Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N+:9]([O-:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]1[CH2:17][CH2:16][CH:15]=[CH:14][CH:13]=1>>[CH2:7]([CH:8]1[CH:17]2[CH:12]=[CH:13][CH2:14][CH2:15][CH:16]2[O:11][N:9]1[CH3:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=CCCC=C1
Reactant: C[N+]([O-])=CCc1ccccc1
Product: CN1OC2CCC=CC2C1Cc1ccccc1
Temperature: 25 °C
Yield: 87 %

Procedure:
N-(2-Phenylethylidene)methylamine N-oxide (797 mg, 5.34 mmol) and 1,3-cyclohexadiene (3 ml) were heated together at 70° C. in a sealed tube under nitrogen for 14 hours. The solution was cooled to room temperature and the excess 1,3-cyclohexadiene was removed under reduced pressure to yield a viscous oil (1.07 g, 87%). This crude product was purified by flash chromatography using 60:40 v/v petroleum ether (fraction of bp 40°-60° C.):ethyl acetate as the solvent system to give the title compound (Rf=0.34) as a pale yellow oil (375 mg, 35%), νmax (film) 3030, 2920, 2840, 1605, 1495, 1455, 1090 cm-1 ; δH (400 MHz; CDCl3 --Me4Si) 1.80-2.00 (4H, br m), 2.20-2.25 (1H, m), 2.60-2.65 (3H, s), 2.75-2.95 (2H and 1H, m), 4.20-4.25 (1H, br), 5.6-6.0 (2H, br m), 7.20-7.30 (5H, br m); M/z 229 (MH+ 100%) (Found: MH+ 230.1545; C15H19NO requires MH+ 230.1574).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([OH:17])=[O:16])[CH2:5][O:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:22][CH2:23]O>>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([O:17][CH2:22][CH3:23])=[O:16])[CH2:5][O:4][CH2:3]1
Reactant: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The title compound was prepared according to the procedure described by H. H. Otto, Helvetica Chimica Acta, 2004, 87, 90 using (3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (D44, 3.13 g, 13.33 mmol) in EtOH (30 mL), cooling in an ice bath before adding Thionyl Chloride (1.46 mL) dropwise, and then stirring at R.T. for 6 hours. Added more thionyl chloride (1 mL) and stirring at R.T. overnight. Added more thionyl chloride (1 mL) and stirred for 4 hours, added further thionyl chloride (0.5 mL) and stirred overnight again. Added thionyl chloride (0.2 mL) and left stirring for 5 hours. Solvent evaporated to afford the title compound as an orange oil in quantitative yield.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:23]([NH2:25])[CH3:24].[ClH:26].CCO>CO>[ClH:26].[CH2:23]([NH:25][CH2:22][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1)[CH3:24]
Reactant: CCN
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCNCC(O)COc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Yield: 36 %

Procedure:
According to Method B, the title compound was synthesized from the reaction of 7-(2,3-epoxypropoxy) flavone and 70% aqueous ethylamine followed by treatment with HCl/EtOH, as white prisms, m.p. 244°-46° (MeOH) in 36% yield. The free base was obtained after column purification as white crystals, m.p. 164°-65° (MeOH/ehter), yield 39%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:16][C:17]([C:22](C)(C)[O:23][SiH2]C(C)(C)C)=[C:18]([O:20][CH3:21])[CH:19]=2)=[CH:9][C:8]=1[F:31])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:31][C:8]1[CH:9]=[C:10]([O:13][CH2:14][C:15]2[S:16][C:17]([CH2:22][OH:23])=[C:18]([O:20][CH3:21])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32]
Reactant: CCOC(=O)CCc1ccc(OCc2cc(OC)c(C(C)(C)O[SiH2]C(C)(C)C)s2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2cc(OC)c(CO)s2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
To a solution of 3-{4-[5-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-thiophen-2-ylmethoxy]-2-fluoro-phenyl}-propionicacid ethyl ester (0.5 g, 1.0 mmol) in THF (5 mL) is added tetra-n-butylammoniumfluoride (1M solution in THF, 2 mL, 2.0 mmol) at 0° C. and the reaction mixture is stirred for 30 minutes at 25° C. The reaction mixture is quenched with water and evaporated to a residue. The residue is extracted with EtOAc, washed with water (15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (0.4 g,). 1H NMR (400 MHz, DMSO d6) δ7.41 (s, 1H), 7.19-7.15 (t, J=8.8 Hz, 1H), 6.85-6.75 (m, 2H), 5.32 (br, 1H), 4.85 (s, 2H), 4.55 (s, 2H), 4.04-4.00 (q, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.58 (s, 1H) 3.16-3.12 (t, J=15.2 Hz, 3H), 2.79-2.76 (t, J=14.8 Hz, 2H), 2.55-2.51 (t, J=15.2 Hz, 2H), 1.28-1.22 (t, J=7.2 Hz, 3H),
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)[N:3]=1.[H-].[Na+].I[CH3:33]>C1COCC1>[CH3:33][N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide (50 mg) was dissolved in THF (2.5 mL) and sodium hydride (60% w/w oil dispersion, 0.005 g, 1 eq.) was added at 0° C. After 5 minutes iodomethane was added (5 uL, 1.0 eq.) and the mixture was warmed to room temperature. After 10 h the solution was partitioned between water (3 mL) and ethyl acetate (3×5 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude was purified by flash chromatography on silica gel, eluting with a gradient from dichloromethane to dichloromethane-methanol (98:2) affording the title compound in 61% yield (0.02 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](N(CC)C(C)C)([CH3:33])[CH3:32].C(Br)C=C>C(Cl)Cl>[CH2:33]([NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1)[CH:31]=[CH2:32]
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1

Procedure:
To a solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.39 mmol) in CH2Cl2 (˜0.4 mL) was added N,N-diisopropylethylamine (90 μL, 0.52 mmol). Allyl bromide (35 μL, 0.40 mmol) was dissolved in CH2Cl2 (˜9.6 mL) and added to the amine mixture at a rate of 5.5 mL/hour. The resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed consecutively with H2O (5 mL), saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL). The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel (200:1:1 followed by 100:1:1—EtOAc:MeOH:NH4OH) followed by radial chromatography on silica gel (250:1:1—EtOAc:MeOH:NH4OH) afforded AMD9725 (36 mg, 21%) as a light yellow foam. 1H NMR (CDCl3) δ1.56-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.24-2.31 (m, 1H), 2.65-2.77 (m, 1H), 2.77-2.91 (m, 1H), 3.21 (d, 2H, J=5.7 Hz), 3.69 (s, 2H), 3.73 (s, 2H), 3.97 (d, 1H, J=16.8 Hz), 4.04-4.16 (m, 1H), 4.17 (d, 1H, J=16.8 Hz), 5.07 (d, 1H, J=9.9 Hz), 5.15 (dd, 1H, J=17.1, 1.2 Hz), 5.88 (ddt, 1H, J=17.1, 10.5, 6.0 Hz), 7.10-7.19 (m, 5H), 7.35 (d, 2H, J=7.8 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.45-7.57 (m, 1H), 7.58-7.68 (m, 1H), 8.69 (d, 1H, J 4.2 Hz); 13C NMR (CDCl3) δ20.83, 22.89, 28.67, 47.95, 51.11, 52.33, 53.17, 59.68, 110.37, 115.39, 118.11, 120.91, 121.66, 127.59, 128.07, 134.13, 136.17, 136.60, 137.48, 138.56, 146.38, 155.80, 156.94. ES-MS m/z 438.3 (M+H). Anal. Calcd. for C28H31N5.0.8H2O: C, 74.40; H, 7.27; N, 15.49. Found: C, 74.36; H, 7.25; N, 15.31.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[CH:9][O:10][C:11]=2[CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[CH:9][O:10][C:11]=2[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: OCCCCc1ocnc1-c1ccc(Cl)s1
Reactant: COc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccccc1OCCCCc1ocnc1-c1ccc(Cl)s1
Reaction time: 1 h

Procedure:
To a mixture of 4-(5-chloro-2-thienyl)-5-oxazolebutanol (800 mg), 2-methoxyphenol (770 mg), tributylphosphine (1.24 g) and tetrahydrofuran (10 ml) was added dropwise a toluene solution of diethyl azodicarboxylate (40%, 2.61 g) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(5-chloro-2-thienyl)-5-[4-(2-methoxyphenoxy)butyl]oxazole was obtained as an oil (420 mg, 37%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C(O[CH:14](N(C)C)[N:15]([CH3:17])[CH3:16])(C)(C)C>>[CH3:14][N:15]([CH3:17])[CH:16]=[C:7]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:8])[C:2]1=[O:1]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1O
Product: CN(C)C=C1CCCC(O)C1=O

Procedure:
2-Hydroxy-cyclohexanone (114 mg, 1.0 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (188 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][N:5]2[C:6]3[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([CH:18]=O)=[C:10]3[CH:4]2[CH2:3]1.B#B.CO.C(O)(=O)C>O1CCCC1>[CH3:1][N:2]1[CH2:25][CH2:24][N:5]2[C:6]3[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([CH3:18])=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CCN2c3ccccc3Cn3c(c(C=O)c4ccccc43)C2C1
Agent: B#B
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c2n(c3ccccc13)Cc1ccccc1N1CCN(C)CC21
Reaction time: 1 h

Procedure:
To a solution of 1.4 g of 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxaldehyde in 35 ml tetrahydrofuran is added 17 ml of 1M diborane in tetrahydrofuran. The reaction mixture is heated at reflux temperature for 5 hours. The reaction is then treated with 10 ml methanol and 3.5 ml acetic acid and heating is continued for an additional 1 hour. The solvent is evaporated under reduced pressure and the residue is dissolved in methylene chloride and washed with 5% sodium hydroxide solution. The methylene chloride layer is separated and the solvent evaporated under reduced pressure to yield 1,3,4,16b-tetrahydro-2,16-dimethyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine which is converted to the hydrochloride salt, mp 293°-298° dec.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=O)[C:13](=[N:15][OH:16])[CH3:14])[CH:8]=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2].[NH2:18][NH:19][C:20]([NH2:22])=[S:21]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[N:18][NH:19][C:20]([NH2:22])=[S:21])[C:13](=[N:15][OH:16])[CH3:14])[CH:8]=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)C(C)=NO)ccc1Cl
Reactant: NNC(N)=S
Product: CC(=O)Nc1cc(C(=NNC(N)=S)C(C)=NO)ccc1Cl
Yield: 92.6 %

Procedure:
3'-Acetamido-4'-chloro-2-hydroxyiminopropiophenone (70.75 g) was reacted with thiosemicarbazide (28.4 g) in the same manner as Example 1-(1) to give 3'-acetamido-4'-chloro-2-hydroxyiminopropiophenone thiosemicarbazone (84.36 g).
Reaction SMILES: [Na].[C:2]1([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][N:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:21][C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=O)C.Cl>C(O)C>[C:2]1([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][N:17]=2)[NH:14][C:13](=[O:18])[CH:12]3[C:22](=[O:21])[C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2cc(Sc3ccccc3)ncc2N1
Reactant: CCOC(=O)c1cccs1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2cnc(Sc3ccccc3)cc2C1C(=O)c1cccs1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Pellets of sodium metal (264 mg, 11.5 mmol) were added to dry ethanol (10 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, a slurry of 5-phenylthio-6-azaoxindole (560 mg, 2.3 mmol) in ethanol (5 mL) was added. The mixture was warmed to 50° C. at which point ethyl-2-thiophene carboxylate (0.55 mL, 4.6 mmol) was added. The mixture was then heated at reflux for 30 hours. After cooling to room temperature, the mixture was poured into ice/water and the pH adjusted to 1 by addition of 6N HCl solution. The precipitated solid was collected by filtration, dried and subjected to flash chromatography on silica gel using 9:1 chloroform/methanol as eluant. Fractions containing the desired product, 5-phenylthio-3-(2-thenoyl)-6-azaoxindole were combined and evaporated under reduced pressure to leave a gold solid (620 mg, 76%); m.p. 248°-252° C. (dec).
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH:21]([NH2:26])[CH2:20]1)=[O:18])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:15][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH:21]([NH:26][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:20]1)=[O:18])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N)C1
Reactant: O=C(Cl)COc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)C(NC(=O)COc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
Phenoxyacetyl chloride (0.15 mL, 1.06 mmol) was added dropwise to a stirred solution of 3-amino-4-hydroxy-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.23 g, 1.06 mmol) and TEA (0.18 mL, 1.27 mmol) in DCM (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes and a saturated solution of NaHCO3 was added. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 4-hydroxy-3-[(phenoxyacetyl)amino]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.36 g, 98% yield) that was used in the next step without further purification. C18H26N2O5 LCMS: Rt 2.03, m/z 351 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].C(=O)(O)[O-].[K+].[CH:15]1([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:22][CH2:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:1]=1
Reactant: OCC1CCCCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(OCC2CCCCC2)n1
Yield: 99.4 %

Procedure:
To cyanuric chloride (3.76 g, 20.0 mmol) dissolved in toluene (20 mL) was added potassium bicarbonate (2.80 g, 20.0 mmol) and 18-crown-6 (0.1614 g, 0.6 mmol) followed by dropwise addition of cyclohexylmethanol (2.5 mL, 20 mmol) in 15 mL of toluene (15 mL). The reaction mixture was allowed to stir at reflux for about 18 hours under nitrogen. The reaction mixture was passed through a plug of Celite and concentrated using a rotary evaporator and dried over night under vacuum to give 113 as an oil (5.212 g, 99% recovery).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=O.C1N(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.[OH:35][C:36]([CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)=[O:37]>CN(C=O)C.C(N(CC)CC)C>[CH3:1][NH:2][CH2:3][C:4]([CH:38]([CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)[C:36](=[O:35])[OH:37])=[O:6]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CNCC(=O)O
Agent: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O

Procedure:
The N-methyl glycine-linked DOTA-biotin conjugate was prepared by an analogous method to that used to prepare D-analine-linked DOTA-biotin conjugates. N-methyl-glycine (trivial name carcosine, available from Sigma Chemical Co.) was condensed with biotin-NHS ester in DMF and triethylamine to obtain N-methyl glycyl-biotin. N-methyl-glycyl biotin was then activated with EDCI and NHS. The resultant NHS ester was not isolated and was condensed in situ with DOTA-aniline and excess pyridine. The reaction solution was heated at 60° C. for 10 minutes and then evaporated. The residue was purified by preparative HPLC to give [N-methyl-N-biotinyl)-N-glycyl]-aminobenzyl-DOTA.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([OH:11])=[O:10].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1](=[N:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(S(=O)(=O)N=Cc2ccccc2)cc1

Procedure:
In the same manner as Example 2, 4.00 g (38 mmol) of benzaldehyde, 7.58 g (38 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of toluene were heated for 36 hours to afford 7.40 g (71%) of SULF-4 as a light tan powder: IR (Nujol) 3800-2600 (br), 1685, 1600, 1283, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ 9.05 (s, 1), 8.2-7.2 (m, 9).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]2)=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: OC1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: OC1CCN(c2ccc(F)cc2C(F)(F)F)C1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (4.6 g), 3-hydroxypyrrolidine (1.5 g), palladium(II) acetate (193 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.07 g) and cesium carbonate (16.8 g) in toluene (90 mL) was stirred under an argon gas atmosphere at 85° C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-65:35) to give the title compound (3.58 g, yield 84%) as a yellow oil.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.[O:18]([CH2:25][C:26](OCC)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.C(O)(=O)C>[O:27]=[C:26]([CH2:25][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)COc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1ccccc1)OC
Reaction time: 0.33 h

Procedure:
40.1 g. of dimethyl methylphosphonate were dissolved in 200 ml. of anhydrous tetrahydrofuran, to which 154 ml. of a 2N n-butyllithium solution in n-hexane were added dropwise whilst maintaining the temperature from -60°C. to -70°C. After stirring for 20 minutes, 15 g. of ethyl phenoxyacetate in 80 ml. of tetrahydrofuran were added to the solution. The mixture was stirred at the same temperature for 2 hours and then at room temperature overnight. The reaction mixture was neutralized with acetic acid and concentrated under reduced pressure. The residue was dissolved in a small amount of water and extracted with diethyl ether. The ethereal extracts were washed with an aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by distillation in vacuo to give 18.9 g. of the title compound having the following characteristics:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH:17]=1
Reactant: Brc1cncc(Br)c1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
Sodium hydride (1.53 g of 80% in mineral oil, 51 mmol) was slowly added to a solution of 4-fluorophenol (5.6 g, 50 mmol) in DMF (100 mL) as it was stirred and cooled (ice water bath) under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (5.9 g, 25 mmol) was added and the mixture was then heated at 90° C. (bath temperature) for 62 h. The mixture was cooled, diluted with water (150 mL), poured into 5N sodium hydroxide (150 mL), and extracted with diethyl ether (2×150 mL). The combined ether extracts were washed with water, dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel, using 5% ethyl acetate:hexane as eluent, to yield 1.4 g (21%) of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=[O:5].[C:12]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[C:22](=[O:27])[NH:21][N:20]=[CH:19]2)([CH3:15])([CH3:14])[CH3:13].CC([O-])=O.[K+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>O1CCOCC1.[Cu]I>[Br:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([N:21]2[N:20]=[CH:19][C:18]3[C:23](=[C:24]([F:26])[CH:25]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:17]=3)[C:22]2=[O:27])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)cc(F)cc1Br
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cc(F)cc(Br)c3C=O)ncc2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
To a solution of 102a (767 mg, 2.72 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one 101h (300 mg, 1.36 mmol) in dioxane (50 mL) was added KOAc (267 mg, 2.72 mmol), CuI (259 mg, 1.36 mmol), and 4,7-dimethoxy-1,10-phenanthroline (327 mg, 1.36 mmol). After bubbling nitrogen through the resulting solution for 30 min, the mixture was stirred at 90 degree for 10 h. It was allowed to cool down to room temperature and H2O (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic layers was washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with PE/EA (15:1) to afford 102b (172 mg, 30%). LCMS: [M+H]+ 421. 1H NMR (500 MHz, CDCl3) δ 10.20 (s, 1H), 8.20 (s, 1H), 7.49-7.51 (m, 3H), 7.25 (m, 1H), 1.36 (s, 9H).