Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 8.5 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol), Piperidine (102 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 232 (46.2 mg, yield: 8.5%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.78-7.77 (m, 2H), 7.50-7.40 (m, 1H), 7.18 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.64 (s, 4H), 3.16 (s, 2H), 1.63-1.57 (m, 4H) ESI-MS: m/z=543 [M+H+]
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([C@@:1]2([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cn([C@@]2(C(=O)c3ccc([N+](=O)[O-])cc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 58 %

Procedure:
Thymidine (2.42 g; 10 mmol) is dried by coevaporation in pyridine, then taken up in 200 ml of anhydrous pyridine and cooled to 4° C. p-Nitrobenzoyl chloride (2.04 g; 11 mmol) is added. The temperature is allowed to rise and the reaction is left overnight at room temperature. The reaction is stopped with 5 ml of saturated sodium bicarbonate. The reaction mixture is concentrated and then taken up in 500 ml of chloroform. The organic solution obtained is washed with 2×500 ml of 0.5 M NaHCO3 and then with 250 ml of saturated NaCl. The aqueous phases are counter-extracted with 100 ml of CHCl3. The organic phases are evaporated. The pure product is obtained by column chromatography on silica. It is eluted with 5% of methanol in chloroform. Yield=58%.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[C:45]([NH:47]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:47][C:45]1[CH:44]=[C:14]([CH:13]=[C:12]([O:11][CH2:10][C:7]2[S:8][CH:9]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[N:6]=2)[CH:46]=1)[C:15]([NH:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)(=[O:35])=[O:36])[CH:28]=[CH:27][C:19]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:16]
Reactant: [H][H]
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cc(NC(=O)OCc2ccc([N+](=O)[O-])cc2)cc(OCc2nc(C(C)(C)C)cs2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cc(N)cc(OCc2nc(C(C)(C)C)cs2)c1
Yield: 42.1 %

Procedure:
Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]-5-(4-nitrobenzyloxycarbonylamino)benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (0.50 g, 0.57 mmol) was dissolved in a mixed solution of ethanol (10 ml) and tetrahydrofuran (10 ml), 10% palladium-carbon (0.10 g) was added to the solution, and the mixture was stirred at room temperature for 3 hours in an atmosphere of hydrogen. The reaction solution was filtered and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent=acetone:chloroform=3:100) and crystallized from acetonitrile to give ethyl 2-[3-amino-5-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4- chlorophenylsulfonyl)propyl]phenoxyacetate (0.17 g, 0.24 mmol, 43%) as light yellow crystals. Its structure is shown in Table 30.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].CC[O-:15].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>CO.CCCCCC.C1(C=CC(O)=CC=1)O>[C:10]([OH:11])(=[O:15])[CH:8]=[CH2:6].[C:17]([OH:20])(=[O:3])[CH:18]=[CH2:19].[CH2:10]([OH:11])[C@H:8]([C@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:12])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: CC[O-]
Reactant: C=CC(=O)Cl
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: C=CC(=O)O
Temperature: 17 °C
Reaction time: 10 h

Procedure:
9.1 g mannitol (D(-)-Mannitol, Merck, for determination of boric acid) is mixed to an emulsion in 120 ml methanol (Merck, dried for analysis purposes) in a round flask, and is subsequently dissolved through boiling in reflux. 18 g of sodium ethylate is then slowly added (Merck, 30% in methanol) and boiled in reflux for one hour. A felt of long needles is formed. Methanol is then evaporated off in a vacuum and the mixture is mixed to an emulsion four times in n-hexane and once again the solvent is removed and the mixture is dried in a desiccator. 11.5 g of a light yellow crystaline substance is obtained. This is mixed to an emulsion in 120 ml n-hexane in a 250 ml round flask and maintained at 17 degrees C. Under heavy agitation, 9.1 g acryloyl chloride is slowly added (Merck, stabilised for synthesis). After 5 hours of agitation and 10 hours standing, 0.1 g of hydroquinone is added and the mixture is dried in a vacuum. 21.3 g of a mannitol diacrylate and common salt mixture is formed. The mixture is dissolved in 200 ml deionised water and subsequently, by means of an ion exchanger, (Amberlite IR 120, acidic) separated from the common salt. 0.1 g hydroquinone is introduced into the eluate, the water is removed and drying in a desiccator is then undertaken. 15.3 g of a light yellow substance remains. This is completely soluble in water or in acrylic acid. It is hard to dissolve in acetone, methanol, ethanol or ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:28]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(N)c1ccccc1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nc(-c3ccccc3)ncc2C1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step B, 509 mg, 2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in absolute ethanol (4 mL) was heated to reflux for about 3 d, cooled to room temperature, and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (Biotage Flash 40S™, 10→15% ethyl acetate/hexanes) to give 304 mg (49%) of the title compound of Example 101, Step C as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H), 1.50 (s, 9H); MS (APCI) 312 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(N(C)C)=C(C)C.C(N(CC)C(C)C)(C)C.[C:41]([O:45][C:46](=[O:49])[CH2:47][NH2:48])([CH3:44])([CH3:43])[CH3:42]>ClCCl>[C:41]([O:45][C:46](=[O:49])[CH2:47][NH:48][C:14]([C:13]1[CH:12]=[N:11][C:10]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:17]=1)=[O:15])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a suspension of 3.66 g 5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid in 40 ml dichloromethane was added 1.469 g Ghosez's reagent ((1-chloro-2-methyl-propenyl)-dimethyl-amine)) and the mixture was stirred at ambient temperature for 30 min. To the resulting solution was added 3.224 g N,N-diisopropylethylamine and 1.44 g glycine-t-butylester and the mixture was stirred at ambient temperature for 30 min. The reaction mixture was quenched by addition of 10% aqueous citric acid. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to 1:1 to yield 4.10 g of the title compound as white foam. MS (EI): 477.0608 (M−H).
Reaction SMILES: [H-].[K+].[CH2:3]([OH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.I[CH2:13][Sn:14]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:23]([Sn:14]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][O:11][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCCc1ccccc1
Temperature: 0 °C
Yield: 87.7 %

Procedure:
Potassium hydride (35 wt % in mineral oil, 2.29 g, 20.0 mmol, 2.0 equiv) was stirred in hexanes (10 mL) for 5 min, and then stirring was stopped and the solid allowed to settle. Most of the hexanes layer was removed by pipette, and the residual solvent removed under vacuum. The resulting dry KH powder was suspended in THF (20 mL) and phenethyl alcohol (1.22 g, 10.0 mmol, 1 equiv) was added (causing gas evolution). After stirring at 23° C. for 2.5 h, a thick precipitate formed. The mixture was cooled to 0° C. and a solution of iodomethyltributyltin (prepared according to Seitz, et al., Synth. Commun. (1983), vol. 13, 129) (6.46 g, 15.0 mmol, 1.5 equiv) in THF (15 mL) was added via cannula over 10 min. The mixture was warmed to 23° C. for 3.5 h, and then cooled to −78° C. The reaction was quenched with saturated aqueous NH4Cl solution (25 mL), warmed to 23° C., and extracted with Et2O (200 mL). The organic extracts were dried over MgSO4, filtered, and concentrated. Purification of the residue by flash column chromatography (hexanes) afforded tributyl-phenethyloxymethyl-stannane (3.73 g, 88% yield) as a colorless liquid. Rf=0.63 (4% EtOAc in hexanes). IR (cm−1) 2955, 2924, 2852, 1464, 1082. 1H NMR (CDCl3) δ0.90 (t, J=7.2, 15H), 1.31 (sextet, J=7.4, 6H), 1.50 (quintet, J=7.4, 6H), 2.86 (t, J=7.0, 2H), 3.54 (t, J=7.0, 2H), 3.75 (s, 2H), 7.15-7.33 (m, 5H). 13C NMR (CDCl3) δ9.01, 13.66, 27.28, 29.12, 36.36, 61.94, 76.38, 125.94, 128.17, 128.91, 139.50.
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: Oc1cccc(F)c1
Reactant: C[C@@H](CCl)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cccc(F)c1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To the compound (500 mg) obtained in Step 3 were added 3-fluorophenol (84 μl), potassium carbonate (250 mg) and DMF (2 ml), and the mixture was stirred overnight at 95° C. The reaction mixture was diluted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound as a crude product.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[OH-].[Na+].Br[C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:3]1[N:2]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[N:1]=[CH:6][CH:5]=[CH:4]1
Reactant: C[C@H](Br)C(=O)O
Reactant: O=c1cccn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)n1ncccc1=O
Temperature: 90 °C

Procedure:
To 3(2H)-pyridazinone (1.19 g, 12.3 mmol) was added 5 N sodium hydroxide solution (4.9 ml) followed by (2S)-2-bromopropanoic acid (1.11 ml, 12.3 mmol). The reaction mixture was heated at 90° C. for 1 h. After cooled downed to ambient temperature, 2 N hydrochloric acid (6.2 ml) was added and the reaction mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were collected and the solvent was removed in vacuo to afford the title compound as pale yellow solid. 2-[6-Oxopyridazin-1(6H)-yl]propanoic acid: 1H NMR (D2O): δ 8.07 (dd, J=4.1, 1.6 Hz, 1H), 7.53 (dd, 9.3, 3.9 Hz, 1H), 7.09 (dd, J=9.4, 1.6 Hz, 1H), 5.46 (m, 1H), 1.64 (d, J=7.3 Hz, 3H).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=S.[CH:13]([NH:15][NH2:16])=O>C(O)CCC>[CH:13]1[N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][C:2]2=[N:16][N:15]=1
Reactant: NNC=O
Reactant: S=C1CCNc2ccccc2N1
Solvent: CCCCO
Product: c1ccc2c(c1)NCCc1nncn1-2
Yield: 37.3 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g) and 0.80 g of N-formyl-hydrazine in 8 ml of n-butanol is stirred and refluxed for 18 hours and the solvent removed under vacuum. Ice water is added to the residual solid and the mixture filtered to give 0.312 g of a gray solid, m.p. 162-165° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ncc(-c2ccc(F)cc2)n[nH]1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2cnc(Cl)nn2)cc1

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3(2H)-one (1.0 g, 5.23 mmol) and phosphoryl chloride (8.0 mL) in chloroform (5.0 mL) was heated under reflux conditions overnight. After cooling, the volatiles were removed under reduced pressure. The residue was dissolved in dichloromethane (60 mL) and was poured into ice with stirring. The mixture was neutralized with aqueous 2N potassium carbonate and filtered through a pad of Celite. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the desired product. (600 mg, 54.6%) 1H-NMR (300 MHz, CDCl3): 8.88 (s, 1H), 8.06-8.12 (m, 2H), 7.06-7.14 (m, 2H). LCMS: (M+H)=210.1/212.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([CH:26]4[CH2:28][CH2:27]4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:21]([C:19]2[C:18]([CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:11]3[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:20]=2)[S:22]([CH3:25])(=[O:23])=[O:24])[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38]
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.00 g, 4.77 mmol), 2-choro-4-fluoronitrobenzene (1.68 g, 9.55 mmol), and potassium carbonate (1.98 g, 14.3 mmol) in 4:1 DME/water (20 mL) in a sealed vessel was heated to 100° C. with stirring. After 18 hours the mixture was treated with an additional 2.00 g portion of potassium carbonate, heated at 100° C. for another 15 hours, and then stirred at RT for 3 days. The mixture was partitioned between EtOAc and water. After separating the phases, the aqueous portion was extracted with two additional portions of EtOAc. The combined EtOAc solutions were washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) to afford a tacky, yellow foam. This material was crystallized from hexane/EtOAc to give the title compound (1.78 g, 65%) as a light yellow solid. LCMS (m/z, ES+)=574 (M+H+).
Reaction SMILES: [F:1][CH2:2][S:3](Cl)(=[O:5])=[O:4].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1>O.C(O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][S:3]([CH2:2][F:1])(=[O:5])=[O:4])=[N:23][CH:24]=1
Reactant: O=S(=O)(Cl)CF
Reactant: ClCc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(CF)Cc1ccc(Br)cn1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
Commercially available fluoromethanesulfonyl chloride (975 mg, 7.36 mmol) is added dropwise to a solution of sodium sulfite (1.85 g, 14.7 mmol) and sodium bicarbonate (1.24 g, 14.7 mmol) in water (2 mL). The reaction mixture is heated in a microwave reactor to 100° C. for 20 minutes. After cooling to room temperature commercially available 5-bromo-2-(chloromethyl)pyridine (894 mg, 3.68 mmol) in ethanol (2 mL) is added. The mixture is heated in a microwave reactor to 100° C. for 20 minutes. The reaction mixture is cooled to 0° C. and the solid filtered off and discarded. The filtrates are diluted with saturated sodium carbonate (10 mL), extracted with tertiarybutyl methyl ether (50 mL). The organic layer is separated, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound (150 mg): m/z 268.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O1CCCC1.C([Li])CCC.[C:19](=[O:21])=[O:20].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:5]([F:8])=[CH:4][N:3]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ncc1F
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-fluoropyridine (5.0 g) in tetrahydrofuran (100 mL) was 2.6 mol/L n-butyllithium tetrahydrofuran solution (12 mL) in a dropwise manner at −70° C., and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added excessive amounts of dry-ice at −70° C., and this mixture was stirred at room temperature for 12 hours. This mixture was poured into water, and this mixture was extracted with diethyl ether. To this obtained aqueous layer was added 1 mol/L hydrochloric acid (2 mL), and this mixture was extracted with ethyl acetate. This organic layer was concentrated to give the title compound (5.2 g).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1>[C:15](=[O:16])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCCC1
Reaction time: 0.08 h
Yield: 90.5 %

Procedure:
To a solution of cyclohexanol (1.0 g, 10 mmol) in THF (20 mL) at 0° C. was added pyridine (0.97 mL, 12 mmol). After 5 min stirring under N2, a solution of 4-nitrophenyl chloroformate (2.2 g, 11 mmol) in THF (15 mL) was added slowly. After addition, the reaction mixture was stirred at 0° C. for 30 min, and then at RT for 3 h. The precipitate was filtered, the filtrate was concentrated. The resulting residue was chromatographed (40 g silica gel) eluting with EtOAc (0-20%) in hexanes to give the title compound (2.4 g, 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:4]=2)=[O:10])=[CH:12][CH:13]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: CC(C)(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to tert-butylamine via Procedure G. The product was purified on reverse phase HPLC to yield N1-tert-butyl-N4-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 408 (M)+.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:12]([S:19][CH2:20][CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC>>[CH2:12]([S:19][CH2:20][CH2:21][NH:22][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCSCc1ccccc1
Reactant: CCOC(=O)c1cccnc1
Agent: CC
Product: O=C(NCCSCc1ccccc1)c1cccnc1

Procedure:
30 grams of ethyl nicotinate and 80 grams of 2-benzylthio ethylamine are heated for 12 hours at 170°-180° C. The ethane liberated during the reaction is removed by means of a Dean Stark apparatus. After cooling, the reaction mixture is dissolved in 400 cc of carbon tetrachloride; by addition of petroleum ether, the N-(2-benzylthioethyl)nicotinamide crystallizes: 47 g. By crystallization in a mixture of carbon tetrachloride and cyclohexane, there are recovered colorless crystals of the above product melting at 79° C.