Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:18].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([F:18])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (S)-N-BOC-proline, 24e, (215.3 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 148.0 mg of 25e as a faintly yellow oil. FTIR (neat) 1850 cm−1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[N:15]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:23][CH2:22][CH2:21][CH2:20][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: NCCCN1CCCC1
Product: Cc1[nH]c2c(c1C(=O)NCCCN1CCCC1)CCCC2=O
Yield: 82.4 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 3-(pyrrolidin-1-yl)propan-1-amine 0.27 g (2.1 mmol) was reacted to give 0.25 g (82%) of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]1[C:15]#[N:16])[CH:2]=[CH2:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:4]1[CH:8]=[C:7]([C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH:6]=[C:5]1[C:15]#[N:16])[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C(O)C(F)(F)F)cc1C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1cc(C(=O)C(F)(F)F)cc1C#N
Reaction time: 3 h

Procedure:
To a room temperature solution of 1-allyl-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrrole-2-carbonitrile (1.6 g, 7 mmol, 1 equiv.) in 50 mL of CH2Cl2 was added Dess-Martin periodinane (3.6 g, 8.3 mmol, 1.2 equiv). After 3 hours, the reaction was diluted with CH2Cl2 and made basic with saturated NaHCO3. The organic layer was separated and the aqueous extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hexanes (0-15% gradient) to provide 1-allyl-4-(2,2,2-trifluoro-acetyl)-1H-pyrrole-2-carbonitrile which was used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH:15]=[C:14]1[C:22](OCC)=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH:15]=[C:14]1[CH2:22][OH:23])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cnccc2n1CCCCO[Si](C)(C)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCn1c(CO)cc2cnccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a solution of 8-a (1.14 g, 3.14 mmol) in dry THF (100 mL) was added drop wise LAH (CAS 16853-85-3) (a 2M solution in THF, 1.89 mL, 3.77 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of ethyl acetate and methanol. Then it was poured into an ice water solution. The resulting mixture was filtered on celite and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography, eluting with heptane/ethyl acetate. After evaporation compound 8-b was obtained as a colorless oil (980 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].S(Cl)(Cl)=O>CN(C)C=O>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:12]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N)nc1
Temperature: 80 °C

Procedure:
6-Aminonicotinic acid, 40 g (or 6-aminonicotinic acid phosphoric salt, 62 g), was mixed with anhydrous ethanol 500 ml. The mixture was externally cooled by an ice water bath. Thionyl chloride, 50 ml, was slowly added into the mixture. (N,N-Dimethylformamide, 50 ml, may be added to dissolve any still undissolved phosphoric salt.) The reaction mixture was heated to 80° C. for 5 hours and was then evaporated to a syrupy reside which crystallized on addition of acetone. These crystals were separated by filtration and were redissolved in 400 g of ice water. 4N KOH was added to the solution to adjust the pH to 8. The white crystals thus formed were separated again by filtration and were washed with water. The yield of practically pure 6-aminonicotinic acid ethyl ester was 41.8 g. This product had an Rf value of 0.79 on thin-layer chromatogram using a solvent system of benzene:methanol, 1:1.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:15][C:16](=[O:17])[NH:18][CH2:19][CH2:20][C:21]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (3.81 g, 26.4 mmol) in CH2Cl2 (34 mL) at 0° C. was added 3-[(tert-butoxycarbonyl)amino]propanoic acid (5.0 g, 26.4 mmol), DMAP (4.84 g, 39.6 mmol), and EDC (6.08 g, 31.7 mmol). The mixture was stirred at rt for 5 h. The resulting mixture was washed with 10% aq. KHSO4 (4×), dried (Na2SO4) and concentrated to afford the title compound which was used without further purification. LRMS (ESI) m/z 316.1 [(M+H)+; calcd for C14H21NO7: 316].
Reaction SMILES: C(OC)(=O)[CH2:2][SH:3].C[O-].[Na+].Cl[C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]=O.[OH-].[Na+].Cl>CO.O>[N+:19]([C:16]1[CH:17]=[CH:18][C:11]2[S:3][CH:2]=[CH:13][C:12]=2[CH:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)CS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc2sccc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Methyl thioglycolate (14.3 g, 135 mmol) in methanol (250 mL) at 40° C. is treated dropwise with 25% sodium methoxide in methanol (37 mL, 160 mmol) and the resulting mixture mechanically stirred at 50° C. for 30 min. 2-chloro-5-nitrobenzaldehyde in methanol (250 mL) is added in a steady stream to give a heavy precipitate which is heated at 50° C. for 1 h. Sodium hydroxide (50% aqueous, 15 mL) is added and heating continued for 2 h, then cooled to ice bath temperature and acidified with concentrated hydrochloric acid. An additional 200 mL of water is added during this process to facilitate stirring. The resulting solids are collected by filtration, washed with water, and dried in vacuo at 45° C. overnight. The dried solids are suspended in quinoline (120 mL), copper metal (7.2 g) is added and the mixture is heated at 190° C. for 2 hr. The mixture is allowed to cool, then poured onto 500 g of ice, 6 N hydrochloric acid (500 mL) is added and then extracted with of dichloromethane. The organic layers are combined and washed with 6 N hydrochloric acid, dried, and flash chromatographed on silica gel eluting with 10-40% ethyl acetate in heptane to give 16.2 g (81%) of the title compound. 1H NMR (CDCl3) δ8.75 (s, 1 H), 8.22 (dd, J=2.3, 10 Hz, 1 H), 8.0 (d, J=10 Hz, 1 H), 7.68 (d, J=6 Hz, 1 H), 7.53 (d, J=6 Hz, 1 H); MS (−ESI) m/z 221.8 (M−H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][N:26]=[N+:27]=[N-:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Yield: 107.4 %

Procedure:
To a solution of (2-hydroxyethyl)carbamic acid t-butyl ester (1.5 g, 6.2 mmol) in tetrahydrofuran (75 ml) were added diphenylphosphoryl azide (3.0 ml, 13.9 mmol), triphenylphosphine (3.7 g, 14.1 mmol), and a 40% solution of diethylazodicarboxylate in toluene (5.1 g, 13.9 mmol) in an ice bath under an atmosphere of nitrogen, and then the mixture was stirred for 4 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1) as the eluant to afford (2-azidoethyl)carbamic acid t-butyl ester (1.24 g, yield 72%) as a colorless and transparent syrup.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:10]([Cl:11])=[CH:9][N:8]([CH:12]([F:14])[F:13])[N:7]=1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:11][C:10]1[C:6]([CH:4]=[O:5])=[N:7][N:8]([CH:12]([F:13])[F:14])[CH:9]=1
Reactant: CON(C)C(=O)c1nn(C(F)F)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nn(C(F)F)cc1Cl
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide (164 mg, 0.68 mmole) in THF (5 ml) was added at 0° C. a solution of LiAlH4 (1M in THF, 0.35 ml) and stirring was continued for 30 min. The mixture was quenched at −15° C. with saturated aqueous KHSO4, extracted with diethyl ether, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (4:1) to give the title compound (71 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6](S(C)=O)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].[CH3:32][NH2:33]>>[C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6]([NH:33][CH3:32])=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2]
Reactant: CN
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(S(C)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Product: CNc1nc(Nc2cc(C(=O)NOC)ccc2C)c(C#N)c(N(C)CC(C)(C)C)n1

Procedure:
3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfinyl-pyrimidin-4-ylamino}-N-methoxy-4-methyl-benzamide (33 mg) and methylamine (2.5 mL, 2 M in THF) were heated in a sealed tube at 75° C. for overnight. After the solvent was removed in vacuo, the residue was purified by silica gel column chromatography to afford the product (7.3 mg). MS (m/z): 412 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(OCC)(=O)C.[H][H]>C(O)C.[Pt](=O)=O>[F:1][C:2]1[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:5]=[C:6]([NH2:8])[CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-n2cccn2)c(F)c1

Procedure:
A solution of 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole (3 g, 14.5 mmol) and platinum(IV) oxide (100 mg) in ethanol (100 ml) with ethyl acetate (100 ml) was reduced under 40 psi hydrogen for 30 min, then filtered and the solvent removed, to give 5-fluoro-4-(pyrazol-1-yl)phenylamine as a colourless oil: MS (ES+) m/z 178 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([CH2:18][CH3:19])[C:8](=[O:20])[NH:7][C:6]1=[O:21])[CH:2]=[CH:3]C.C(N1C(SC2C=CC=CC=2)=C(CC)C(=O)NC1=O)C=CC1C=CC=CC=1.CC(C)=CCN1C(SC2C=CC=CC=2)=C(CC)C(=O)NC1=O.C(OCC=CCN1C(SC2C=CC=CC=2)=C(CC)C(=O)NC1=O)C.C(OCC=CCN1C(SC2C=CC=CC=2)=C(CC)C(=O)NC1=O)C1C=CC=CC=1.C(N1C(SC2C=CC=CC=2)=C(CC)C(=O)NC1=O)C#C>>[CH2:1]([N:5]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([CH2:18][CH3:19])[C:8](=[O:20])[NH:7][C:6]1=[O:21])[CH:2]=[CH2:3]
Reactant: CC=CCn1c(Sc2ccccc2)c(CC)c(=O)[nH]c1=O
Agent: C#CCn1c(Sc2ccccc2)c(CC)c(=O)[nH]c1=O
Agent: CCOCC=CCn1c(Sc2ccccc2)c(CC)c(=O)[nH]c1=O
Agent: CCc1c(Sc2ccccc2)n(CC=C(C)C)c(=O)[nH]c1=O
Product: C=CCn1c(Sc2ccccc2)c(CC)c(=O)[nH]c1=O

Procedure:
1-(2-butenyl)-5-ethyl-6-phenylthio-2,4-pyrimidinedione; 1-cinnamyl-5-ethyl-6-phenylthio-2,4-pyrimidinedione; 1-(3-methyl-2-butenyl)-5-ethyl-6-phenylthio-2,4-pyrimidinedione; 1-(4-ethoxy-2-butenyl)-5-ethyl-6-phenylthio-2,4-pyrimidinedione; 1-(4-benyloxy-2-butenyl)-5-ethyl-6-phenylthio-2,4-pyrimidinedione; 1-propargyl-5-ethyl-6-phenylthio-2,4-pyrimidinedione;
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][O:25]C(=O)C)[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@@:9]1(C)[C:32]([O-:34])=[O:33])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][OH:25])[CH2:10][C@H:9]1[C:32]([OH:34])=[O:33])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(=O)OCC(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@@H]1CN(C(=O)OC(C)(C)C)[C@](C)(C(=O)[O-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reaction time: 12 h
Yield: 94.1 %

Procedure:
To a solution of 1-BOC-2-methyl-(2S,4S)-4-{[3-(acetyloxy)-2,2-dimethylpropanoyl](4,4-methylcyclohexyl)amino}pyrrolidine-2-carboxylate (1.02 g, 2.05 mmol) prepared in Step A in methanol (10 ml) and water (10 ml), was added NaOH (246 mg, 6.15 mmol), and stiffed for 12 h. After the reaction finished, the reaction solution was concentrated in vacuo, acidified with 1N HCl, and extracted with EtOAc. The organic extracts were washed with 1N HCl, dried MgSO4, and concentrated in vacuo to give the title compound (0.85 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC[O-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[NH2:1][C:2]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: ClCc1ccccc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a solution of 2-aminobenzimidazole (2) (Aldrich, 6 g., 45 mmol) in EtOH (10 mL) was added EtONa (21% in EtOH, 16.83 mL, 45 mmol) and benzyl chloride (5.70 mL, 50 mmol) and the brown solution was refluxed for 3 days under N2 gas. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated in vacuo. The resulting brown solid was filtered hot in 300 mL acetone and crystallized from approximately 100 mL of acetone, and gave 3 as brown crystals (3.91 g., 39%). Recrystallization of the mother liquor afforded additional 3 as brown crystals (0.70 g., 7%). 1H-NMR (DMSO-d6) δ 5.27 (s, 2H), 6.61 (s, 2H), 6.82 (t, J=8.8 Hz, 1H), 6.93 (t, J=6.4 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.15 (d, 7.2 Hz, 1H), 7.20 (d, 6.8 Hz, 2H), 7.24 (d, 7.6 Hz, 1H), 7.31 (t, 7.6 Hz, 2H); 13C-NMR (DMSO-d6) 45.11, 108.30, 115.19, 118.49, 120.88, 127.39, 127.66, 128.91, 134.60, 137.64, 143.34, 155.46.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:15]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:13][OH:14])(C)(C)C.Cl>CO>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:13][OH:14]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C#N)cc1
Agent: Cl
Solvent: CO
Product: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-{5-[(4-cyano-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-carbamic acid tert-butyl ester (5) (1.06 g) was dissolved in 50 mL MeOH. HCl (5-6 N in i-prOH, 30 mL) was added and the mixture was stirred overnight at RT. The mixture was evaporated to dryness and used as such in the next reaction.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:63])[C@H:60]([CH3:62])[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:63])[C@H:60]([CH3:62])[NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.4 g, 3.2 m mole), 1-hydroxybenzotriazol (476 mg, 3.5 m mole) and L-alanine benzylester p-toluene sulfonate (1.3 g, 3.5 m mole) were dissolved in DMF (5 ml), and WSC (0.64 ml) was added thereto while cooling to -15° C. The reaction was continued for 3 hours under cooling and then overnight at room temperature, and ethyl acetate (100 ml) was added thereto. The mixture was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and dried with anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure leaving an oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-alanine benzylester material.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([C:27]([F:29])([F:30])[F:28])=[O:36])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(SC(F)(F)F)cc4)no3)cc2C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(S(=O)C(F)(F)F)cc4)no3)cc2C)cc1

Procedure:
To a mechanically stirred solution of 5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-3-{4-[(trifluoromethyl)sulfanyl]phenyl}-1,2,4-oxadiazole (Example 105, 570 mg, 1.32 mmol) in dichloromethane (215 mL) was added 3-chloroperoxybenzoic acid (408 mg, 1.66 mmol) at a temperature of 0° C. The reaction mixture was stirred over night at the same temperature. Then saturated aqueous sodium bicarbonate solution (80 mL) was added, and the mixture was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the title compound was obtained as a white solid after purification by MPLC (silica, cyclohexane/ethyl acetate 4:1) (346 mg, 59%): 1H NMR (400 MHz, DMSO-d6) 8.38 (d, 2H), 8.11 (d, 2H), 7.18 (d, 2H), 7.12 (d, 2H), 6.92 (s, 1H), 5.43 (s, 2H), 2.32 (s, 3H), 2.27 (s, 3H); ES-MS m/z 447, HPLC RT (Method E) 2.44 min.
Reaction SMILES: [Na+].[NH2:2][C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([S:9]([O-:12])(=[O:11])=[O:10])[CH:8]=1.C([O-])(O)=O.[Na+].Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O1CCOCC1.O>[CH:36]1[C:37]2[CH:25]([CH2:24][O:23][C:21]([NH:2][C:3]3[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([S:9]([OH:12])(=[O:10])=[O:11])[CH:8]=3)=[O:22])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]=2[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])cc1N
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)O)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2,4-dimethylbenzenesulfonic acid sodium salt (3.0 g, 13.4 mmol) in dioxane (37 mL) and water (37 ml) was added NaHCO3 (2.5 g, 29.6 mmol) and 9-fluoreneylmethyl chloroformate. The mixture was then stirred at room temperature overnight and then quenched with 1N HCl and extracted with EtOAc. The organic layers were concentrated in vacuo. Purification by silica gel chromatography (0-10% MeOH/DCM) resulted in the title compound.
Reaction SMILES: [C:1]([Cl:6])([C:3](Cl)=O)=O.CN(C=O)C.[N:12]1[C:17]2[CH:18]=[CH:19][S:20]C=2C(=O)[NH:14][CH:13]=1>O>[Cl:6][C:1]1[C:3]2[S:20][CH:19]=[CH:18][C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=c1[nH]cnc2ccsc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2ccsc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a stirred solution of (COCl)2 (7.33 mL, 84.11 mmol) in anhydrous (CH2Cl)2 (20 mL) at 0° C. under nitrogen was added DMF (4.47 mL, 57.18 mmol). After 20 min a solution of thieno[3,2-d]pyrimidin-4(3H)-one (19) (4 g, 26.28 mmol) in anhydrous (CH2Cl)2 (5 mL) was added drop wise to the reaction mixture which was stirred for 20 min at 0° C., warmed to room temperature over another 20 min, heated at 80° C. for 1.5 hours, and cooled to room temperature. Finally, the reaction mixture was poured into water and extracted with DCM. The extract was washed sequentially with water, brine, dried over Na2SO4, filtered and evaporated to afford the title compound 20 (4.36 g, 97% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.02 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 7.75 (d, J=5.2 Hz, 1H).