Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][C:13](Cl)=[O:14].CCN(CC)CC>C(Cl)Cl>[Cl:11][CH2:12][C:13]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:14]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCCc2ccccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (3, 2.00 g, 15.0 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added chloroacetyl chloride (1.80 g, 16.0 mmol) followed by dropwise addition of Et3N (2.50 mL, 18.0 mmol). The reaction was stirred overnight under N2. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with 5% HCl (15 mL), water (2×15 mL), and saturated NaCl (15 mL). Dried over MgSO4, filtered, and concentrated to give 3.05 g of 4. This crude material was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>CN(C)P(N(C)C)(N(C)C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: O=Cc1ccccc1Cl
Reactant: Fc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=Cc1ccccc1Sc1ccccc1F
Yield: 76.8 %

Procedure:
A solution of 43.8 g 2-fluorothiophenol (I. Cervena et al., Collect. Czech. Chem. Commun. 44, 2139, 1979) in 85 ml of hexamethylphosphoramide is treated in a nitrogen atmosphere first with a solution of 13.6 g sodium hydroxide in 26 ml of water and then with 45.0 g of 2-chlorobenzaldehyde. Then the mixture is heated for 3.5 hours to 100° C. It is next poured into 500 ml of water and the product extracted with benzene. The extract is dried with magnesium sulfate and evaporated. The residue crystallizes after mixing with 120 ml of petroleum ether. There are obtained 57.1 g (77%) 2-(2-fluorophenylthio)benzaldehyde, crystallizing from benzene and melting in pure state at 56°-57° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[C:33](O)=[O:34])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[C:33](=[O:34])[NH:18][C:16]1[CH:17]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[C:13]([Cl:19])=[CH:14][CH:15]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (750 mg), (R)-N-Boc-2-piperidinecarboxylic acid (664 mg) and HBTU (1.37 g) in dry DMF (40 ml) containing N-methylmorpholine (1.2 ml) was stirred at room temp for 18 h. The mixture was then evaporated and the residue was purified by chromatography. Elution with 5:1 petrol:ethyl acetate gave a yellow oil (310 mg)
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18](=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH:21]=[C:18]1[CH2:17][CH2:16][N:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=2)[CH2:20][CH2:19]1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCC(=Cc3cccc(Cl)c3)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@@H](O)c1nccc(N2CCC(=Cc3cccc(Cl)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-1-{4-[4-(3-chloro-benzylidene)-piperidin-1-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 176, Step C, 0.62 g, 1.55 mmol) in methanol (8 mL) was added 1 N aqueous sodium hydroxide (1 mL) then stirred for 4 h at ambient temperature. The mixture was diluted with chloroform and washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound as a white solid, 0.31 g (61%). 1H NMR (CDCl3, 300 MHz) δ 1.51 (d, 3H), 2.46 (m, 2H), 2.56 (m, 2H), 3.07 (m, 2H), 3.77 (m, 2H), 4.35 (d, 1H), 4.69 (q, 1H), 6.36 (s, 1H), 6.40 (d, 1H), 7.07 (m, 1H), 7.12-7.28 (m, 3H), 8.18 (m, 1H); mp: 45-55° C.; MS (Cl) 330 (MH+); [α]D+16.8 (c 1.0, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(OCC)(=O)C.[Pd]>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAC was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 hour to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the solution was adjusted to 4 with aqueous NaOH. The mixture was extracted with more ethyl acetate. The combined organic layers were washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 hour. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. Ethyl 2fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=1)[CH3:2].Cl>C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(C(=O)OC)nc2c(C3CC3)cccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOc1cc(C(=O)O)nc2c(C3CC3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.0 mL of 5N NaOHaq was added to a solution of 1.10 g of methyl 4-ethoxy-8-cyclopropylquinoline-2-carboxylate in 5 mL of CHCl3/MeOH (1:1) and the mixture was stirred at room temperature for 3 hr. After the addition of 3.0 mL of 5N HCl aq, the mixture was extracted by CHCl3. The organic layer was washed by satd. brine, dried over NaSO4, then concentrated to afford 4-ethoxy-8-cyclopropylquinoline-2-carboxylic acid as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:13][CH3:14])([CH3:12])[CH3:11])[CH:5]=1)[CH3:2].[I:15]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([O:13][CH3:14])([CH3:11])[CH3:12])[CH:7]=[CH:8][C:9]=1[I:15])[CH3:2]
Reactant: CCOc1cccc(C(C)(C)OC)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOc1cc(C(C)(C)OC)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
To a solution of 1-ethoxy-3-(1-methoxy-1-methyl-ethyl)-benzene (5.15 g, 26.51 mmol) in acetonitrile (60 mL) were added N-iodosuccinimide (8.349 g, 37.11 mmol) and trifluoroacetic acid (1.02 mL, 13.26 mmol). The mixture was stirred at room temperature overnight. It was then concentrated in vacuo and the residue was taken in ethyl acetate. After washing with saturated solution of sodium bicarbonate, water and brine, the organic layer was dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 9.39 g of 2-ethoxy-1-iodo-4-(1-methoxy-1-methyl-ethyl)-benzene as light brown oil.
Reaction SMILES: C1(OC([N:10]2[CH2:15][CH2:14][C:13]([CH3:26])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(C)C)[CH:17]=3)[CH2:12][CH2:11]2)=O)C=CC=CC=1.Br.C(O)(=O)C>O>[OH:22][C:18]1[CH:17]=[C:16]([C:13]2([CH3:26])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)Oc1cccc(C2(C)CCN(C(=O)Oc3ccccc3)CC2)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC1(c2cccc(O)c2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A solution of 4-methyl-4-(3-(1-methylethoxy)phenyl)-1-piperidinecarboxylic acid phenyl ester (Preparation 52, 2.4 g, 6.80 mmol) in 1:1 47% aqueous hydrobromic acid:glacial acetic acid (8 ml) was heated under reflux for 16 h. The solution was allowed to cool to room temperature and water (5 ml) was added. The aqueous layer was extracted with methyl tert-butyl ether (3×10 ml) to remove phenol as by-product. The pH was adjusted to 10.3-10.5 with 15% w:v aqueous sodium hydroxide solution and the mixture was left at room temperature for 2 h to allow the product to precipitate. After cooling to 0° C. the precipitate was filtered and washed with cold water (5 ml) to give 4-(3-hydroxyphenyl)-4-methylpiperidine as a solid (776 mg, 60%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:9]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CCl)ccc1CC1CCCCC1
Temperature: 75 °C
Yield: 100 %

Procedure:
To a solution of (4-(cyclohexylmethyl)-3-(trifluoromethyl)phenyl)methanol (0.060 g, 0.220 mmol) in toluene (2 mL) was added thionyl chloride (1.32 mmol). The reaction was heated to 75° C. for 3 h and quenched with water at 0° C. The mixture was extracted with hexanes (twice). The combined organics were washed with saturated NaHCO3(aq), dried over MgSO4, and concentrated to give the title compound as an oil (0.220 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.06 (m, 2H), 1.12-1.23 (m, 3H), 1.61-1.74 (m, 6H), 2.66 (d, J=6.95 Hz, 2H), 4.59 (s, 2H), 7.30 (d, J=7.96 Hz, 1H), 7.47 (d, J=7.96 Hz, 1H), 7.63 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH2:10]([NH:13][OH:14])[CH2:11][CH3:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:3]2[O:2][C:11]([CH:10]=[N+:13]([CH2:5][CH2:6][CH3:7])[O-:14])=[CH:12][CH:4]=2)=[CH:5][CH:4]=1
Reactant: CCCNO
Reactant: COc1ccc(S)cc1
Product: CCC[N+]([O-])=Cc1ccc(Sc2ccc(OC)cc2)o1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 4-methoxybenzenethiol and N-n-propylhydroxylamine. The title compound was isolated in 76.6% yield as slightly yellowish crystals, m.p. 63.0° C. (Rf=0.17 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][N:8]([N:11]=CC2C=CC=CC=2)[C:7]1=[O:19].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.CN(C)C=O>Cl.[Pd]>[ClH:21].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:32][C:31]([CH:33]=[N:11][N:8]3[CH2:9][CH2:10][N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])[C:7]3=[O:19])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Reactant: CN(C)CCCN1CCN(N=Cc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.2 %

Procedure:
A solution of 4.8 g (0.017 mole) of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone (prepared as described in Part III above) in 125 ml of 2N HCl is treated with 1 g of 5% Pd/C (50% H2O) and placed on the Parr reduction apparatus, with the theoretical amount of H2 being absorbed over a 30 minute period. The catalyst is removed by filtration and the solvent is removed in vacuo. The residual oil is dissolved in 100 ml of dimethylformamide and treated all at once with 3.51 g (0.0170 mole) of 5-(4-chlorophenyl)-2-furancarboxaldehyde (prepared as described in U.S. Pat. No. 4,882,354 to Huang et al., (issued Nov. 21, 1989), assigned to Norwich Eaton Pharmaceuticals, Inc., see Example 3, cols. 7 & 8, hereby incorporated by reference herein) with dissolution. A 1.0 g portion of 3 Angstrom molecular sieves is added and the reaction is stirred 16 to 18 hours at ambient temperature. The resulting mixture is heated to reflux with dimethylformamide being added to dissolution. The molecular sieves are removed by filtration and the solvent is removed in vacuo. The residual semi-solid is crystallized by trituration with ether. The solid is recrystallized from S.D.A. #32, (activated charcoal) and dried in a vacuum pistol over refluxing ethyl acetate to yield 2.7 g of 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-(3-dimethylaminopropyl)-2-imidazolidinone hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[CH:18][N:19]([CH3:20])[C:15]=4[CH:14]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][Mg]Br>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[CH:18][N:19]([CH3:20])[C:15]=4[CH:14]=3)([OH:12])[CH3:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1cnc2ccc(C(=O)c3cnc4ccc(Cl)nn34)cc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cnc2ccc(C(C)(O)c3cnc4ccc(Cl)nn34)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(3-methyl-3H-benzoimidazol-5-yl)-methanone (Stage 185.4, 560 mg, 1.796 mmol) was dissolved in THF (50 mL) with heating under Argon. The solution was let to cool down and methylmagnesium bromide (3 M, 0.719 mL) was added. The mixture was stirred at rt for 1 h. To complete the reaction, more methylmagnesium bromide (3 M, 0.30 mL) was added and the RM was stirred 30 min longer. It was then diluted with EtOAc and washed with a saturated NaHCO3 sol. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dried under vacuum overnight to afford the title compound as an off white foam (tR 1.84 min (conditions 8), MH+=328).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=3[CH3:17])=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cn2)s1
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3sc(NC(C)=O)nc3C)nc2)cc1

Procedure:
Using an analogous procedure to that described in Example 83, N-[5-(5-aminopyridin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide was reacted with 4-methoxyphenylsulfonyl chloride to give the title compound; 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.47 (s, 3H), 3.81 (s, 3H), 7.09 (d, 2H), 7.55 (m, 2H), 7.73 (d, 2H), 8.26 (m, 1H), 10.42 (s, 1H), 12.05 (s, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:24]2)=[CH:29][CH:30]=1
Reactant: N[C@@H]1CCN(Cc2ccc(F)cc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccc(F)cc3)C2)cn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
A mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg, 1.41 mmol), (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (565 mg, 2.11 mmol) and triethylamine (928 mg, 9.17 mmol) was stirred at 100° C. for 6 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (35% EtOAc/hexane˜50% EtOAc/hexane) to give ethyl (2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (245 mg, 47%) as an oil.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:47])[CH2:24][C@@H:25]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:21].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1COCC1.CO>[CH2:20]([O:22][C:23](=[O:47])[CH2:24][C@@H:25]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[N:26]([CH3:1])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)(=[O:28])=[O:29])[CH3:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (3.9 g, 15 mmol) was added to a solution of sulfonamide 16-6 (4.5 g, 10 mmol) in THF (30 mL). To this solution was added a solution of diethyl azodicarboxylate (2.4 mL, 15 mmol) in THF/MeOH (10 mL/2.02 mL). A vigorous exotherm occurred and the reaction was stirred overnight at room temperature. The dark mixture was concentrated. The dark oily residue was purified by flash chromatography (40% EtOAc/hexanes) to give the desired product 16-7.
Reaction SMILES: C(OC1C(N)=C([C:15]2[N:19]=[C:18]([C:20]3[S:24][C:23]([NH:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=4)=[N:22][C:21]=3[NH2:38])[O:17][N:16]=2)C=CC=1C(O)=O)(C)(C)C.[OH-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[NH2:25][C:26]1[CH:27]=[C:28]([C:15]2[N:19]=[C:18]([C:20]3[S:24][C:23]([NH:25][C:26]4[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=4)=[N:22][C:21]=3[NH2:38])[O:17][N:16]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc(Nc2nc(N)c(-c3nc(-c4ccc(C(=O)O)c(OC(C)(C)C)c4N)no3)s2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc(N)c(-c3nc(-c4cccc(N)c4)no3)s2)cc(OC)c1OC
Yield: 189 %

Procedure:
A solution of 267 mg (0.49 mmol) of 3-(3-t-butyloxycarboxy-aminophenyl)-5-[2-[(3,4,5-trimethoxyphenyl)amino]-4-amino-5-thiazolyl]-1,2,4-oxadiazole (prepared according to Example B(2)) in 3 mL of 50% trifluoroacetic acid in dichloromethane was stirred for 60 minutes at ambient temperature and then poured onto ice. 3N NaOH was added dropwise until the solution was basic, and the mixture was extracted with EtOAc. The organic layer was washed with NaHCO3 and brine, and dried over Na2SO4. The solvent was removed to yield 204 mg (95% yield) of the title compound as a light yellow solid.