Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]#N>C(#N)C1C=CC=CC=1>[C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N#Cc1ccco1
Reactant: C#CCCCCCC
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccco1
Reaction time: 22 h
Yield: 62 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 22 h at 65° C. showed the presence of 1.24 mmol (62% yield) of 2-(1-octynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]3[C:18]4[CH2:25][CH2:24][CH2:23][C:19]=4[C:20](=[O:22])[O:21][C:16]=3[CH:15]=2)[CH2:6][CH2:5]1.[O-:28][C:29]#[N:30].[K+].Cl>O>[ClH:1].[NH:3]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]3[C:18]4[CH2:25][CH2:24][CH2:23][C:19]=4[C:20](=[O:22])[O:21][C:16]=3[CH:15]=2)[CH2:6][CH2:5]1)[C:29]([NH2:30])=[O:28]
Reactant: NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1

Procedure:
A mixture of 4.15 g. (0.01 mole) 7-[3-(4-aminopiperidino)-propoxy]-2,3-dihydrocyclopenta[c][1]benzopyran-4(1H)-one dihydrochloride, 4.0 g. potassium cyanate, 50 ml. water and 30 ml. 2 N hydrochloric acid is stirred for 3 days at ambient temperature, filtered and the precipitate extracted with hot ethanol. There are thus obtained 2.4 g. (57% of theory) of the desired compound; m.p. 244°-245° C.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.[BH4-].[Na+]>C(O)C.C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C@@H:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: COC(=O)c1ccc2c(c1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)CC[C@@H]2N[C@@H](C)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To 713 mg of methyl 1-oxoindane-5-carboxylate were added 612 mg of (1S)-1-(4-methoxyphenyl)ethanamine, 0.23 ml of acetic acid, 600 mg of Molecular Sieves 4A, and 12 ml of toluene, followed by heating to reflux using a Dean-Stark type reflux device for 4 hours under reduced pressure (213 mbar). Then, 0.23 ml of acetic acid and 300 mg of Molecular Sieves 4A were added thereto, followed by heating to reflux using a Dean-Stark type reflux device for 4 hours under reduced pressure (213 mbar). The insoluble material was removed by filtration and the solvent was then evaporated under reduced pressure to obtain an intermediate product. To a solution of the obtained intermediate product in 13 ml of ethanol was added 161 mg of sodium borohydride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The solvent was evaporated under reduced pressure, and to the obtained residue were added water, a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 452 mg of methyl (1S)-1-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}indane-5-carboxylate.
Reaction SMILES: [CH2:1]1[CH:3]([CH2:4][N:5]2[C@@H:15]3[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]5[O:24][C@H:9]6[C:10]([CH2:12][CH2:13][C@:14]3([OH:25])[C@:8]6([C:18]=45)[CH2:7][CH2:6]2)=[O:11])[CH2:2]1.[CH3:26]C(C)=O.C[Br:31]>CN(C)C=O>[CH3:26][N+:5]1([CH2:4][CH:3]2[CH2:2][CH2:1]2)[C@@H:15]2[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]4[O:24][C@H:9]5[C:10]([CH2:12][CH2:13][C@:14]2([OH:25])[C@:8]5([C:18]=34)[CH2:7][CH2:6]1)=[O:11].[Br-:31]
Reactant: CBr
Reactant: CC(C)=O
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Solvent: CN(C)C=O
Product: C[N+]1(CC2CC2)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Product: [Br-]

Procedure:
2.5 gm (7.35 millimols) of N-cyclopropylmethylnoroxymorphone were dissolved in a mixture consisting of 50 ml of absolute acetone and 0.5 ml of dimethylformamide, and the resulting solution was admixed with 4.25 gm (44.8 millimols) of methyl bromide. The reaction mixture was then allowed to stand for three weeks at room temperature in a sealed pressure vessel. Thereafter, the contents of the vessel were evaporated, and the residue was crystallized from methanol and recrystallized from methanol/ether, yielding 1.0 gm of the methobromide which had a melting point of 253° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.C(OCC)(=O)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OCCc1ccc(I)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCCc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 90 °C
Yield: 59.4 %

Procedure:
A mixture of 1.14 g (4.60 mmol) of 2-(4-iodophenyl)ethanol, 0.88 g (6.89 mmol) of 4-chlorophenol, 2.99 g (9.20 mmol) of cesium carbonate, 0.14 g (1.38 mmol) of N,N-dimethylglycine and 0.087 g (0.46 mmol) of cuprous iodide in 4 ml of dioxane is heated at 90° C. for 24 hours with thorough stirring under an argon atmosphere. It is cooled to ambient temperature and taken up in 150 ml of ethyl acetate and 50 ml of water. After the phases have settled and been separated, the organic phase is washed with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with an 85/15 then 75/25 mixture of cyclohexane and ethyl acetate, to give 0.68 g of product in the form of an oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: c1nc[nH]n1
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1c(=O)c(Cn2cncn2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 1,2,4-triazole (0.033 g) in dimethylformamide (0.7 ml) was stirred at ice-bath temperature with 60% sodium hydride (0.02 g) for 10 mins under nitrogen and then a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.14 g) in dimethylformamide (1.7 ml) was added to it. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and then washed several times with water. The organic layer was dried and evaporated under reduced pressure. The resulting crude reaction product was chromatographed on silica-gel (4 g). Elution with 2.5% methanol-ethyl acetate gave 1-hexyl-3-(1,2,4-triazol-1-ylmethyl)-4-methoxy-6-methyl-2(1H)-quinolinone as white crystals (80%). That the expected product was obtained was confirmed by the spectral data: MS: m/e 354 (M.+); NMR (CDCl3): δ4.15 (s, H, OCH3), 5.42 (s, 2H, CH2), 7.86, 8.5 (s, 2H, CH=).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:26])=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[O:26]=[C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]1[CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:27])[C:4]([OH:28])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCCCn2c(=O)ccc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCn2c(=O)ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
A solution of 4-[3-(1,2-dihydro-2-oxo-1-quinolinyl)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.5 g) in hot methanol (50 mL) was treated with sodium carbonate (0.14 g) in water (1.5 mL), and the reaction was stirred at room temperature for 5 hours. After the methanol was removed in vacuo, dichloromethane and water were added and the rnixmre was acidified with 3N hydrochloric acid. The precipitated solid was faltered off, dried and then crystallized from ethyl acetate-tetrahydrofuran to afford 0.337 g of 4-[3-(1,2-dihydro-2-oxo-1-quinolinyl)propoxy]-alpha-oxobenzeneacetic acid, mp 183°-186° C.
Reaction SMILES: C(N(CC)CC)C.[N+](C1C=C[C:14]([O:17]C=O)=CC=1)([O-])=O.Cl.[NH2:21][C@H:22]([C@@H:46]([OH:57])[CH2:47][C@H:48]([C:50](=[O:56])[NH:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH3:49])[CH2:23][C@@H:24]([CH:43]([CH3:45])[CH3:44])[CH2:25][NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41]>ClCCl>[CH2:52]([NH:51][C:50]([C@H:48]([CH3:49])[CH2:47][C@H:46]([OH:57])[C@@H:22]([NH:21][CH:14]=[O:17])[CH2:23][C@@H:24]([CH:43]([CH3:45])[CH3:44])[CH2:25][NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[O:56])[CH2:53][CH2:54][CH3:55]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](CNC(=O)c1cccc(OC)c1OCCCOC)C(C)C
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](CNC(=O)c1cccc(OC)c1OCCCOC)C(C)C)NC=O
Reaction time: 0.5 h

Procedure:
Triethylamine (0.034 ml) and formic acid 4-nitrophenyl ester (28 mg) are added at room temperature, with stirring, to a solution of (2S,4S,5S,7R)-N-(4-amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-octyl)-3-methoxy-2-(3-methoxypropoxy)-benzamide hydrochloride (Example 6a) (67 mg) in dichloromethane (4 ml). The resulting reaction solution is stirred for a further 30 minutes and is then concentrated by evaporation. The residue is purified by FC (18 g of silica gel; eluant E, then ethyl acetate-hexane-methanol 5:5:1). (2S,4S,5S,7R)-N-(7-Butylcarbamoyl-4-formylamino-5-hydroxy-2-isopropyl-octyl)-3-methoxy-2-(3-methoxypropoxy)-benzamide is obtained in the form of a white foam: Rf (L)=0.58. HPLC Rt =13.2 min. MS(FAB) m/e 552 (M+ +1).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.Cl.[CH3:12]O>>[ClH:1].[CH3:12][O:9][C:8](=[O:10])[CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1c[nH]cn1

Procedure:
A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00 g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18 hr. The solvent was evaporated in vacuo to afford the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)[O:12]1.[BH3-][C:40]#N.[Na+].CC(O)=O.C=O>CO.O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:40])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24]2)[O:12]1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a mixture of benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (3.76 g, 7.2 mmol) and NaBH3CN (5.9 g, 93.6 mmol) in MeOH (40 mL) was added AcOH to adjust to pH=6. Then, 37% HCHO (8.7 mL, 122.4 mmol) was added and the mixture was stirred at 30° C. for 1.5 h. Water (15 mL) was added and the mixture was concentrated in vacuo. Then, the mixture was extracted with DCM (30 mL×3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by SGC (DCM: MeOH=100:1-20:1) to obtain the target (2.4 g, yield: 67%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.27 (s, 1H), 8.22 (d, J=2.5 Hz, 1H), 7.35-7.30 (m, 5H), 6.22 (s, 1H), 5.55-5.52 (m, 1H), 5.09 (s, 2H), 5.04-5.01 (m, 1H), 4.40-4.38 (m, 1H), 2.76-2.65 (m, 3H), 2.29-2.22 (m, 2H), 2.18 (s, 3H), 2.11-1.95 (m, 2H), 1.78-1.71 (m, 2H), 1.64-1.61 (m, 2H), 1.59 (s, 3H), 1.41-1.39 (m, 1H), 1.38 (s, 3H) ppm; ESI-MS (m/z): 537.3 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([N:8]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
A solution of 1.0 g (0.005 mole) of (rac)-3-cyclopentylamino-butanoic acid ethyl ester in 25 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 25 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.0 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butanoic acid ethyl ester (IV-3)
Reaction SMILES: [C:1]([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)([CH3:9])([CH3:8])[CH3:7].CI>C1COCC1>[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[C:14]=1[CH3:1])([CH3:9])([CH3:7])[CH3:8]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(NC(=O)OC(C)(C)C)ccnc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
tert-Butyllithium (29 mL of 1.7M in pentane, 50 mmol) was added dropwise to a vigorously stirring solution of (2-chloropyridin-4-yl)carbamic acid tert-butyl ester (4.57 g, 20 mmol) in THF (150 mL) at −78° C. under nitrogen. The reaction mixture was kept at this temperature for 4 hours before adding a solution of methyl iodide (3.41 g, 24 mmol) in THF (20 mL). Warmed the reaction mixture to 0° C. over 2 hours, and quenched the reaction with saturated aqueous ammonium chloride solution (100 mL). Extracted into ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to dryness. Flash column chromatography on silica gel gave the product as a white solid (2.93 g, 12 mmol). 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.98 (d, 1H), 6.58 (br s, 1H), 2.30 (s, 3H), 1.52 (s, 9H). ESI MS (M+1)+: 243, 245 (Cl).
Reaction SMILES: C[Si](C)(C)[C:3]1[O:11][C:10]2[C:5](=[N:6][C:7]([CH3:12])=[CH:8][CH:9]=2)C=1.[Cl:15]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.CCOC(C)=O.[CH2:33]([Cl:35])Cl>CCCCCC>[Cl:15][C:3]1[O:11][C:10]2[C:5](=[N:6][C:7]([CH3:12])=[CH:8][CH:9]=2)[C:33]=1[Cl:35]
Reactant: ClCCl
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1ccc2oc([Si](C)(C)C)cc2n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc2oc(Cl)c(Cl)c2n1
Temperature: 0 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
To a solution of 2-trimethylsilyl-5-methylfurano[3,2-b]pyridine (1.05 g, 5.15 mmol) in CH2Cl2 (16 mL) at 0° C. was added trichloroisocyanuric acid (1.2 g, 5.15 mmol). The mixture was stirred at 0° C. for 30 rain and then at r.t. for 20 hr. A solution of 30% EtOAc in hexane was added. The resulting mixture was filtered through a short bed of silica gel and eluted with more 30% EtOAc in hexane. Evaporation of the filtrate gave 1.0 g (96%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCc1ccc2c(c1)OCO2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1ccc2c(c1)OCO2
Yield: 76.1 %

Procedure:
A solution of 2-benzo[1,3]dioxol-5-yl-ethanol (Intermediate D2) (1 g; 6.0 mmol) in dichloromethane (40 mL) was treated with the Dess-Martin periodinane (commercially available from Lancaster) (2.65 g, 6.25 mmol) at rt for 2 h. Silica gel was added to the mixture and the solvent was removed under vacuum. The solids were placed onto a column of silica gel and the product was eluted with a mixture of ether:hexanes to give benzo[1,3]dioxol-5-yl-acetaldehyde (Intermediate D3) 0.75 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-:13].[Na+].Cl.C([OH:18])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([OH:18])=[O:13])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CCO
Reactant: N#CC1(c2ccc(Br)cn2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A flask charged with a stir bar, 1-(5-bromo-pyridin-2-yl)-cyclopropanecarbonitrile (1.00 g), 25% aqueous NaOH solution (1 mL), and ethanol (10 mL) was heated to 100° C., and the mixture was stirred at this temperature for 14 h. After cooling to room temperature, the solution was poured into ice-cold saturated aqueous Na2HPO4 solution and the resulting mixture was adjusted to pH 4 by the addition of 1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was recrystallized from diisopropyl ether to give the title compound as a yellowish solid. Yield: 0.58 g (53% of theory); LC (method 1): tR=0.60 min; Mass spectrum (ESI+): m/z=242/244 (Br) [M+H]+.
Reaction SMILES: [Na].C([O:4][C:5]([C:7]1([C:26](OCC)=[O:27])[CH2:11][CH2:10][CH2:9][N:8]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=O)C.[NH2:31][C:32]([NH2:34])=[O:33].Cl.C([OH:38])C>>[Br:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:15]2[N:14]=[CH:13][C:12]([N:8]3[C:7]4([C:5](=[O:4])[NH:34][C:32](=[O:33])[NH:31][C:26]4=[O:27])[CH2:11][CH2:10][C:9]3=[O:38])=[CH:17][CH:16]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(Br)cc2)nc1
Reactant: NC(N)=O
Reactant: CCO
Agent: Cl
Agent: [Na]
Product: O=C1NC(=O)C2(CCC(=O)N2c2ccc(Oc3ccc(Br)cc3)nc2)C(=O)N1
Temperature: 25 °C

Procedure:
Sodium metal (29 mg, 1.26 mmol) was added to 1.3 mL of ethanol and stirred until homogeneous. of 1-[6-(4-Bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.42 mmol) was added, followed by urea (75 mg, 1.26 mmol) and the mixture was stirred for 5 minutes at 80° C. The mixture was cooled to ambient temperature, acidified with 1M hydrochloric acid and extracted 3× with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (3:1 hexane-ethyl acetate), affording 28 mg of 1-[6-(4-Bromo-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone as a colorless solid. HPLC Ret. time: 2.201 min; MS (APCl, m/z): 436 [M−H]−; 438 [M+H]+.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[N+:14]([C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])([O-:16])=[O:15].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)C>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:17]=1[N+:14]([O-:16])=[O:15])[OH:20]
Reactant: Fc1cccc(F)c1
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc(C(O)c2c(F)cccc2F)c1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 1 h

Procedure:
77.5 ml of a 1.6M solution of n-butyllithium (1.5 eq.) in hexane are added dropwise in order to maintain a temperature of less than or equal to −70° C. to a solution of 12.3 ml of 1,3-difluorobenzene (1.5 eq.) in 150 ml of tetrahydrofuran over 1 hour. After an additional 1 hour at −70° C., a solution of 15 g of 2-nitro-3-methoxybenzaldehyde in tetrahydrofuran is added over 1 hour still at −70° C. The reaction medium is stirred for 4 hours at −70° C. and then brought to a temperature of −5° C. over 1 hour. The reaction medium is then diluted by adding diethyl ether and then slowly hydrolyzed with a saturated aqueous solution of ammonium chloride. After decantation, the organic phase is washed with water and then dried over anhydrous sodium sulfate. The residue is chromatographed on silica gel, eluting with a dichloromethane/cyclohexane mixture (1/1) (v/v) in order to obtain 13.4 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[Cl:10].[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([C:11](=[O:13])[CH3:12])=[C:6]([OH:8])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cl)c(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc(Cl)c(Br)cc1O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
The 2-bromo-1-chloro-4-methoxybenzene (25.0 g, 113 mmol) [Oakwood cat#035670] was dissolved in carbon disulfide (250 mL), and the acetyl chloride (12 mL, 170 mmol) and aluminum trichloride (37.6 g, 282 mmol) were added. The reaction was heated to reflux and monitored by LC/MS. After heating for 1 h, the reaction became two layers. The reaction allowed to cool to room temperature and poured over ice. The slurry was extracted with ethyl acetate 3×, the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 1-(4-bromo-5-chloro-2-hydroxyphenyl)ethanone as a solid (28.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 12.12 (s, 1H), 7.78 (s, 1H), 7.31 (s, 1H), 2.62 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:7]([Cl:11])[CH2:8][CH2:9][CH3:10].O1CCOCC1>[N+](C)([O-])=O>[Cl-:11].[CH2:7]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH3:10]
Reactant: c1ccncc1
Reactant: CCCCCl
Solvent: C[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCCC[n+]1ccccc1
Product: [Cl-]

Procedure:
Pyridine and excess n-butyl chloride were heated under reflux in nitromethane for 24 hours and then cooled, and the reaction solution was poured into dioxane, thereby precipitating the crystals formed. Thus, crude crystals of butylpyridinium chloride (BPC) were obtained. These were purified by recrystallizing them in methanol/dioxane solvent two or three times and then fully dried in vacuum.