc2)C(=O)NCCNCCNCCNCCN1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(CC2CNCCNCCNCCNCCNCCN2)cc1
Temperature: 0 °C
Yield: 55 %

Procedure:
A solution of BH3 in THF (100 mmol) was added dropwise to a stirred suspension of 3-(4-nitrobenzyl)-2,6-dioxo-1,4,7,10,13,16-hexaazacyclooctadecane (4) (10 mmol) in THF (50 ml) at 0° C. under nitrogen atmosphere. The solution was heated at reflux for 36 hours. Methanol was added slowly to the solution at 0° C. after which the solvent was removed and the residue was dissolved in methanol (50 ml); the resulting mixture was cooled at 0° C. and gaseous HCl was bubbled through the solution and then the mixture was refluxed for 12 hours. The resulting precipitate was collected washed with ether to give a white powder. The solid was dissolved in water and was loaded on a column of DOWEX 1X-8 anion-exchange resin (OH− form). The column was eluted with water; alkaline fractions were collected, and the water was removed under vacuum to give pale yellow oil. The yield was 55%.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[N:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=1>>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[CH2:2][N:12]1[CH2:13][CH:14]=[C:15]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:17]1
Reactant: ICC1Cc2ccccc2C1
Reactant: c1ccc2[nH]c(-c3ccncc3)cc2c1
Product: C1=C(c2cc3ccccc3[nH]2)CCN(CC2Cc3ccccc3C2)C1

Procedure:
From 22c and 27a. 1H NMR (CDCl3) d 2.50-2.55 (m, 2H), 2.65 (broad s, 2H), 2.70-2.85 (m, 5H), 3.00-3.15 (m, 2H), 3.25 (d, 2H), 6.05 (broad s, 1H), 6.45 (s, 1H), 7.05 (t, 1H), 7.10-7.25 (m, 5H), 7.30 (d, 1H), 7.55 (d, 1H), 8.10 (broad s, 1H). MS m/z (%): 329 (MH+, 5%), 160 (4%),131 (4%),91 (6%),44 (100%).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.CN(C)[CH:22]=[O:23].Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[CH:22]=[O:23])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 12.96 g (60 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 300 mL THF under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -65° C., 52.35 mL (123 mmol) 2.35M n-butyllithium in hexanes. The reaction was stirred at -78° C. for ca. 30 minutes. To the reaction mixture was added 4.64 mL (60 mmol) of N,N-dimethylformamide dropwise. The reaction mixture was allowed to warm to room temperature and stir for ca. 2 hours. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The THF phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (25% ethyl acetate/80% hexanes) affording 5.72 g of the title compound as a white solid, m.p. 101.5°-103° C. 1H NMR (CDCl3, 200 MHz.) δ: 10.25(s,1H), 6.81(d,1H), 6.6(d,1H), 4.93(bs,1H), 3.98(s,3H), 1.27(s,9H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH2:13]1[O:16][CH:14]1[CH3:15]>O1CCCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][CH:14]([OH:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: CC1CO1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)Cn1ccc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred suspension of sodium hydride (60%, 1.26 g, 31.6 mmol) in tetrahydrofuran (30 mL) at 0° C. under Ar was added dropwise a solution of 6-chloroindole (4.0 g, 26 mmol) in tetrahydrofuran (30 mL). The mixture was stirred for 1 h and (RS)-propylene oxide (3.7 mL, 53 mmol) was added. The mixture was warmed to room temperature, stirred for 48 h and partitioned between aqueous ammonium chloride solution (100 mL) and ether (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-hexane (1:9)] to give the product (2.78 g, 50% yield) as a pale yellow oil. Data for the compounds produced using General Method A, step (a) are listed in Table 3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].O1CCCC1.CS(Cl)(=O)=O.Cl.[NH2:28][C:29]([CH3:34])([CH2:32][CH3:33])[C:30]#[CH:31]>C(OCC)(=O)C.O.C(N(CC)CC)C>[CH3:34][C:29]([NH:28][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1)([CH2:32][CH3:33])[C:30]#[CH:31]
Reactant: C#CC(C)(N)CC
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#CC(C)(CC)NC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: -30 °C
Yield: 60.6 %

Procedure:
In a 1000 mL, three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer were placed 10 g of 4-acetamido-3-nitrobenzoic acid, 200 mL of tetrahydrofuran and 31 mL of triethylamine. The resulting well-stirred mixture was cooled to -30° C. and 3.9 mL of methane sulfonyl chloride were added dropwise while keeping the reaction temperature at -30° C. The resulting suspension was stirred at -30° C. for 30 minutes, after which 6.7 g of 3-amino-3-methyl-1-pentyne hydrochloride were added slowly over a 20 minute period. After the addition was complete, the reaction mixture was stirred at -30° C. for an additional 30 minutes. The reaction mixture was then poured into a mixture of 400 mL water and 200 mL of ethyl acetate. The phases were separated and the aqueous layer was then extracted with ethyl acetate (2×150 mL). The combined organic phases were washed sequentially with water (1×200 mL), 5% aqueous hydrochloric acid (2×200 mL), water (1×200 mL), 2% aqueous sodium hydroxide (2×200 mL) and water (1×200 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed in the rotary evaporator, yielding 8.2 g of N-(3-methylpent-1-yn-3-yl)-4-acetamido-3-nitrobenzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[F:9].C([Li])CCC.[F:15][CH2:16][C:17](OCC)=[O:18]>C1COCC1>[F:15][CH2:16][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[F:9])=[O:18]
Reactant: Cc1cccc(Br)c1F
Reactant: CCOC(=O)CF
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)CF)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 1-bromo-2-fluoro-3-methylbenzene (7.0 g, 37.0 mmol) in THF (60 mL) was brought to −78° C. followed by the dropwise addition of butyllithium (15.55 ml, 38.9 mmol). The resulting mixture was stirred at −78° C. for 1 h then neat ethyl 2-fluoroacetate (3.76 ml, 38.9 mmol) was added dropwise. After 30 min the reaction went to completion. The reaction was quenched at −78° C. with saturated NH4Cl, warmed to rt and transferred to a separatory funnel. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-10% EtOAc/hexanes to afford a colorless oil that turned into a white solid as 2-fluoro-1-(2-fluoro-3-methylphenyl)ethanone (5.03 g, 29.6 mmol, 80% yield). MS m/z=171 [M+H]+. Calculated for C9H8F2O: 170.05.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]([O:16]C)=[O:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[OH-].[Na+].C(O)(=O)C>CO>[CH2:1]([C:3]1[C:4]([C:14]([OH:16])=[O:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCc1c(C(=O)OC)noc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1c(C(=O)O)noc1-c1ccccc1
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A solution of methyl 4-ethyl-5-phenylisoxazole-3-carboxylate (194 mg, 0.839 mmol) and 1N aqueous sodium hydroxide (1.26 mL, 1.258 mmol) in methanol (3 mL) was heated to 100° C. for 10 minutes under microwave. The reaction mixture was acidified with acetic acid until the pH was about 4. The mixture was concentrated, and the residue was suspended in water (2 mL) and stirred for 20 minutes. The solid was collected by vacuum filtration and dried to give 4-ethyl-5-phenylisoxazole-3-carboxylic acid (148 mg). The compound had an HPLC ret. time=2.93 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=218+.