Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([OH:4])[CH3:3].[CH2:5]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6]>ClCCl>[Br-:1].[OH:4][CH2:2][CH2:3][N+:7]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:5][CH3:6]
Reactant: CCN(CC)CC
Reactant: CC(O)Br
Solvent: ClCCl
Product: CC[N+](CC)(CC)CCO
Product: [Br-]
Yield: 41 %

Procedure:
Hydroxyethyltriethylammonium bromide was obtained as follows: ##STR14## Bromoethanol (distilled, 2 g, 16 mmole) and triethylamine (1.62 g, 16 mmole) were heated in dichloromethane (30 ml) at 40° C. for 16 hours. After cooling the precipitate was filtered and dried over phosphorus pentoxide to yield hydroxyethyltriethylammonium bromide as a white powder, 1.47 g, 6.5 mmole, 41% yield.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].CC1C=CC(S(O[CH2:34][C@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][O:36]1)[C:12]4=[O:20]
Reactant: Cc1nc2cc3c(cc2o1)C1(CO3)C(=O)Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: BrCC1CCCCO1
Product: Cc1nc2cc3c(cc2o1)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 2-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one was obtained (52%) as a colorless solid: mp 188-190° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.37-7.30 (m, 2H), 7.23-7.05 (m, 2H), 6.98-6.93 (m, 2H), 6.00-5.93 (m, 1H), 5.43-5.38 (m, 1H), 4.42-4.26 (m, 1H), 4.05-3.75 (m, 4H), 2.35-2.33 (m, 3H) 2.09-1.79 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.6, 175.3, 164.4, 164.3, 151.2, 151.1, 146.2, 146.1, 144.9, 144.6, 138.7, 138.6, 130.5, 130.4, 129.6, 124.6, 124.4, 123.0 (2C), 114.0, 113.9, 111.8, 111.6, 110.6, 110.5, 110.3, 109.8, 88.7, 88.4, 76.1, 76.0, 68.5, 68.3, 44.7, 44.4, 29.8, 28.9, 26.2, 25.7, 14.7, 14.6; MS (ES+) m/z 414.9 (M+39).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20]Br)[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8].[F-].[K+].[F:25][B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>C(#N)C.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20][F:25])[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: F[B-](F)(F)F
Reactant: O=C1O[C@@H](Cn2cc(CBr)nn2)CN1c1ccc(I)c(F)c1
Agent: CCCC[n+]1ccn(C)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1O[C@@H](Cn2cc(CF)nn2)CN1c1ccc(I)c(F)c1
Temperature: 90 °C
Yield: 45 %

Procedure:
A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-bromomethyl-1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (6.94 g, 14.4 mmol), potassium fluoride (4.19 g, 72.1 mmol), and 1-butyl-3-methylimidazolium tetrafluoroborate (18.4 mL) in acetonitrile (250 mL) and water (1.5 mL) was heated to 90° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated to dryness. The involatile residue was purified by chromatography on silica gel [elution with ethyl acetate] gave the title compound as an off-white amorphous solid (2.7 g, 45%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:23])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@@H:10]([OH:23])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@@H](O)CC[C@@H]1N2Cc1ccccc1
Reaction time: 0.75 h
Yield: 7.8 %

Procedure:
(1R*,5S*,6S*)-8-Benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 19b; 750 mg, 1.91 mmol) was dissolved in THF (5 ml) and methanol (25 ml) was added. The mixture was cooled to +5° C. and treated with sodium borohydride (184 mg, 4.8 mmol). The reaction mixture was stirred for 45 minutes, quenched with saturated aqueous NH4Cl (10 ml) and concentrated in vacuo. The aqueous residue was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to give crude product as a 10:1 mixture of diastereoisomers. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-30%) to give the (1R*,2R*,5S*,6S*)-isomer (710 mg, 92%) and the (1R*,2S*,5S*,6S*)-isomer (59 mg, 8%) of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[C:13]([F:25])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:3]=1.[CH2:34]([Sn](CCCC)(CCCC)C=C)[CH2:35]CC.CC1C=CC(C)=CC=1>C(OCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Si:27]([O:26][C:4]1[CH:3]=[C:2]([CH:34]=[CH2:35])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[C:13]([F:25])[CH:12]=3)=[N:7][C:6]=2[CH:5]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)c2oc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)nc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccc(C)cc1
Solvent: CCOCC
Product: C=Cc1cc(O[Si](C)(C)C(C)(C)C)cc2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (0.63 g, 0.79 mmol) was added into a mixture of 7-bromo-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)-1,3-benzoxazole (14.7 g, 26.6 mmol), tributyl(vinyl)tin. (10.5 g, 33.25 mmol) and p-xylene (85 mL). The reaction mixture was stirred at 90° C. for 24 h, cooled to room temperature, diluted with ethyl ether (100 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 50/1) gave a white solid (11.8 g, 89% yield, m.p. 93–95° C.); MS m/e 500 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C=O)C.O>[CH2:20]([O:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([OH:13])[C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol) and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was added benzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight, diluted with 200 mL water and acidified to pH 1 by slow addition of concentrated hydrochloric acid. The solution was extracted with 1:1 ethyl acetate/ether (6×) and the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to an orange solid. The solids were suspended in DCM (200 mL) and stirred overnight. The solids (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) were removed by filtration and the filtrate was concentrated to an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as the di-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:1]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:14])[CH3:15])[C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc(N3CCOCC3)cc2c1=O
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 20.3 %

Procedure:
To a solution of 7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (0.8 g, 0.0028 mol) in DMF (8 ml), was added potassium carbonate (2 g, 0.014 mol). After 5 min, bis (2-chloroethyl) ether (0.41 g, 0.0028 mol) was added and the solution was heated to 140° C. for 24 hours. After this time LC-MS indicated the complete consumption of starting material and the mixture was cooled, concentrated under vacuum and purified by flash column chromatography (elution: 70% heptane, 30% EtOAc) to give the title compound (0.2 g, 20% yield) as a white solid.
Reaction SMILES: FC(F)(F)[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.C(Br)C1C=CC=CC=1.[CH3:21][C:22]1[CH:26]=[C:25]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:24][C:23]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:7]([N:29]1[CH2:30][CH2:31][N:27]([C:25]2[S:24][C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:22]([CH3:21])[CH:26]=2)[C:28]1=[O:32])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)cc1C
Yield: 94 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with benzyl bromide to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 94% yield: 1H NMR (300 MHz, CDCl3) δ 7.39-7.25 (m, 5H), 6.15 (s, 1H), 4.48 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.83-3.75 (m, 2H), 3.48-3.40 (m, 2H), 2.49 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 345.3 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:20][C:21](=[O:24])CBr)C.[CH2:25]1COCC1>>[C:12]1([CH:11]2[C:9](=[O:10])[CH:3]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][C:21]([OH:24])=[O:20])=[CH:25]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCCC1=CC(c2ccccc2)C(=O)C=C1
Reaction time: 0.17 h

Procedure:
To a solution of 6.0 g of 60% sodium hydride in 150 ml of THF was added dropwise a solution of 29.4 g of deoxybenzoin in 150 ml THF. The mixture was stirred for 10 min., 16.8 ml of ethylbromoacetate was added dropwise, and the reaction was then heated at reflux under nitrogen overnight. The reaction was then partitioned between ether and 5% aqueous sodium bicarbonate, washed twice with ether dried over magnesium sulfate, filtered and concentrated to 41.08 g of a brown oil. The crude product was mixed with 200 ml of methanol, 30 ml of water and 10 ml of 50% sodium hydroxide and then heated to reflux under nitrogen overnight. After this time the reaction was concentrated, partitioned between water and ether, washed twice with ether and dried over magnesium sulfate. The ether extracts were then concentrated and the residue triturated with cold ether to afford 6.45 gms of a yellow solid, mp 137-139° C. 1H NMR (CDCl3) δ: 2.74 (dd, 1H), 3.43 (dd, 1H), 5.04 (dd, 1H), 7.1-7.5 (m, 8H), 7.93 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([OH:19])[CH:16]=[CH:15]2)=[C:7]([NH:20][C@H:21]([CH2:29][OH:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:6]=1)=[O:4].N1C=CC=CC=1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([O:19][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:16]=[CH:15]2)=[C:7]([NH:20][C@H:21]([CH2:29][OH:30])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:6]=1)=[O:4]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(C(=O)OC)nc32)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
9-((1R,4S)-4-Hydroxy-cyclopent-2-enyl)-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Intermediate WA) is dissolved in THF (dry). Pyridine is added and the reaction mixture is cooled to 0° C. Ethyl chloroformate is added dropwise keeping the temperature below 10° C. The reaction mixture is warmed to RT and stirred for 2 hours. The reaction mixture is reduced in vacuo and portioned between EtOAc and (1 M) HCl(aq). The organics are washed with water, brine, dried (MgSO4) and reduced in vacuo. The resulting residue is columned to give the title compound.
Reaction SMILES: C(OC(N1C([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)C2CC1CC2)=O)(C)(C)C.[CH2:27]([O:34][C:35]([N:37]1[CH2:43][CH2:42][C:39]2([CH2:41][CH2:40]2)[CH2:38]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OC(N1C(C(=O)NCC(C2C=[CH:66][C:65]([Br:68])=[CH:64][CH:63]=2)=O)C2CC1CC2)=O)(C)(C)C>>[CH2:27]([O:34][C:35]([N:37]1[CH:43]([C:14]2[NH:15][C:16]([C:19]3[CH:20]=[CH:21][C:22]4[C:23](=[CH:63][CH:64]=[C:65]([Br:68])[CH:66]=4)[CH:24]=3)=[CH:17][N:18]=2)[CH2:42][C:39]2([CH2:41][CH2:40]2)[CH2:38]1)=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC2)C1
Product: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), substituting 642-(6-Bromo-naphthalen-2-yl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH3:37][S:38][CH2:39]P(=O)(OCC)OCC.[H-].[Na+].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:37]/[S:38]([CH3:39])=[O:58])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CSC)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/S(C)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.8 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (2.0 g), diethyl (methylthio)methylphosphonate (0.89 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.20 g) at room temperature and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give colorless crystals. To a mixture of the obtained crystal and tetrahydrofuran (50 mL) was added m-chloroperbenzoic acid (0.66 g) at room temperature, and the mixture was stirred at the same temperature for 2 hrs. Saturated sodium sulfite aqueous solution was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (100:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(E)-2-(methylsulfinyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.81 g, yield 36%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 156-157° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:12]([NH:14][CH3:15])=[O:13].[C:25](Cl)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)(Cl)Cl>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][N:19]1[C:18]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N:8]=[C:42]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CNC(=O)c1ccc(NCCN(C)C)c(N)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)NC)ccc2n1CCN(C)C
Reaction time: 2.5 h

Procedure:
Triethylamine (1.00 ml) was added to a solution containing 3-amino-4-{[2-(dimethylamino)ethyl]amino}-N-methylbenzamide (1.500 g) in chloroform (15 ml), and then stearoyl chloride (2.20 mnl) was added thereto while being cooled with ice. After being stirred for 2.5 hours, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (5.3 ml) was added to a solution containing the residue (3.030 g) in ethanol (30 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (3.737 g) was purified by silica gel column chromatography (silica gel 75 g, chloroform:methanol=50:1-30:1), thereby yielding the entitled compound (2.225 g) as pale yellow solid.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([N+]([O-])=O)=O>CS(C)=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: F
Reactant: Nc1cc(Cl)cnc1Cl
Agent: O=N[N+](=O)[O-]
Solvent: CS(C)=O
Product: Fc1cc(Cl)cnc1Cl
Yield: 92.1 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 60 ml of dimethyl sulfoxide is added dropwise at a temperature in the range from 0° C. to +10° C. Over 11/2 hours, 24.7 g (0.325 mol) of dinitrogen trioxide are introduced into this solution at a temperature in the range from +°50 C. to 60° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after a total of 3 hours at 50° C. to 60° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate. The solution is separated by distillation, affording 38.2 g (92.1% of theory) of 2,5-dichloro-3-fluoropyridine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.I[CH3:30]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5[CH3:30])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CI
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: CN(C)C=O
Product: Cc1c(C(C)(C)C)[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc12

Procedure:
A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (75 mg, 0.20 mmol) and iodomethane (125 μL, 2.0 mmol) in N,N-dimethylformamide (1 mL) was heated at 120° C. in a sealed tube for 24 h. The reaction was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 390.5. found 391.3 (M+1)+; retention time 2.04 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.39 (s, 1H), 7.51 (m, 1H), 7.13-7.11 (m, 1H), 7.03-6.90 (m, 4H), 6.03 (s, 2H), 2.25 (s, 3H), 1.40-1.38 (m, 11H), 1.03-1.01 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:23])[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:4]1.F[B-](F)(F)F.[CH3:33][O+](C)C.O>C(Cl)Cl>[Cl-:1].[Cl:1][CH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([CH3:33])([CH3:23])[CH2:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[N:5]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:4]1
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)N(S(C)(=O)=O)CC2CCl
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: C[N+](C)(Cc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)N(S(C)(=O)=O)CC2CCl
Product: [Cl-]
Reaction time: 96 h
Yield: 198.9 %

Procedure:
A mixture of 31 (79 mg, 0.19 mmol) and trimethyloxonium tetrafluoroborate (105 mg, 0.71 mmol) in CH2Cl2 (5 mL) was stoppered and stirred at 20 C for 4 days. Water was added and the mixture stirred until most of the oily solid dissolved. The separated organic layer was dried (Na2SO4) and evaporated, dry column chromatography, eluting with EtOAc/petroleum ether (1:2), gave recovered starting material (24 mg, 30%). The aqueous phase was combined with the remaining oily solid, evaporated, and the residue extracted with MeOH. The resulting crude ammonium salt was converted to the chloride form by ion exchange chromatography on Dowex 50 WX8 resin (1.5 mL), loading the sample in MeOH:water (1:1) and washing until the eluate was neutral, then eluting with 1:1 MeOH:2N HCl (10 mL) followed by MeOH.backslash.4N HCl (1:1) (10 mL). The combined eluate was evaporated to give 3-(chloromethyl)-6-[N,N-dimethyl-N-(4-nitrobenzyl)-ammonio]-1-(methanesulfonyl)indoline chloride (11) as a white foam (87 mg). 1H NMR (CD3OD) a 8.17 (d, J=8.2 Hz, 2 H, ArH), 7.63 (br d, J=8.3 Hz, 1 H, H-4 or 5), 7.57 (br d, J=8.3 Hz, 1 H, H-4 or 5), 7.51 (s, 1 H, H-7), 7.41 (d, J=8.2 Hz, 2 H, ArH), 5.22 (s, 2 H, NCH2Ar), 4.32-4.25 (m, 1 H), 4.06-4.01 (m, 2 H), 3.96-3.93 (m, 2 H), 3.75 (s, 6 H, NMe2), 3.02 (s, 3 H, NSO2CH3). 13C NMR a 150.7, 146.0, 145.8, 136.1, 135.7 (C-6,8,9,1,4), 135.3, 124.8 (C-2 and 6, 3 and 5), 128.2, 117.9, 107.6 (C-4,5,7), 73.1 (NCH2Ar), 55.3 (C-2), 54.6 (NMe2), 47.8 (CH2Cl), 42.8 (C-3), 36.4 (SO2CH3).