Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][C:23]=2[F:34])([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]1.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][C:11]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][C:23]=2[F:34])([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2ccc(F)c(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCOc4ccc(F)c(F)c4)CC3)c2c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 83.4 %

Procedure:
A mixture of 0.38 g of ethyl 1-[2-(3,4-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 2.1 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 17 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and was then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 10 g), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and dried in a desiccator (10 kPa). 0.3 g of 1-[2-(3,4-difluoro-phenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([CH3:39])[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=C)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:42].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:40])[N:7]([C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[O:42])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:28]=2)=[O:25])=[CH:21][CH:22]=1)[CH3:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc(NC(=O)Nc2ccc(-n3cnc4c(N(C)C(=O)OC(C)(C)C)ncnc43)cc2)cc1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.1 %

Procedure:
In a mixed solution of 10 mL of tetrahydrofuran and 5 mL of water, 324 mg (0.59 mmol) of methyl-(9-{4-[3-(3-trifluoromethyl-4-vinylphenyl)ureido]phenyl}-9H-purin-6-yl)-carbamic acid tert-butyl ester was dissolved, and 200 μL of a 0.1 M osmium tetraoxide aqueous solution and 510 mg (2.38 mmol) of sodium periodate were added thereto, and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The product was purified by a silica gel column (hexane:ethyl acetate=1:2) to obtain 243 mg (75%) of a target product as a white crystal.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:14]=3[S:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1>>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([NH:20][C:19]3[C:14]4[S:13][CH:12]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[C:15]=4[N:16]=[CH:17][N:18]=3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(NC4CCNCC4)ncnc23)cc1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(Nc3ncnc4c(-c5ccc(S(C)(=O)=O)cc5)csc34)CC2)nc1

Procedure:
The procedure of intermediate 10 was repeated using 7-(4-methanesulfonyl-phenyl)-N-(piperidin-4-yl)thieno[3,2-d]pyrimidin-4-amine obtained in Example 110 and 2-chloro-5-ethylpyrimidine to obtain the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c2ccccc2cc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c2ccccc2cc2ccccc12

Procedure:
A mixture of 18.85 g of 9-anthroic acid and 60 ml of thionyl chloride is heated under reflux for 1 hour. The excess thionyl chloride is removed under vacuum (30 mm; 90° bath temperature); 50 ml of toluene is added and the mixture is concentrated again. This operation is repeated once more to give 20.6 g of 9-anthroyl chloride as a very moisture-sensitive, yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][OH:24])=[O:22])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=[N:16]1.C(N(CC)CC)C.[CH3:35][NH:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][O:24][S:37]([NH:36][CH3:35])(=[O:39])=[O:38])=[O:22])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=[N:16]1
Reactant: CNS(=O)(=O)Cl
Reactant: O=C(CO)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.8 %

Procedure:
A stirred solution of 0.48 gram (0.0012 mole) of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-hydroxymethylcarbonylamino-4-nitropyrazole and 0.27 gram (0.0027 mole) of triethylamine in 28.5 mL of methylene chloride was cooled in an ice-water bath. Methylaminosulfonyl chloride (0.55 gram, 0.0043 mole) was added dropwise, and the mixture was allowed to warm to room temperature and stir for four hours. The reaction mixture was filtered to remove a salt that had formed. The filtrate was extracted in succession with water, dilute hydrochloric acid, a saturated, aqueous sodium bicarbonate solution, and water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving a brown oil. This oil was purified by column chromatography on silica gel, which was eluted with ethyl acetate: n-heptane (1:1) to yield an oil. This oil crystallized in methylene chloride and n-heptane to yield 0.07 gram of 1-(2,3,5,6-tetrafluoro-4-trifluoro methylphenyl)-5-methylaminosulfonyloxymethylcarbonylamino-4-nitropyrazole as an ivory-colored solid (Compound 21 of Table 1). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:4][CH2:3]1.[C:16]([C:18]1[O:22][C:21]([C:23](Cl)=[O:24])=[CH:20][CH:19]=1)#[N:17].CCN(C(C)C)C(C)C>>[F:15][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:23]([C:21]2[O:22][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[O:24])[CH2:4][CH2:3]1
Reactant: Nc1ccccc1N1CCC(F)(F)CC1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2ccccc2N2CCC(F)(F)CC2)o1
Yield: 36.2 %

Procedure:
Using a procedure similar to Example 3, step (d), 2-(4,4-difluoro-piperidin-1-yl)-phenylamine (76 mg, 0.35 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (62 mg, 0.40 mmol) in the presence of DIEA (134 μL, 0.770 mmol) to afford 42 mg (36%) of the title compound as a tan solid. 1H-NMR (CDCl3; 400 MHz): δ 9.60 (br s, 1H), 8.44 (dd, 1H, J=1.3, 8.1 Hz) 7.32 (d, 1H, J=3.8 Hz), 7.27-7.21 (m, 3H), 7.18-7.13 (m, 1H), 3.07-3.04 (m, 4H), 2.29-2.21 (m, 4H); Mass spectrum (ESI, m/z): Calcd. for C17H15F2N3O2, 332.1 (M+H), found 332.1.
Reaction SMILES: Br[C:2]1[C:3]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=1.[S:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[CH:36]=[C:35]1[Sn](CCCC)(CCCC)CCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C.[F-].[K+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]Br.O1CCOCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([NH:20][C:3]2[C:2]([C:35]3[S:34][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH:36]=3)=[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[N:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=3)[N:6]=[CH:5][N:4]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CSc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2s1
Agent: Cl[Pd]Cl
Agent: [Cu]Br
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2-c2cc3ccccc3s2)nc1
Yield: 83 %

Procedure:
A mixture of N-{5-bromo-6-[2-(5-methylthiopyrimidin-2-yloxy)ethoxy]-pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (200 mg), 2-benzothienyl tributyltin (460 mg), bis(triphenylphosphine)palladium (II) chloride (51 mg), triphenylphosphine (28 mg), copper (I) bromide (21 mg), a few crystals of 2,6-di-tert-butylcresol and dioxane (6 ml) is refluxed for two hours. After cooling, the reaction solution is diluted with ethyl acetate and an aqueous potassium fluoride solution, and the mixture is stirred at room temperature for 60 minutes. The insoluble materials are removed by filtration, and the filtrate is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; methylene chloride:acetone=30:1), and recrystallized from ethyl acetate to give the title compound (182 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N([O-])=O.[Na+].[K].[SH:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1>Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:14][C:15]2[N:19]=[CH:18][NH:17][N:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Sc1nc[nH]n1
Agent: Cl
Agent: O=N[O-]
Agent: [K]
Solvent: O
Product: Clc1cccc(Sc2nc[nH]n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
m-Chloroaniline (3.8 g) is dissolved in a mixture of conc. HCl (5 ml) and crushed ice (5 g) and held at 0° C. An aqueous solution (5 ml) of sodium nitrite (2.2 g) is poured slowly into the mixture so that the reaction temperature will not exceed 4° C. The resulting solution is added at 40°-50° C. to a solution consisting of a potassium salt of 3-mercapto-1,2,4-triazole (4.5 g) dissolved in water (30 ml) and the mixture is stirred at the same temperature for another 30 minutes.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[O:9]=[C:7]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: COc1ccc(/C=C(\CSC(C)=O)C(=O)O)cc1
Product: COc1ccc(/C=C(\CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-methoxyphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH2:20][CH3:21])[CH:3]=1.[NH3:22].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[NH2:22][CH2:17][C:13]1[C:12]([CH2:19][CH2:20][CH3:21])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[NH2:22][CH2:17][C:13]1[C:12]([CH2:19][CH2:20][CH3:21])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N
Reactant: CCCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCCc1c(CN)cccc1Oc1cc(Cl)ccc1C#N
Yield: 111.5 %

Procedure:
4-Chloro-2-(3-chloromethyl-2-propylphenoxy)-benzonitrile (0.16 g, 0.50 mmol) in ammonia (7N in methanol, 25 mL, 175 mmol) was stirred for 65 h at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (58 mg, 0.50 mmol) in methanol (3 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 2-(3-aminomethyl-2-propyl-phenoxy)-4-chloro-benzonitrile hemifumarate (200 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 59.2 %

Procedure:
Diethyl 2-acetamidomalonate (5.0 g) was dissolved in 64 ml of dry ethanol and 1.71 g of sodium ethoxide was added thereto. A solution of 8.4 g of octadecyl bromide in 20 ml of dry ethanol was added thereto while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 6.4 g of diethyl 2-acetamido-2-octadecylmalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:30][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)O)cc1Cl
Reactant: Nc1cnccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (267 mg, 0.75 mmol) in methylene chloride (10 mL) was treated with N,N-dimethylformamide (3 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.90 mmol). The reaction mixture was stirred at 25° C. for 30 min and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (10 mL) and was treated dropwise with a solution of 2-aminopyrazine (143 mg, 1.50 mmol) in tetrahydrofuran (10 mL) and pyridine (0.30 mL, 3.75 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then diluted with a 1N aqueous citric acid solution (25 mL) and concentrated to remove tetrahydrofuran. The remaining aqueous residue was then extracted with a 3/2 solution of chloroform/methanol (2×25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/2 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-N-pyrazin-2-yl-propionamide (266 mg, 81%) as an off-white foam: EI-HRMS m/e calcd for C20H22ClN3O4S (M+H)+ 436.1093, found 436.1099.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:37]=[CH:36][C:8]([O:9][C:10]2[C:11]([CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:29]([O:31]C(C)(C)C)=O)=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:22]=[CH:21][NH:20][N:19]=4)=[N:15][C:14]=3[CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.O1CCOC[CH2:40]1>>[CH3:1][S:2]([C:5]1[CH:37]=[CH:36][C:8]([O:9][C:10]2[C:11]([CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:29](=[O:31])[CH3:40])=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:22]=[CH:21][NH:20][N:19]=4)=[N:15][C:14]=3[CH:23]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc2[nH]c(-c3cc[nH]n3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: C1COCCO1
Agent: Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3cc[nH]n3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
49.2 mg of t-butyl 2-(6-(4-methanesulfonyl-phenoxy)-2-(1H-pyrazol-3-yl)-3H-benzimidazol-5-yl)-pyrrolidin-1-carboxylate was dissolved in 1 ml of 4 N hydrochloric acid-dioxane, and the reaction liquid was stirred at room temperature for 2 hours. The reaction solvent was evaporated away under reduced pressure, and 0.012 ml of acetic anhydride was added to 2 ml of a pyridine solution of the resulting residue, and stirred at room temperature for 30 minutes. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a brown solid.
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:11]1[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of iodine (46.0 g, 0.180 mol) and silver sulfate (56.3 g, 0.180 mol) in anhydrous ethanol (500 mL) was added 4-nitroaniline (25.0 g, 0.180 mol) and the reaction mixture was stirred for 5 h at rt. The resulting yellow solution was filtered and concentrated in vacuo. The resulting residue was dissolved into 400 mL ethyl acetate, washed with 1N sodium hydroxide solution (2×250 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to yield 45.5 (95%) of compound 489A, as a yellow solid. HPLC: 98% at 2.837 min (retention time) (Shimadzu VP-ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.1% trifluoracetic acid, 4 mL/in, monitoring at 220 nm). MS (ES): m/z 265.08 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17](OC)=[O:18])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)=[O:18])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2sc3cc(Cl)ccc3c2S(=O)(=O)N1C
Reactant: Nc1nccs1
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sc3cc(Cl)ccc3c2S1(=O)=O
Yield: 56 %

Procedure:
Prepared analogous to Example 1 from methyl 7-chloro-4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-aminothiazole with a yield of 56% of theory.
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11]C)=[C:9]([CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].B(Cl)(Cl)Cl.O>C(Cl)Cl>[OH:2][C:3]1[C:10]([OH:11])=[C:9]([CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1c(C)ccc(C=O)c1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C=O)c(O)c1O
Temperature: -20 °C
Yield: 43.7 %

Procedure:
14 (770 mg, 4.6 mmol) was placed in solution in DCM (8 mL) under nitrogen and the solution was cooled down at −20° C. while stirring. Boron trichloride 1M in DCM (10 mL, 9.2 mmol) was added slowly over 15 minutes keeping the temperature below −20° C. The reaction mixture turned from yellow to dark red and was left stirring and warming up overnight. More boron trichloride (5 mL) was added in the morning at T<−20° C. and the reaction was left stirring overnight after which the reaction appeared complete by LC-MS. The mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and evaporated. The crude product was columned on silica with neat DCM to yield 306 mg of 15:
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]=2[CH:18]=1
Reactant: CC(C)N
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Reaction time: 24 h
Yield: 57 %

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (750 mg, 1.44 mmole) was refluxed in ethanol (10 mL) with isopropylamine (1.22 mL, Aldrich) under nitrogen for 18 hours. A second portion of isopropylamine (1.22 mL) was added and reflux continued for an additional 24 hours. Volatiles were evaporated, the residue was redissolved in ethanol, 1N sodium hydroxide (1.44 mL) was added, and volatiles were reevaporated. The residue was chromatographed on a silica gel column. Title compound was eluted with 10% methanol-chloroform as a colorless glass. The glass was crystallized from ethyl acetate-hexanes to give (±)-(1R*, 2S*, 3S*, 5S*)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white crystals (305 mg, 57%); m.p. 213°-214° C.; 1H-NMR(DMSO-d6) identical with that of the enantiomer described in Example 75.