Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:34]([O-])=O)=[C:13]([NH:15][C:16]3[S:17][C:18]([C:31]([NH2:33])=[O:32])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])[N:20]=3)[CH:14]=2)[CH2:4][CH2:3]1.[CH:37](O)=O>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:34]=[CH:37][N:15]([C:16]4[S:17][C:18]([C:31]([NH2:33])=[O:32])=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[C:27]([F:30])([F:29])[F:28])[N:20]=4)[C:13]=3[CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccccc4C(F)(F)F)c(C(N)=O)s3)c2)CC1
Reactant: O=CO
Agent: [Pd]
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccccc5C(F)(F)F)c(C(N)=O)s4)c3c2)CC1
Reaction time: 18 h

Procedure:
A mixture of 0.060 g (0.12 mmole) of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17c) in 7 mL of formic acid and 0.007 g of 10% palladium on carbon catalyst was stirred under an atmosphere of hydrogen for 18 hours. The mixture was filtered through a pad of Diatomaceous earth, washing the filter pad with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane and saturated sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-75:25) gave 0.034 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (I.17) as a white solid. MH+/Z=501
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.082 mL, 0.48 mmol) and nicotinoyl chloride hydrochloride (35.6 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/methanol) afforded N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-nicotinamide (58.9 mg, 70%) as a white solid: mp 240-242° C.; EI-HRMS m/e calcd for C23H24N4O2S (M+) 420.1619, found 420.1625.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](CC(O)=O)=[CH:2]1.SCC1N=CC=C[C:13]=1[C:14]([OH:16])=[O:15]>>[S:1]1[CH:2]=[CH:3][CH:4]=[C:5]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cccnc1CS
Reactant: O=C(O)Cc1ccsc1
Product: O=C(O)Cc1cccs1

Procedure:
3-thienylacetic acid; 1- or 2-furylacetic acid; 2-, 3- or 4-pyridylacetic acid; 2-mercaptomethylnicotinic acid;
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19](I)=[CH:20][CH:21]=2)[N:16]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([S:1][C:2]3[CH:3]=[C:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:21]=2)[N:16]=1
Reactant: Clc1cc(-c2ccccc2)c2ccc(I)cc2n1
Reactant: CCC(O)(CC)c1cccc(S)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(Cl)nc3c2)c1
Temperature: 60 °C

Procedure:
10l (900 mg, 4.6 mmol), 2-chloro-7-iodo-4-phenyl-quinoline (10m, 1.6 g, 4.6 mmol), iPr2NEt (1.6 mL, 9.2 mmol), Pd2dba3 (104 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132 mg, 0.2 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N2 for 10 minutes. The reaction was heated to 60° C. for 1 hour, and then diluted with saturated aqueous NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10n.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8]/[CH:9]=[CH:10]/B1OC(C)(C)C(C)(C)O1)([CH3:4])([CH3:3])[CH3:2].Br[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH:30]=2)[C:25]2=[N:36][NH:37][C:38](=[O:39])[N:24]2[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH:30]=2)[C:25]2=[N:36][NH:37][C:38](=[O:39])[N:24]2[CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=c1[nH]nc2c3cc4ccccc4cc3c(Br)cn12
Reactant: CC(C)(C)OC(=O)NC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc3ccccc3cc12
Temperature: 150 °C

Procedure:
To a solution of tert-butyl[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]carbamate (3-3) (32.5 mg, 0.115 mmol, 4 eq) and 6-bromobenzo[g][1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (7-6) (9.0 mg, 0.029 mmol, 1 eq) in THF (0.5 ml) was added a solution of cesium carbonate (18.7 mg, 0.058 mmol, 2 eq) in water (0.2 ml), and the resulting mixture was deoxygenated with nitrogen and treated with Pd(dppf) (1.0 mg, 0.0014 mmol, 0.05 eq). The reaction mixture was deoxygenated again, and heated in a sealed tube under microwave irradiation for 8 min at 150° C. The resulting suspension was filtered through a pad of Celite washing with DMF, and the filtrate was purified on RP HPLC (MeCN/Water with TFA) to afford the desired coupling product 7-7. LRMS m/z: found 391.2, calcd. (M+H) 391.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].C1C=C([Cl:18])C=C(C(OO)=O)C=1.BrC1C=CC(C(OC)=O)=[N+]([O-])C=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:18])[N:6]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: COC(=O)c1ccc(Br)c[n+]1[O-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)c(Cl)n1
Temperature: 60 °C
Yield: 33 %

Procedure:
A mixture of 5-bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 50 g, 0.23 mol) and m-CPBA (CAN 937-14-4, 80 g, 0.46 mol) in 400 mL dry methylene chloride was heated to 60° C. for 20 h. After that, the mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine (2×200 mL) and evaporated to dryness. The residue was purified with by column chromatography (silica gel, 300 g, eluting with 15% ethyl acetate in petroleum ether) to obtain a brown oil. The brown oil, 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol) was added into phosphoryl trichloride (CAN 10025-87-3, 80 mL) at 0° C. over 1 h, then the mixture was heated to 95° C. for 1 h. After that the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3×50 mL) and the organic layer was evaporated to dryness to obtain the product as a white solid (19 g, 59%); MS (EI): m/e=249.9 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:28][CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Product: CS(=O)(=O)Nc1ccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)cc1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with N-methylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine via General Procedure A to give crude 4-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)-N-methylsulfonylbenzenamine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 125 after purification by reverse HPLC. MS (Q1) 485 (M+)
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[CH2:18]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH3:19].C(N(CC)CC)C>C(#N)C>[CH2:18]([S:20]([N:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:27][CH2:28]1)(=[O:22])=[O:21])[CH3:19]
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Reactant: CCS(=O)(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(Cc2nnnn2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
5-(Chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (79 mg, 0.301 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) and 1-(ethylsulfonyl)piperazine (53.6 mg, 0.301 mmol, Sigma-Aldrich) were dissolved in acetonitrile (1.5 ml). Triethylamine (0.046 ml, 0.331 mmol) was added, and the mixture was heated at 120° C. in a microwave with stirring for 20 min. The reaction mixture was concentrated in vacuo and the residue was purified by high pH MDAP to yield the title compound as a colourless solid (89 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH:17]([OH:20])([CH3:19])[CH3:18]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:20][CH:17]([CH3:19])[CH3:18])=[O:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)O
Reactant: CC(C)OC(=O)c1cc(N=C=O)ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Reaction time: 8 h

Procedure:
NMR (CDCl3): 1.39 (6H,d), 5.26 (1H,m), 6.98-7.52 (3H,m). 1-Methylethyl 2-chloro-5-isocyanatobenzoate (3 g, 0.013 mole) in tetrahydrofuran (5 ml) was added to isopropyl alcohol (5 ml) in tetrahydrofuran (5 ml). A few drops of triethylamine were added and the reaction mixture left at ambient temperature overnight. Removal of the solvent and crystallization from isopropyl alcohol gave the title compound, m.p. 108°-109° C. (2.7 g).
Reaction SMILES: [N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:30](O)(=[O:38])[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[OH:33][C:32]1[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=1[C:30]([N:4]1[CH2:5][CH2:6][N:1]([C:7](=[O:29])[CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH2:2][CH2:3]1)=[O:38]
Reactant: O=C(O)c1ccccc1O
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCN(C(=O)c2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
To a mixture of 1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 2.95 mmol), salicylic acid (0.61 g, 4.43 mmol) and Et3N (0.89 g, 8.85 mmol) in CH3CN (10 mL) was added HATU (1.68 g, 4.43 mmol). The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure and the residue was extracted with EtOAc (4×50 mL). The combined organic layers were washed successively with 1N aqueous HCl, water, 5% NaHCO3 and water, and dried over MgSO4. The solvent was removed under reduced pressure. Purification of the crude product by prep-HPLC afforded 1-(4-(2-hydroxybenzoyl)piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (300 mg, 19.6%) as a light yellow oil. Mass calculated for C33H44N2O3=516.71; found: [M+H]+ 517.6.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[S:15][C:16]3[C:22]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[C:19]([O:29][CH3:30])[C:17]=3[N:18]=2)=[O:12])=[CH:9][N:8]=1>O1CCOCC1>[CH2:1]([O:3][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[S:15][C:16]3[C:22]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=[C:19]([O:29][CH3:30])[C:17]=3[N:18]=2)=[O:12])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1
Temperature: 50 °C
Yield: 53 %

Procedure:
To a stirred solution of 0.24 ml (4.94 mmol) ethanol in 5 ml dioxane at room temperature was added 270 mg (6.18 mmol) sodium hydride (55% dispersion in mineral oil) and the mixture heated at 50° C. for 30 min. 500 mg (1.23 mmol) 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide was then added and the mixture heated at 80° C. for 16 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether afforded 270 mg (53%) 6-ethoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide as a white crystalline solid. ES-MS m/e (%): 437 (M+Na+, 26), 415 (M+H+, 100).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].OS(O)(=O)=O.[CH3:19]O>>[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)[C:9]([O:11][CH3:19])=[O:10]
Reactant: NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(CN)ccc1Cl

Procedure:
To a solution of 5-(aminomethyl)-2-chlorobenzoic acid hydrochloride (17.0 g, 76.5 mmol) in methanol (200 mL) was added conc. H2SO4 (15 mL). The reaction mixture was refluxed for 15 h. The reaction mixture was concentrated and water was added. The aq. solution was basified with sodium bicarbonate. The reaction mixture was extracted with 10% MeOH:DCM and concentrated to afford 15.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.1 (br s, 2H), 3.73 (s, 2H), 3.85 (s, 3H), 7.50 (s, 2H), 7.77 (s, 1H); MS (m/z): 200.05 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3](O)=[O:4].S(Cl)(Cl)=O.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([NH:33][C:3](=[O:4])[CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])(=[O:32])=[O:31]
Reactant: CS(N)(=O)=O
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1nn(-c2cc(CC(Cl)C(=O)NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 120 °C
Yield: 33.8 %

Procedure:
In a manner similar to Example 4, the reaction of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (compound 2) with 5 mL of thionyl chloride produced a residue. To this residue was added 0.50 g (0.0052 mole) of methanesulfonamide. The mixture was stirred and heated at 120° C. for two hours. The mixture was cooled, diluted with methylene chloride, and a resultant precipitate was removed by filtration. The filtrate was washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 0.21 g of N-methylsulfonyl-2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionamide as a foam, Compound 25 of Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.O>CN(C=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH2:28][CH2:27][CH2:26][O:1][C:2]2[CH:3]=[C:4]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=4[CH:12]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc2oc(-c3cccc(O)c3)cc2c1
Reactant: N#Cc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCCCOc2cccc(-c3cc4cc(C#N)ccc4o3)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 2-(3-hydroxphenyl)-5-cyanobenzofuran (125) (1.176 g, 5 mmol) and K2CO3 (0.829 g, 6 mmol) in dry DMF (25 mL) was heated up to 60° C. 4-(3-Bromopropoxy)benzonitrile (129) was added in one portion and the reaction was kept at 80-100° C. overnight. The mixture was cooled down to room temperature and poured into iced water (100 mL) and stirred for 30 min. A precipitate formed was separated by filtration, washed with water (50 mL) and ethanol (50 mL). Drying under high vacuum and recrystallization from the mixture of DMF and ethanol afforded the desired product as white solid (1.65 g, 84%): mp 157-158° C. (DMF/EtOH). 1H NMR (DMSO-d6) δ8.24 (d, J=1.6 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.77 (dd, J=8.6, 1.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.52 (m, 1H), 7.45 (dd, J=7.8, 7.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.07 (dd, J=7.8, 1.7 Hz, 1H), 4.35-4.15 (m, 4H), 2.30-2.15 (m, 2H). HPLC (method B) tR 9.63 min (100.0 area %). Anal. (C25H18N2O3) C, H, N.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15](I)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.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>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15]([C:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(-c3cccc(F)n3)ccnc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3n2S(=O)(=O)c2ccccc2)CC1

Procedure:
A mixture of Example 309C (4 g, 7.09 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.63 g, 8.51 mmol), Pd(Ph3P)4 (0.410 g, 0.355 mmol), and an aqueous solution (15 mL) of sodium bicarbonate (1.788 g, 21.28 mmol) in dimethylformamide (50 mL) was stirred at 80° C. overnight. The reaction mixture was cooled, treated with water, and extracted with ethyl acetate (three times). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was triturated with a mixture of ethyl acetate and petroleum ether (1:1). The solids were filtered and vacuum oven-dried to give the title compound. MS (ESI+) m/z 535 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[O:14]1C=CC=[CH:16][CH:15]1OCCBr.O>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:16][CH2:15][OH:14]
Reactant: BrCCOC1C=CC=CO1
Reactant: COc1ccc(O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(OCCO)cc1OC
Reaction time: 0.33 h

Procedure:
A mixture of 3,4-dimethoxyphenol (155 mg, 1.0 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) in DMA (6 ml) was stirred for 20 min under an atmosphere of nitrogen. 2-(2-Pyranyloxy)ethylbromide (220 mg, 1.0 mmol) was added dropwise. The reaction mixture was stirred for 6 hours at room temperature and then the mixture was poured into water (100 ml). The mixture was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were dried (MgSO4). The organic phase was concentrated and the residue was dissolved in 2-propanol (30 ml) and 4 N HCl (20 ml) was added. The mixture was heated at reflux temperature for 30 min and then stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml). The organic solution was dried (MgSO4) and the solvent was evaporated. The oily residue was purified on silica gel (50 g) eluting with a mixture of heptane and ethyl acetate (3:2). This afforded 100 mg (50%) of 2-(3,4-dimethoxyphenoxy)ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.Cl[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>C(O)CCC>[N+:27]([C:25]1[CH:24]=[CH:23][N:22]=[C:21]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=3)[CH2:3][CH2:2]2)[CH:26]=1)([O-:29])=[O:28]
Reactant: CS(=O)(=O)Nc1ccc(OCC2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CS(=O)(=O)Nc1ccc(OCC2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1
Reaction time: 18 h

Procedure:
A mixture of the product of part (v) (0.50 g), 2-chloro-4-nitropyridine (0.28 g) and sodium bicarbonate (1.00 g) in n-butanol (20 ml) was heated under reflux with stirring for 18 hours. The mixture was cooled, filtered, and the residue was washed with ethanol. The combined filtrate and washings were evaporated to give a gum which was chromatographed on silica gel eluting with ether. Earlier fractions gave impurity and the pure product was eluted in the later fractions. The product fractions were combined and evaporated to give the product, (0.21 g), m.p. 183.5°-184.5° (from ethanol).