Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)[OH:16]>>[F:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:9][C:10](=[O:14])[C:11]2=[O:16]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(F)c(F)c1
Product: O=C1Nc2cc(F)c(F)cc2C1=O
Temperature: 80 °C

Procedure:
A 24.5 g portion of N-(3,4-difluorophenyl)-2-(hydroxyimino)acetamide was added portionwise with stirring to 95 ml of concentrated sulfuric acid with the temperature kept between 60° and 70° C. The temperature of the reaction mixture was then raised to 80° C. for 20 minutes followed by cooling to room temperature. The mixture was then poured onto crushed ice and the resulting solid collected, giving 21.3 g of the desired compound as brick red crystals, mp 218°-220° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=C)[CH2:4][CH2:3]1.[OH:12]OS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CCOC(C)=O>CN(C=O)C.O=[Os](=O)(=O)=O>[C:9]([C@@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][C@H:6]1[OH:8])(=[O:12])[CH3:11]
Reactant: O=S([O-])OO
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)[C@@H]1CC[C@@H](C)C[C@H]1O
Reaction time: 0.08 h
Yield: 34 %

Procedure:
(−)-Isopulegol (60 mg) was dissolved in DMF (4 mL), and OsO4 (0.05 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (0.235 g) was added in one portion and the reaction had a final volume (6 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (360 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (50 mL×3) and brine (50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. (1R, 2R, 5R)-2-Acetyl-5-methyl cyclohexanol and (1R, 2R, 5R)-2-Acetyl-5-methyl cyclohexanyl formate were obtained in 44% and 34% yield respectively after purification by silica gel column chromatography.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:32])[N:21]([CH3:31])[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:31][N:21]([CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:20](=[O:32])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (1.43 g, 3.10 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. Trifluoroacetic acid (5 ml) was added. The solution was stirred at 0° C. for 90 min. Dichloromethane (35 ml) and saturated sodium hydrogen carbonate solution were added. Solid sodium hydrogen carbonate was added until pH 7. The phases were separated. The aqueous phase was extracted with dichloromethane (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo to give 0.91 g of crude (2R)-N-methyl-2-methylamino-3-(2-naphthyl)-N-(3-phenylpropyl)propionamide, which was used without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([OH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)O1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[F:33])[NH:29][CH:28]=[C:27]2[CH:34]=[O:35].C(=O)([O-])[O-].[K+].[K+].S([O-])(O)(=O)=O.[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1COCC1.C1(C)C=CC=CC=1>[F:33][C:32]1[CH:31]=[C:30]2[C:26]([C:27]([CH:34]=[O:35])=[CH:28][NH:29]2)=[CH:25][C:24]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])=[CH:13][CH:14]=1
Reactant: O=Cc1c[nH]c2cc(F)c(Br)cc12
Reactant: CC1(C)OB(c2ccc(-c3ccccc3O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 115 °C
Yield: 24.1 %

Procedure:
A glass tube was charged with 4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-ol (73.5 mg, 0.25 mmol),5-bromo-6-fluoro-1H-indole-3-carbaldehyde (60 mg, 0.25 mmol), toluene (1.2 mL), THF (0.6 mL), EtOH (0.6 mL), and 2.0M potassium carbonate solution (0.6 mL, 1.2 mmol). Nitrogen was then bubbled through the mixture for 5 minutes then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.5 mg, 0.025 mmol) was added. The tube was sealed and heated to 115° C. for 2 hours. The reaction was cooled to room temperature, opened, and neutralized with 1.0M sodium hydrogensulfate then diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (x2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methylene chloride and methanol, silica was added, and the solvent removed in vacuo. The dry-loaded silica gel was then subjected to flash column chromatography (20% to 100% ethyl acetate/heptane) to provide the title compound as a white solid (20 mg, 24%). MS (ES+) 332.3 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.24 (br. s, 1H) 9.96 (s, 1H) 9.59 (s, 1H) 8.36 (s, 1H) 8.19 (d, 1H) 7.67 (d, 2H) 7.58 (d, 2H) 7.46 (d, 1H) 7.33 (d, 1H) 7.18 (t, 1H) 6.97 (d, 1H) 6.91 (t, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cc1

Procedure:
In analogy to example 19, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 4-methoxycarbonylphenylboronic acid was prepared the title compound as yellow oil, MS (ESI+): m/z=437.2 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)Cc1cccc(Oc2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 17.1 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 2,4-dichlorophenol (7.4 g.), anhydrous potassium carbonate (8.6 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give 2-[2-nitro-3-(2,4-dichlorophenoxy)phenyl]acetic acid (2.4 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(CO)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 4-[4-(benzyloxy)-phenoxy]-3-nitrobenzaldehyde (2.48 g, 7.1 mmol) in ethanol (100 ml) was added sodium borohydride (0.27 g, 7.3 mmol), followed by stirring at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The solvent was dried and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform - ethyl acetate (4:1)] to give 4-[4-(benzyloxy)phenoxy]-3-nitrobenzyl alcohol (2.48 g).
Reaction SMILES: C(N1CCC(=O)CC1)C1C=CC=CC=1.C(N)CC.FC1C=C[C:23]([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:23]([N:26]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29](=[O:36])[NH:28][CH2:27]1)[CH2:22][CH3:21]
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Agent: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCCN
Product: CCCN1CNC(=O)C12CCNCC2

Procedure:
This compound was prepared from 1-benzyl-4-piperidone and propylamine in analogy of the procedure described for the synthesis of 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one. 1-Propyl-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as colorless powder: MS (ISP): 198.1 MH+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[N:3]=1.[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:14]([NH:13][C:4]2[N:3]=[C:2]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:7]=[C:6]([C:8]3[S:12][CH:11]=[N:10][CH:9]=3)[N:5]=2)[CH3:15])=[CH:17][CH:18]=1
Reactant: C[C@H](Nc1nc(Cl)cc(-c2cncs2)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cncs2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
To 155 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine, 53 mg of 2-aminopyrazine, 72 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 196 mg of tripotassium phosphate and 81 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 4 ml of 1,4-dioxane, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 5 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 105 mg of the objective compound as pale yellow powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2ocnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2ocnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of benzo[d]oxazole-5-carboxylic acid (7.8 g, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (7.0 g, 1.5 eq), HOBt (7.76 g, 1.2 eq) and EDCI (11 g, 1.2 eq) in 100 mL CH2Cl2 was added Et3N (19 g, 4.0 eq) dropwise at 0° C. The mixture was then stirred at rt overnight, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (6.0 g, 51%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.16 (1H), 7.80 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 3.56 (s, 3H), 3.41 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])[CH:5]=[CH:6][C:7]=1[CH3:8].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:26])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CSc2cccc[n+]2[O-])cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CS(=O)c2cccc[n+]2[O-])cc1C

Procedure:
The procedure employed is identical to that of Example 68 using 7.4 gm (0.03 mol) 2-(3,4-dimethylphenylmethylthio)pyridine N-oxide in 50 ml of chloroform with 6 gm (0.03 mol) MCPBA (85%) in 100 ml chloroform.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]([CH3:26])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>>[CH3:25][S:22]([C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:10]3[N:9]([CH3:26])[C:8]4[CH:27]=[CH:28][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)[S:14][C:15]=2[CH:21]=1)(=[O:23])=[O:24]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(S(C)(=O)=O)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(S(C)(=O)=O)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 87.1 %

Procedure:
2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (1.75 g) was prepared by following General Procedure E starting from 2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (2.08 g), and LiOH (10.0 ml, 2.0 N solution in water). LC/MS: m/z 404.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([C:21]([OH:23])=O)=[CH:9][CH:10]=2)[N:5]=1)=[O:3].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C=O)C>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:2]([NH2:1])=[O:3])[CH:13]=2)=[CH:19][CH:18]=1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C(=O)O)cc2n1
Reactant: C1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C(=O)N3CCCC3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
2-(Aminocarbonyl)-4-(4-fluorophenyl)quinoline-7-carboxylic acid (5-3, 50.0 mg, 0.161 mmol, 1.0 equiv), pyrrolidine (11.5 mg, 0.161 mmol, 1.0 equiv.), BOP (93.0 mg, 0.209 mmol, 1.3 equiv.), and TEA (0.0670 mL, 0.483 mmol, 3 equiv) were dissolved into DMF (1.0 mL) and stirred at room temperature for 1 hour. The mixture was diluted with methylene chloride, washed with water, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-Fluorophenyl)-7-(pyrrolidin-1-ylcarbonyl)quinoline-2-carboxamide (5-4, 50.0 mg, 85.0%) as a colorless solid. 1H NMR (500 MHz, CDCl3): δ 8.324 (d, J=1.47 Hz, 1H); 8.273 (s, 1H); 8.251 (br s, 1H); 8.026 (d, J=8.78 Hz, 1H); 7.762 (dd, J1=8.54 Hz, J2=1.71 Hz, 1H); 7.501-7.529 (m, 2H); 7.246-7.286 (m, 2H); 6.750 (br s, 1H); 3.765 (tr, J=6.95 Hz, 2H); 3.567 (tr, J=6.68 Hz, 2H); 2.055 (quint, J=6.78 Hz, 2H); 1.962 (quint, J=6.65 Hz, 2H). LRMS m/z (M+H)+ 364.1 found, 364.1 required.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([Cl:11])=[CH:8][C:6]=2[N:7]=1.[I-].CC1NC=C[N+]=1C.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=[O:27].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:27])[C:5]2[S:10][C:9]([Cl:11])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sc(Cl)cc2n1
Reactant: O=Cc1cccs1
Agent: Cc1[nH]cc[n+]1C
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(c1cccs1)c1nc(Cl)nc2cc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72 %

Procedure:
A stirred solution of Example 3 (6.86 g, 29 mmol) in tetrahydrofuran (200 ml) was treated with dimethylimidazolium iodide (2.13 g, 9.6 mmol), thiophene-2-carbaldehyde (3.19 ml, 35 mmol) and sodium hydride (1.51 g, 38 mmol). The mixture was first stirred at room temperature for 25 min and then heated, with stirring, to 70° C. for 3 h. The reaction mixture was cooled to room temperature and reduced in vacuo. The residue was partitioned between water and dichloromethane. The organic fraction was separated, dried over sodium sulfate and reduced in vacuo. Trituration with methanol gave the title compound in 72% yield, 95% purity. LC-MS m/z=279.1 [M+H]+; RT=3.77 min; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 7.40-7.42 (1H, m), 7.95 (1H, s), 8.31 (1H, d, J=4.5 Hz), 8.61 (1H, d, J 4.5 Hz).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccc(F)cc12
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Yield: 49.9 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-5-fluoro-3-methyl-1-benzofuran (400 mg) synthesized in Example A37(3) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (336 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4), the title object compound (321 mg, 50%) was obtained as a pale-brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: COCCNCCOC
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: COCCN(CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield {3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-bis-(2-methoxy-ethyl)-amine as colorless oil, MS: 418 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1/[CH:10]=[C:11](/[N+]([O-])=O)\[CH3:12].Cl.[OH2:17]>CO.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11](=[O:17])[CH3:12]
Reactant: O
Reactant: C/C(=C\c1c(Cl)cc(Cl)cc1Cl)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To the stirred solution of 1,3,5-trichloro-2-((E)-2-nitro-propenyl)-benzene (5 g, 18.72 mmol) in H2O (20 ml) and MeOH (60 ml), iron powder (2.355 g, 42.12 mmoles) and conc. HCl (11.5 ml, 112 mmol) was added at ambient temperature under nitrogen environment. The reaction mixture was stirred at 70° C. for 1 hour. After 1 hour additional iron powder (2.355 g, 42.12 mmoles) and conc. HCl (11.5 ml, 112 mmol) was added, while stirring was continued for 2 hours at 70° C. After completion of the reaction, (confirmed by TLC) reaction mass was cooled to ambient temperature and MeOH was evaporated. The resulting residue was diluted with water and extracted with ethyl acetate (3×80 ml). Combined ethyl acetate layer was washed with water and brine and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuum. The crude material was purified by column chromatography (silicagel 60-120μ mesh, hexane/ethylacetate 95:5) to afford 3.7 g (83.3% of theory) of 1-(2,4,6-Trichloro-phenyl)-propan-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][CH2:26][CH2:25][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.35 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.50 mmol of. 2-morpholin-4-yl-ethylamine LC/MS [1.74 min; 471 (M+1)].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[N:24]=[C:25]([C:31]#[N:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=O)=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([O:15][N:24]=[C:25]([C:31]#[N:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=NOC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g) and ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) are dissolved in ethyl acetate (10 ml). To the solution is added triethylamine (0.7 ml) and the mixture is stirred at room temperature for 1 hour. After allowing to stand overnight, to the reaction mixture is added ethyl acetate. The mixture is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give ethyl 2-(N-benzyloxycarbonyl-L-prolyloxyimino)-2-cyanoacetate (1.9 g) as an oily substance.
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[C:19]([F:20])=[C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[C:16]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:15]=2)[C:11](=O)[O-:12])=CC=1)([O-])=O.[CH3:33][NH:34][C:35]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=1.C(O)(=O)C>C1COCC1>[F:20][C:19]1[C:14]([NH:10][C:11](=[O:12])[N:34]([CH3:33])[C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=2)=[N:15][C:16]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])=[CH:17][C:18]=1[O:21][CH2:22][C:23]([F:25])([F:24])[F:26]
Reactant: CNc1ccc(Br)cc1
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)c1F
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)c1F)c1ccc(Br)cc1
Reaction time: 288 h
Yield: 48.1 %

Procedure:
4-Nitrophenyl-3-fluoro-4,6-bis(2,2,2-trifluoroethoxy)pyridin-2-ylcarbamate (520 mg, 1.1 mmol) was dissolved in anhydrous THF (3 mL). To this solution was added N-methyl-4-bromoaniline (200 mg, 1.1 mmol). The reaction was allowed to stir for 12 d. The THF was evaporated and the crude material purified by reverse phase chromatography (HPLC grade CH3CN and H2O, both with 0.1% acetic acid) to afford the product as a tan solid (275 mg, 48% yield): mp 89-90° C.; 1H NMR (CDCl3) δ 8.78 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 6.79 (d, J=4.7 Hz, 1H), 5.04-4.95 (q, J=8.8 Hz, 2H), 4.94-4.85 (q, J=9.1 Hz, 2H), 3.27 (s, 3H); ESI/MS 520, 522 (M+H), 518, 520 (M−H).