Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])C.[NH:15]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[NH2:16].Cl>C(O)C.O>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[N:15]1[C:8]2[C@@H:9]3[CH2:10][C@@H:11]3[CH2:12][C:7]=2[C:5]([C:4]([OH:3])=[O:14])=[N:16]1
Reactant: NNc1cnccn1
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a stirred suspension of 2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate (300 mg, 1.28 mmol) in ethanol (5 mL) was added 2-hydrazinylpyrazine (141 mg, 1.28 mmol) followed by 6 N HCl (0.5 mL, 3.0 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with H2O and extracted with DCM. The combined organic phases were washed with H2O, dried over MgSO4, and concentrated. Purification by silica gel flash chromatography gave the title compound (150 mg). LCMS m/z=271.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.7 and 3.4 Hz, 1H), 1.22-1.28 (m, 1H), 1.39 (t, J=7.1 Hz, 3H), 2.26-2.30 (m, 1H), 2.77-2.82 (m, 1H), 2.87 (d, J=16.6 Hz, 1H), 2.98 (dd, J=16.6 and 6.3 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 8.40 (dd, J=2.6 and 1.5 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 9.39 (d, J=1.3 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[CH3:16][C:17]1[S:21][C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:16][C:17]1[S:21][C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:24][CH2:23]2)=[N:19][C:18]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1sc(N2CCNCC2)nc1-c1ccccc1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1sc(N2CCN(C(=O)Nc3cccnc3)CC2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (229 mg, 0.848 mmol), 1-(5-methyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.148 ml, 0.848 mmol) in dimethylsulfoxide (2.6 ml) was stirred at 70° C. for 5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 68.4 mg (23.4%) of the desired product as a solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[CH2:12]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:9].[ClH:10].[ClH:10].[C:1]1([NH:7][C:8](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][CH2:24]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: SCCCN1CCN(CCc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O
Product: OC(Nc1ccccc1)=[SH]CCCN1CCN(CCc2ccccc2)CC1
Yield: 67.9 %

Procedure:
The procedure described in Example 2 was followed, using 1.4 g of phenyl isocyanate, 4.0 g of 3-(4-phenethylpiperazin-1-yl)propanethiol dihydrochloride, 2.4 g of triethylamine and 50 ml of methylene chloride, to give 1.9 g (35% of theory) of N-phenyl-S-[3-(4-phenethylpiperazin-1-yl)propyl]thiocarbamate dihydrochloride monohydrate as a white crystalline solid, M.p. 272°-275° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:22]([OH:24])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].B(F)(F)F.[CH3:29]COCC.[ClH:34]>CO.C(O)C>[ClH:34].[CH3:29][O:23][C:22](=[O:24])[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[NH:5][C:3](=[O:4])[CH2:2][NH2:1].[ClH:34]
Reactant: NCC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOCC
Agent: Cl
Agent: FB(F)F
Solvent: CCO
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CN
Temperature: 80 °C

Procedure:
Nα-Glycyl-Nε-carbobenzoxy-L-lysine (10.1 g.) prepared by the method of Rao et al. (J. Biol. Chem., 198,507 1952) was dissolved in methanol (150 ml.) and treated with boron trifluoride etherate (30 ml.) and the mixture heated at 80°C for 25 hours. The solvent was removed in vacuo and the residual oil dissolved in water (100 ml.) and extracted with ether (2 × 50 ml.) and the extracts discarded. The aqueous solution was adjusted to pH 9.0 with 4N sodium hydroxide, saturated with sodium chloride and extracted with ethyl acetate (3 × 50 ml.). The combined extracts were washed with saturated brine, dried (MgSO4) and the solvent removed in vacuo to give a residual oil which was redissolved in ethanol (10 ml.) and treated with an excess of an ethereal solution of hydrogen chloride. The solid was filtered and recrystallised from isopropanol/diisopropyl ether to give Nα-glycyl-Nε-carbobenzoxy-L-lysine methyl ester hydrochloride, needles (4.5 g.) m.p. 122°C. (Found: C, 53.0; H, 6.8; N, 10.8. C17H25N3O5. HCl requires: C, 52.6; H, 6.7; N, 10.8%).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:23]([CH2:24][CH3:25])=[CH:22][N:13]([C@@H:14]2[O:21][C@H:18]([CH2:19]O)[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:26])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:46]=[N+:47]=[N-:48].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:46]([CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[C:23]([CH2:24][CH3:25])[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:26])[CH2:15][C@@H:16]1[OH:17])=[N+:47]=[N-:48]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)nc1NC(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)nc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.1 %

Procedure:
A mixture of 1.436 g of N-benzoyl-2'-deoxy-5-ethylcytidine, 1.072 g of triphenylphosphine, 1.304 g of sodium azide and 1.360 g of carbon tetrabromide in 16 ml of dimethylformamide was stirred at room temperature for 20 hours. 8 ml of methanol were added, the mixture was stirred for 30 minutes and then evaporated. The residue was suspended in 80 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed with water and evaporated. The residue was subjected to flash chromatography on a column of silica gel using ethyl acetate for the elution, there being obtained 1 g of 5'-azido-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine in the form of a white crystalline solid of melting point 125°-126° C.
Reaction SMILES: S[CH:2]([CH3:6])[C:3]([OH:5])=O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)[S:24]([O-])(=O)=O.[F:30][C:31]([I+]C1C=CC=CC=1)([F:36])[C:32]([F:35])([F:34])[F:33]>C(Cl)Cl>[F:30][C:31]([F:36])([CH:2]([CH3:6])[C:3]([OH:5])=[S:24])[C:32]([F:35])([F:34])[F:33]
Reactant: FC(F)(F)C(F)(F)[I+]c1ccccc1
Reactant: CC(S)C(=O)O
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: CC(C(O)=S)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
2.0 ml of methylene chloride, 0.06 ml (0.68 mmol) of 2-mercaptopropionic acid and 140 mg (0.68 mmol) of 2,6-di-tert-butyl-4-methylpyridine were charged in a flask, and 320 mg (0.68 mmol) of pentafluoroethylphenyliodonium trifluoromethanesulfonate was added thereto in small portions while stirring at room temperature, followed by stirring the mixture at room temperature for 20 minutes. The resulting precipitate was filtered, subjected to column chromatography of silica gel and, after eluting iodobenzene with pentane, the desired product was eluted with diethyl ether. Diethyl ether was distilled off from the eluate to obtain 2-pentafluoroethylthiopropionic acid as a colorless liquid. A sample of the product was purified by gas chromatography. Yield, 81%.
Reaction SMILES: O[Li].O.[CH2:4]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:13]([O:15]CCC(C)C)=[O:14])[CH2:5][CH:6]([CH3:8])[CH3:7].Cl>O.CO.C1COCC1>[CH2:4]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:13]([OH:15])=[O:14])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CCOC(=O)c1cc(OCCC(C)C)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.2 %

Procedure:
4.05 g (96.6 mmol) LiOH.H2O were dissolved in a mixture of 100 mL H2O, 30 mL methanol and 40 mL THF. 5.2 g (16 mmol) 9 were added and it was stirred at r.t. for 20 h, during this time turning into a yellow, homogeneous solution. Most of the THF and methanol were taken off by rotovapping, the remaining solution was acidified with 2 N HCl and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried with MgSO4 and put under vacuum, yielding 3.9 g (96%) of a yellow solid, which was pure by NMR. For characterization, a sample was recrystallized from ethyl acetate. mp 142° C.; 1H NMR (CDCl3) δ 8.53 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 7.98 (t, J1=2.4 Hz, J2=2.4 Hz, 1H), 7.94 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H, PhOCH2CH2CH(CH3)2), 1.99-1.80 (m, 1H), 1.80-1.70 (m, 2H), 1.01 (d, J=6.3 Hz, 6H, CH(CH3)2); 13C NMR (acetone-d6) 165.52, 160.75, 150.12, 133.90, 122.35, 116.67, 113.68, 68.41, 38.33, 25.68, 22.74; ESI-MS m/z 252 [M−1]+.
Reaction SMILES: [OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(-c2ccc(CC(=O)O)cc2)cc1)[C@H](O)CCc1cccnc1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(-c2ccc(CC(=O)N3CCCC3)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
Prepared according to the method described in Example 66. (1S,2R)-[4′-(2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy)-biphenyl-4-yl]-acetic acid (Example 55, 0.07 g),pyrrolidine (0.014 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) were dissolved in dimethylformamide (2 ml) and stirred for 16 hours at room temperature. The dimethylformamide was removed by vacuum distillation, the residue was dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a glass (0.068 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(O)COCc1ccccc1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Ethyl 4-benzyloxyacetoacetate (42.1 g) synthesized according to the method describe in U.S. Pat. No. 5,399,722 was dissolved in methanol (300 mL) and sodium borohydride (3.03 g) was added at a temperature of from 5° C. to 10° C. The mixture was stirred for 1 hr and water (300 mL) was added. The solvent was mostly evaporated, and the organic layer extracted twice with MTBE (300 mL) was washed twice with 2% sodium hydrogen carbonate (100 mL) and washed twice with saturated brine (150 mL), dried over anhydrous magnesium sulfate and filtrated. MTBE was evaporated to give ethyl (±)-4-benzyloxy-3-hydroxybutanoate (38.8 g). To a solution of lithium diisopropylamide 1.5 M cyclohexane solution (190 mL) in THF (200 mL) was added a solution of ethyl (±)-4-benzyloxy-3-hydroxybutanoate (29.4 g) in THF (50 mL) at a temperature of from −78° C. to −60° C. and the temperature was raised to −20° C. Separately, 2-iodoethanol (34.4 g) and ethyl vinyl ether (23.1 g) were mixed in the presence of p-toluenesulfonic acid monohydrate (20 mg) to give 2-(1-ethoxyethoxy)ethyl iodide (47.9 g) and 39.3 g thereof was added dropwise at a temperature near −20° C. to 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was poured into a 1N aqueous hydrochloric acid (450 mL), and the mixture was extracted twice with MTBE (200 mL) and washed with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated and methanol (300 mL) and p-toluenesulfonic acid monohydrate (5.3 g) were added to the residue. The mixture was stirred at room temperature for 6 hr. Triethylamine (2.0 g) was added to the reaction mixture and the solvent was mostly evaporated. The residue was extracted with ethyl acetate (300 mL). The organic layer was washed with water (150 mL) and saturated aqueous sodium hydrogen carbonate solution (150 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated. Diisopropyl ether (120 mL) was added to the residue and the mixture was recrystallized to give the title compound (5.65 g) (yellow fine crystals). The peak of syn-form (1′R*,2R*-body) was not detected in NMR and HPLC under the following conditions.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][C@@H:18]3[F:23])([CH3:16])[CH:14]=[CH:13][CH2:12]4)[C@H:9]([CH3:24])[CH2:8][C:7]=2[CH:6]=1)(=O)C.BrN1C(=[O:31])CCC1=O.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>CS(C)=O.O.C(OCC)(=O)C>[F:23][C@H:18]1[CH2:17][C@@:15]2([CH3:16])[C@@H:11]([CH2:12][C@H:13]([OH:31])[CH2:14]2)[C@H:10]2[C@H:19]1[C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=1[CH2:8][C@H:9]2[CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C=CC[C@@H]12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1C[C@H](O)C[C@@]1(C)C[C@@H]2F
Temperature: 0 °C

Procedure:
A solution of 1.67 g (5.22 mmol) of 3-acetyloxy-11βfluoro-7α-methylestra-1,3,5(10),16-tetraene in 30 ml of DMSO and 2.4 ml of water is replaced in portions with 1.36 g of N-bromosuccinimide while being stirred at 0° C., the cold bath is removed after the addition of NBS is completed, and it is stirred for 45 more minutes at room temperature. For working-up, the reaction mixture is poured into ice water, extracted with ethyl acetate, the organic phase is washed with water and dried on sodium sulfate. The crude bromohydrin (2.3 g) is then taken up in 25 ml of dry tetrahydrofuran, mixed with 5 ml (18.6 mmol) of tributyl tin hydride, a first spatula tip full of AIBN (a total of 200 mg dispersed over the reaction time), and stirred for 10 hours at a bath temperature of 80° C. under an argon atmosphere. For working-up, it is diluted with ethyl acetate, the organic phase is washed with dilute hydrochloric acid and water and dried on sodium sulfate. For saponification, the crude product is dissolved in 50 ml of methanol and 5 ml of dichloromethane, and it is mixed with 2.0 g of potassium carbonate. The reaction mixture is stirred for 1.5 hours under argon and poured into ice water for working-up. It is made hydrochloric with dilute acid, and it is extracted with ethyl acetate. The organic phase is washed with water and dried on sodium sulfate. The crude product is chromatographed on silica gel (chloroform-tert-butylmethylether, gradient of up to 95:5), yield 1.16 g (75%), melting point 239–240° C. while decomposing, [α]D+96.8° (c 0.51 methanol).
Reaction SMILES: C([O:5]C(NOCC(O)=O)=O)(C)(C)C.C(OCC)(=O)C.[CH:20]1([N:26]=[C:27]=[N:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.ON1C(=O)CCC1=O>C(#N)C>[CH:29]1([NH:28][C:27]([NH:26][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:5])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NOCC(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyloxycarbonylaminoxy acetic acid was dissolved in ice-cooled ethyl acetate or acetonitrile and treated with N,N′-dicyclohexylcarbodiimide (1.0 equivalent) and N-hydroxysuccinimide (1.0 equivalent). The reaction mixture was stirred at room temperature overnight. The N,N′-dicyclohexylurea formed was removed by filtration and the filtrate was evaporated to dryness in vacuo. The crude Boc-AOA-OSu was either used directly in the next step or purified by recrystallisation from chloroform. Adopted from Kurth et al. J. Med. Chem. 1993, 36, 1255.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=2)=[CH:9][C:8]=1[CH2:33][CH3:34])(=O)=O.C([Sn](CCCC)(CCCC)[C:42]1[N:43]=[CH:44][S:45][CH:46]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:33]([C:8]1[CH:9]=[C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=2)[CH:11]=[CH:12][C:7]=1[C:42]1[N:43]=[CH:44][S:45][CH:46]=1)[CH3:34]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CCc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1-c1cscn1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a stirred solution of 2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl trifluoromethanesulfonate (183 mg, 0.33 mmol) in dioxane (5 ml) was added 4-(tributylstannyl)thiazole (135 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol), lithium chloride (35 mg, 0.82 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:2) to give title compound (25 mg, 15% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([CH3:38])[C:29]1=[O:39]>C(Cl)(Cl)(Cl)Cl>[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([CH2:38][Br:1])[C:29]1=[O:39]
Reactant: Cc1nc2ccccc2n(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(=O)c(CBr)nc2ccccc21

Procedure:
N-bromosuccinimide (3.36 g., 0.0189 mol.) and benzoyl peroxide (0.06 g.) were added to a solution of 1,3-dimethyl-2(1H)-quinoxalinone (3.0 g., 0.017 mol.) in carbon tetrachloride (250 ml.). The mixture was heated at reflux for four hours. Removal of the solvent left a tan solid. Chromatography on silica gel with methylenechloride as the eluent gave a tan solid. Recrystallization from methylene chloride gave light tan needles. (2.33 g., m.p. 192.5°-193.5°. 53%).
Reaction SMILES: [K+].[C:2]([O:6][C:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](/[CH:18]=[CH:19]/[C:20]2[CH:28]=[CH:27][C:23]([C:24]([O-:26])=O)=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])=[C:13]([Cl:32])[CH:12]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:66][C:67]1[CH:76]=[CH:75][C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]=1>C(Cl)Cl>[C:2]([O:6][C:7](=[O:8])[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](/[CH:18]=[CH:19]/[C:20]2[CH:28]=[CH:27][C:23]([C:24](=[O:26])[NH:66][C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=4)[N:68]=3)=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])=[C:13]([Cl:32])[CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: Nc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(/C=C/c2ccc(C(=O)[O-])cc2[N+](=O)[O-])c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(/C=C/c2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[N+](=O)[O-])c(Cl)c1
Reaction time: 0.5 h

Procedure:
To 4-{(E)-2-[4-(2-tert-butoxycarbonylethyl)-2,6-dichlorophenyl]-vinyl}-3-nitrobenzoic acid potassium salt (280 mg, 0.56 mmol) in DCM (6 mL) was added diisopropylethylamine (292 μL, 1.68 mmol) and HATU (320 mg, 0.84 mmol) and the solution was stirred for 30 min. To this was added 2-aminoquinoline (96 mg, 0.66 mmol) and the mixture was stirred 18 h. The reaction mixture was partitioned between ethyl acetate and water, the organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate/heptane to obtain 3-(3,5-dichloro-4-{(E)-2-[2-nitro-4-(quinolin-2-ylcarbamoyl)-phenyl]-vinyl}-phenyl)-propionic acid tert-butyl ester as a white solid. MS (m/z) 592.1 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 11.58 (s, 1H), 8.74 (d, J=1.89 Hz, 1H), 8.43-8.48 (m, 2H), 8.36-8.41 (m, 1H), 8.16 (d, J=8.34 Hz, 1H), 7.99 (d, J=7.33 Hz, 1H), 7.91 (d, J=8.21 Hz, 1H), 7.77 (ddd, J=8.40, 6.95, 1.33 Hz, 1H), 7.56 (dd, J=15.03, 1.14 Hz, 1H), 7.49 (s, 2H), 7.48 (d, J=16.82 Hz, 1H), 7.36 (d, J=16.82 Hz, 1H), 2.85 (t, J=7.26 Hz, 2H), 2.59 (t, J=7.39 Hz, 2H) 1.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.C([N:23]([CH2:26]C)[CH2:24][CH3:25])C.ClC(O[CH2:32][CH3:33])=O>C1(C)C=CC=CC=1>[CH3:26][N:23]([C@@H:24]([CH3:25])[CH2:32][CH3:33])[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[C@H](C)N(C)C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Yield: 23.6 %

Procedure:
Operations are carried out as for Example 7, starting from 1.7 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 2.1 g of triethylamine, 0.75 g of ethyl chloroformate and 0.96 g of N-methyl 2(S)-butanamine, HCl in 60 ml of toluene. After chromatography and recrystallization in cyclohexane, 0.5 g of N-methyl N-(1-(S)-methyl propyl) 1-(2-chlorophenyl) isoquinoline 3-carboxamide melting at 134° C. is obtained. αD27 =+53.7° (0.5% in CHCl3).