Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C@H:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:19]2)=[CH:14][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:64][C:65]([F:73])(S(F)(=O)=O)C(O)=O.O>C(#N)C>[CH2:41]([O:40][C@H:21]1[C@H:22]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:18]([C:15]2[CH:16]=[CH:17][C:2]([Cl:1])=[C:3]([CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][CH:65]([F:73])[F:64])=[CH:9][CH:10]=3)[CH:14]=2)[O:19][C@@H:20]1[CH2:48][O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: FC(F)OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reaction time: 1 h
Yield: 33 %

Procedure:
To a mixture of 2-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)ethanol (intermediate BL) (20 mg, 0.020 mmol) and sodium sulfate (0.40 mg, 0.003 mmol) in anhydrous acetonitrile (0.5 mL) kept at 45° C. was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (4.63 mg, 2.7 μL, 0.026 mmol). The mixture was stirred at this temp for 1 h and poured into 3 mL water. Product was extracted into ether (3×1 mL), dried (Na2SO4) and evaporated. The residue was purified by TLC using 6:1 hexane:EtOAc to obtain intermediate BM (7 mg, yield 33%).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:4]([N:6]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:29])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:10][N:9](C(OCC)=O)[C:8]=2[CH2:7]1)=[O:5]>CO.C(N(CC)CC)C>[CH3:1][O:2][C@H:3]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:4]([N:6]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:29])[C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[N:10][NH:9][C:8]=2[CH2:7]1)=[O:5]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2)c2c1CN(C(=O)[C@H](OC)c1ccccc1)C2
Solvent: CO
Solvent: CCN(CC)CC
Product: CO[C@@H](C(=O)N1Cc2[nH]nc(NC(=O)c3ccc(N4CCN(C)CC4)cc3)c2C1)c1ccccc1
Yield: 46.8 %

Procedure:
A solution of ethyl 5-[(2R)-2-methoxy-2-phenylethanoyl]-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (3.94 g, 7.2 mmol) in methanol (MeOH, 130 ml) and triethylamine (Et3N, 13 ml) was stirred at room temperature for 16 hours (some precipitation occurred). The solid was separated and washed with Et2O, to give 1.6 g of the title compound. Solution was evaporated up to few milliliters, and a second fraction of solid product was separated (1.62 g). The two fractions were joined and analyzed by LC-MS (purity around 90% 254 and 220 nM). After chromatographic purification (short silica gel column, DCM/MeOH 45:5) 2.83 g (83%) of the title compound were obtained as a white solid. M.p 289° C.; [M+H]+ 475;
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[C:17]=1[CH3:24]>>[C:9]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH3:13])[N:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[C:17]=2[CH3:24])[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Reactant: Cc1c(N)ccc(O)c1C
Product: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2C)c1C

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (300 mg, 1.5 mol) and 4-amino-2.3-xylenol (206 mg, 1.5 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 300 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:18])[S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[F:18][CH:2]([F:1])[S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)(=[O:27])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1cc(S(=O)C(F)F)c(=O)c2ccc(F)cc21
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)C(F)F)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a solution of 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (5) (79 mg, 0.287 mmol) in DCM (8 mL) was added ˜80% MCPBA (55.7 mg, 0.258 mmol). The mixture was stirred at a room temperature overnight. An additional amount of MCPBA (15 mg) was added and stirring was continued for 3 days. The mixture was diluted with DCM (10 mL), washed with 5% aqueous Na2CO3 (3×5 mL), the aqueous layers were extracted with DCM (2×10 mL), the combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue, e.g., the crude product, was recrystallized from ethyl acetate to give 27 mg (32%) of white crystals [3-difluoromethyl sulfonyl-7-fluoro-1-methyl-4-quinolone (6)]. The filtrate was chromatographed on silica gel with ethyl acetate-hexane (gradient 1:2, 1:1) to give second crop of the product [3-difluoromethylsulfonyl-7-fluoro-1-methyl-4-quinolone (6)] (32 mg, 38%) for a total yield 70%. This 3-difluoromethylsulfonyl-7-fluoro-1-methyl-4-quinolone gave the following NMR profile:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][OH:14].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:14][CH2:13][C:9]1[N:8]([CH2:7][C:6]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:4]([Cl:3])[CH:5]=2)[CH:12]=[CH:11][N:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(Cl)cc(Cn2ccnc2COCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To NaH in DMF, was added [1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-methanol (see Example 1) in DMF. The reaction mixture was stirred at 40° C. for 30 min and benzyl bromide was dropwise added. The reaction mixture was stirred at 40° C. for another 3 h. The mixture was diluted with EtOAc and washed with water, 1N HCl and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 98:2 as an eluent to afford the title compound (7 mg, 5%); MS m/z 347 [C18H16Cl2N2O+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15](N)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:2].[BrH:22].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.CC#N>[Br:22][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH:4]([N:5]3[CH:9]=[CH:8][N:7]=[CH:6]3)[CH:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[CH:19]=[CH:18][C:13]=2[N:14]=1
Reactant: CCC(CC)C(c1ccc2nc(N)sc2c1)n1ccnc1
Reactant: Br
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(CC)C(c1ccc2nc(Br)sc2c1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (260 mg, 0.866 mmol) and water (4 mL) at 0° C. was added aqueous HBr (0.98 mL, 8.66 mmol) and the mixture was cooled to −0° C. A cold (−10° C.) solution of sodium nitrite (75 mg, 1.08 mmol) in water (1 mL) was added to the reaction mixture over a period of 5 min while maintaining the temperature below −5° C. and the reaction was stirred at −10° C. for 15 min. To a cold (−10° C.) solution of CuBr2 (253 mg, 1.08 mmol) in water (4 mL) was added the reaction mixture and stirred for 10 min at 0° C. MeCN was added to the reaction mixture and then the reaction mixture was stirred for 2.5 h while warming to RT. The reaction was basified with sat. aq. NaHCO3 (pH 7) and then 10 N NaOH (pH 8) followed by celite filtration. The aqueous phase was extracted three times with DCM and the organic extracts were combined and dried over MgSO4, filtered and then concentrated. The crude product was purified by preparative TLC using 5% MeOH in DCM as eluent to afford to 2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole as white solid. MS (ES+): m/z 364 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([OH:21])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C[Si](Cl)(C)C>C(Cl)Cl>[C:22]([NH:26][C:27]([O:21][C:13]12[CH2:19][CH:17]3[CH2:16][CH:15]([CH2:20][C:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)([CH2:18]3)[CH2:12]1)[CH2:14]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N=C=O
Reactant: O=C(NCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)OC12CC3CC(C1)CC(C(=O)NCc1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1-aminoadamantane-3-ol (5.00 g; 30.0 mmol) and potassium carbonate (6.20 g; 45 mmol) in 150 ml of tetrahydrofuran is added benzylchloroformate (4.70 g, 33.0 mmol) in dropwise fashion over a 10 minute period. The mixture is then stirred at room temperature for 2 h and then partitioned between ethyl acetate and water. The product is then extracted into the ethyl acetate and the aqueous layer is washed twice with ethyl acetate (100 ml). The combined organic layers are then washed successively with 100 ml of aqueous 2 N sodium hydroxide, water and brine, dried over sodium sulfate, filtered and concentrated (rotovap/pump) to provide 1-benzylcarbamoyladamantane-3-ol as a white solid in 85% yield. To a clear solution of 1-benzylcarbamoyladamantane-3-ol (1.00 g: 3.32 mmol) and tert-butylisocyanate (380 μl, 3.32 mmol) in 30 ml of methylene chloride is syringe-added trimethylsilyl chloride (20.0 μl, 0.17 mmol). This reaction is then stirred at room temperature for 18 hours, concentrated (rotovap) and purified on silica gel employing a SIMS/Biotage apparatus and 20% ethyl acetate in hexane as eluent to yield 3-[[(tertbutylamino)carbonyl]-oxy]-1-benzylcarbamoyladamantane as a white solid in quantitative yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:6]1=2.[ClH:25]>CO.O1CCOCC1>[ClH:25].[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[CH2:14][NH:15][CH2:16][CH2:17][C:6]1=2
Reactant: COCCn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCCn1c2c(c3ccccc31)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-(2-methoxy)ethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (430 mg) was dissolved in methanol (15 mL). 4N HCl in 1,4-dioxan (1.5 mL) was added and the mixture stirred at room temperature overnight. The solution was concentrated in vacuo, azeotroped once with toluene and dried under vacuum. This gave 5-(2-methoxy)ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride as a grey foam (350 mg, 100% assuming HCl salt).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH2:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[CH3:16]>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:20]1[CH2:21][CH2:22][N:17]([CH2:15][CH3:16])[CH2:18][CH:19]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Reactant: CCN1CCC(=O)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 59.1 %

Procedure:
Beginning with 1.50 gm (7.1 mMol) 5-methanesulfonylamino-1H-indole and 1.25 mL (9.3 mMol) 1-ethyl-4-piperidone, 1.34 gm (58.8%) of the title compound were recovered as a light yellow, crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)O[C:11](=[O:12])[CH2:10][CH2:9]1>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2=[O:12])=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCC(=O)O1
Product: O=C1CCCc2ccc(Br)cc21

Procedure:
7-Bromo-3,4-dihydronaphthalen-1-one was prepared from bromobenzene and succinic anhydride as described in Example 64 (Steps A to C).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][CH:28]([CH:33]=O)[CH2:27]2>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C@H:5]3[CH2:4][CH2:3][C@@H:2]([NH:1][CH2:33][CH:28]4[CH2:27][C:26]5[C:30](=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:35])[F:36])[CH:25]=5)[CH2:29]4)[CH2:7][CH2:6]3)[C:9]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:10][C:11]=2[CH:16]=1
Reactant: O=CC1Cc2ccc(C(F)(F)F)cc2C1
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NCC2Cc3ccc(C(F)(F)F)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and 5-trifluoromethyl-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C27H31ClF3N3O (m/e) calcd 505.2108, obsd 506.1 (M+H).
Reaction SMILES: F[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.CS(C)=O>O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: O=Cc1ncccc1F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ncccc1S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
A mixture of 3-fluoropyridine-2-carbaldehyde (0.70 g), 4-fluorobenzenesulfinic acid sodium salt (1.1 g) and dimethyl sulfoxide (7.0 mL) was stirred at 100° C. for 18 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, and the combined organic extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a pale yellow oil (0.67 g).
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH2:19][OH:20].CCCCC>C(O)C>[N:4]1[N:3]=[C:2]([S:1][CH2:18][CH2:19][OH:20])[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: OCCBr
Reactant: Sc1nnc2ccccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCC
Product: OCCSc1nnc2ccccn12

Procedure:
60 g of 3-mercapto-1,2,4-triazolo(4,3-a)pyridine are dissolved in 500 ml of ethanol. 21 g of sodium carbonate and 29 ml of 2-bromoethanol are then added. The reaction mixture is heated under reflux for 9 hours, the mineral substances are filtered off, the filtrate is then concentrated in vacuo, the concentrate is taken up with water acidified with 0.5N hydrochloric acid and extraction is carried out with chloroform. The aqueous phase is then rendered basic with aqueous ammonia, saturated with sodium chloride and then extracted with chloroform. The chloroform phase obtained is dried over magnesium sulfate and then concentrated in vacuo. The crystals which then form are taken up with pentane, filtered off, washed with pentane and dried to give 69.2 g of 2-[1,2,4-triazolo(4,3-a)pyridin-3-ylmercapto]ethanol in the form of crystals melting at 84° C.
Reaction SMILES: [C:1]([C:6]1[CH:26]=[CH:25][C:9]2[NH:10][C:11]([S:13][CH2:14][C:15]3[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][N:16]=3)=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].C([O-])(O)=[O:28].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:6]1[CH:26]=[CH:25][C:9]2[NH:10][C:11]([S:13]([CH2:14][C:15]3[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][N:16]=3)=[O:28])=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1ccc2[nH]c(SCc3nccc(OC)c3OC)nc2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc2[nH]c(S(=O)Cc3nccc(OC)c3OC)nc2c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
5--Carbethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (95.2% pure) (1.4 g, 0.0036 mol) was dissolved in CH2Cl2 (30 ml). NaHCO3 (0.6 g, 0.0072 mol in H2O (10 ml) was added and the mixture was cooled to +2° C. m-Chloroperbenzoic acid 69.5% (0.87 g, 0.0035 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring. Stirring was continued at +2° C. for 10 min. The phases were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN (15 ml ) giving the title compound (0.76 g, 54%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15]CC3C=CC=CC=3)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]>CCOC(C)=O.CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2ccc(O)cc2o1
Reaction time: 12 h
Yield: 70.1 %

Procedure:
To a solution of 6-benzyloxy-benzofuran-2-carboxylic acid ethyl ester (8.1 g, 27 mmol) in EtOAc/EtOH (3/1, 130 mL) was added Pd/C (0.8 g). The reaction mixture was shaken in a Parr Shaker under H2 (50 psi, 12 h). The reaction mixture was filtered (Celite®), washed with EtOAC (400 mL) and EtOH (100 mL). The filtrate was concentrated and the resulting residue was purified by silica gel flash chromatography using EtOAc:hexanes (0-50%) to provide the title compound as colorless solid (3.9 g, 70%). MS (ESI): mass calcd. for C11H10O4, 206.1.0; m/z found, 207.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.50 (d, J=8.6, 1H), 7.46 (d, J=0.8, 1H), 7.25-7.23 (m, 1H), 6.90 (dd, J=8.5, 2.2, 1H), 6.12 (s, 1H), 4.57-4.30 (m, 2H), 1.49-1.31 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>CC(=O)CC>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[S:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([O-:13])=[O:12]
Reactant: CCOP(=O)(CS)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (569 mg, 1.57 mmol), potassium carbonate (303 mg, 2.36 mmol), diethyl sulfhydrylmethylphosphonate (405 mg, 2.20 mmol) and 2-butanone (5 ml) is heated under reflux for 5 hours. The reaction mixture is then filtered, and the filtrate is concentrated to dryness and purified by prep. TLC to give diethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylthiomethylphosphonate. NMR (CDCl3) δ 5.87 (m, 4H, OCH2CH3), 6.90 (d, 2H, 14 Hz, SCH2 --P) and 8.63 ppm (t, 6H, OCH2CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:69]1[CH2:73][CH2:72][CH2:71][CH:70]1[CH2:74][NH:75][CH2:76][CH2:77][C:78]#[N:79]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:75]([CH2:76][CH2:77][C:78]#[N:79])[CH2:74][CH:70]2[CH2:71][CH2:72][CH2:73][O:69]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: N#CCCNCC1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)CC2CCCO2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.5 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g), TBTU (0.096 g) and HOBT (0.030 g) in DMF (1 ml) was added DIPEA (0.052 ml) followed by 3-[(tetrahydro-furan-2-ylmethyl)-amino]-propionitrile (0.047 g) after 15 min. The reaction was stirred at room temperature for 96 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.078 g) was obtained as a brown oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([NH2:20])=[CH:15][N:14]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([NH:20][C:27]([NH:26][C:24](=[O:25])[C:23]3[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=3[Cl:21])=[O:28])=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(Oc2ccc(Cl)c3c2CCCC3)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1cnc(Oc2ccc(Cl)c3c2CCCC3)c(Cl)c1

Procedure:
A mixture of 0.5 g. of 2-(4-chloro-5,6,7,8-tetrahydro-1-naphthoxy)-3-chloro-5-aminopyridine and 5 ml. of toluene was heated up to 50°. To this resulting solution was added 0.52 g. of 2-chloro-6-fluorobenzoyl isocyanate in 6 ml. of toluene. The mixture was heated at 80° for 1.5 hours, cooled, and filtered to give 0.7 g. of white crystals; mp. 243.5°-244.5°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and benzenesulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, 2H), 7.84 (s, 1H), 7.64-7.53 (m, 3H), 7.20 (m, 5H), 7.11 (m, 1H), 7.02 (d, 1H), 6.84 (d, 1H), 6.78 (d, 1H), 4.33 (s, 2H), 4.31 (s, 2H), 3.65 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H); MS 490 (M+1).