Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[N:14]([CH2:15][O:16][CH3:17])[C:13]3[C:12]4=[N:18][CH:19]([CH2:21]OS(C)(=O)=O)[CH2:20][N:11]4[C:10](=[O:27])[N:9]([CH2:28][CH2:29][CH3:30])[C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[K].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>CN(C)C=O>[CH:1]1([C:6]2[N:14]([CH2:15][O:16][CH3:17])[C:13]3[C:12]4=[N:18][CH:19]([CH2:21][N:36]5[C:32](=[O:42])[C:33]6[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=6)[C:35]5=[O:37])[CH2:20][N:11]4[C:10](=[O:27])[N:9]([CH2:28][CH2:29][CH3:30])[C:8]=3[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCN1C(=O)N2CC(COS(C)(=O)=O)N=C2c2c1nc(C1CCCC1)n2COC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N2CC(CN3C(=O)c4ccccc4C3=O)N=C2c2c1nc(C1CCCC1)n2COC
Temperature: 120 °C
Reaction time: 4 h
Yield: 104 %

Procedure:
Compound 18 (500 mg, 0.98 mmol) obtained in Example 18 was dissolved in N,N-dimethylformamide (10 mL), to the solution was added phthalimide potassium salt (485 mg, 2.62 mmol, 2.7 equivalents), and the mixture was stirred at 120° C. for 4 hours. The reaction mixture was partitioned with ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After the reaction mixture was concentrated, the residue was crystallized from dichloromethane and diethyl ether to obtain the title compound (500 mg, 78%) as white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH3:8].[C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17](O)=[O:18])=[CH:11][CH:10]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:9]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:17]([N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH3:8])=[O:18])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: CNCc1ccco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(Cc1ccco1)C(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 1-(furan-2-yl)-N-methylmethanamine (195 mg, 1.76 mmol), (S)-3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid (500 mg, 1.45 mmol), in CH2Cl2 (3 mL) and DMF (3 mL) was added TEA (0.61 mL, 4.39 mmol) and HATU (724 mg, 1.90 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was quenched with aq. NaHCO3 and extracted with EtOAc. The organic layer was washed with aq. NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using 30%-EtOAc/heptane to 90% EtOAc/heptane to give (S)-tert-butyl 3-(biphenyl-4-yl)-1-((furan-2-ylmethyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (614 mg). HPLC retention time=1.80 minutes (condition B); MS (m+1)=435.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (s, 9H, minor rotamer), 1.34 (s, 9H, major rotamer), 2.61 (s, 3H, major rotamer), 2.83 (s, 3H, minor rotamer), 2.87-2.98 (m, 4H), 4.15-4.32 (m, 2H, minor isomer), 4.20 (d, J=15.1 Hz, 1H, major rotamer), 4.62 (d, J=15.1 Hz, 1H, major rotamer), 4.77 (q, J=7.3 Hz, 1H, major rotamer), 4.95 (q, J=7.3 Hz, 1H, minor rotamer), 5.30 (d, J=8.6 Hz, 1H, minor rotamer), 5.39 (d, J=8.6 Hz, 1H, major rotamer), 6.05 (d, J=2.8 Hz, 1H, minor rotamer), 6.10 (d, J=2.8 Hz, 1H, major rotamer), 6.18 (br. s., 1H, minor rotamer), 6.23 (dd, J=3.2, 1.9 Hz, 1H, major rotamer), 7.10-7.50 (m, 18H).
Reaction SMILES: [C@@H:1]1([NH2:7])[CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:6].[C:8]([O:12][C:13](ON=C(C1C=CC=CC=1)C#N)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>ClCCl.C(N(CC)CC)C>[C:8]([O:12][C:13]([NH:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@@H:1]1[NH2:7])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
cis-1,2-Cyclopentanediamine (WO98/30574) (692 mg) was dissolved in dichloromethane (10 ml), to which triethylamine (1.1 ml) and 2-(tert-butoxycarbonyloxy-imino)-2-phenylacetonitrile (493 mg) were added, and the mixture was stirred at 0° C. for 1 hour. Thereafter, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) were additionally added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=9:1) to obtain the title compound (395 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]([NH:32][CH:33]3[CH2:35][CH2:34]3)=[O:31])[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.[CH3:38][O-:39].[Na+].Cl>CO>[NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]([NH:32][CH:33]3[CH2:35][CH2:34]3)=[O:31])[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([O:39][CH3:38])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4nc(Cl)ccc34)nc(N)c21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C(=O)NC3CC3)nn(CCC(F)(F)C(F)(F)F)c2n1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A methanol (1.5 mL, anhydrous) solution containing 4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N-cyclopropyl-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, as described in Example 176, (62 mg, 0.114 mmol) and sodium methoxide (0.21 ml, 0.91 mmol, 25% in methanol) was stirred for 10 hours at 60° C. The reaction mixture was cooled and adjusted to pH 7.0 with 2N HCl aq. at 0° C. The residue was purified by reverse phase HPLC to afford the indicated product. Chiral separation using SFC on a Chiralcel OJ column provided both enantiomers of the title compound. 1H NMR (500 MHz, CD3COCD3): δ 0.61 (m, 2H); 0.77 (M, 2H); 1.83 (s, 3H); 2.85 (m, 1H); 3.04 (m, 2H); 4.05 (s, 3H); 4.88 (m, 2H); 6.78 (d, J=8.7 Hz, 2H); 7.72 (br, 1H); 7.84 (d, J=8.6 Hz, 1H); 9.13 (d, J=8.6 Hz, 1H). m/z=541.21 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=2)[C:7]=1[CH3:8].[OH-].[Na+].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cn2c(C)c(Br)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(Br)ccc2nc(C(=O)O)cn12
Yield: 76.5 %

Procedure:
To a solution of 0.283 g of ethyl 6-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate in 2 mL of ethanol is added 1 mL of 1 N sodium hydroxide. The reaction mixture is refluxed for 3 hours. After cooling, the reaction medium is acidified with acetic acid. The solid formed is filtered off, washed with water and then dried under vacuum to give 0.195 g of 6-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylic acid in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:16])[CH2:9][CH2:10][NH:11][CH2:12][CH:13]([F:15])[F:14])=[CH:5][N:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[F:25][C:26]1([F:32])[CH2:28][CH:27]1[C:29](O)=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:16])[CH2:9][CH2:10][N:11]([CH2:12][CH:13]([F:15])[F:14])[C:29]([CH:27]2[CH2:28][C:26]2([F:32])[F:25])=[O:30])=[CH:5][N:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1
Reactant: O=C(O)C1CC1(F)F
Reactant: CCN(C(=O)CCNCC(F)F)c1cn(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)CCN(CC(F)F)C(=O)C1CC1(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((2,2-difluoroethyl)amino)-N-ethylpropanamide (0.10 g, 0.28 mmol) in CH2Cl2 (2 mL) were added 2,2-difluoro cyclopropanecarboxylic acid (0.041 g, 0.34 mmol), DMAP (0.034 g, 0.28 mmol) and N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((2,2-difluoroethyl)amino)-N-ethylpropanamide (0.10 g, 0.28 mmol), and the mixture stirred at room temperature for 2 hours. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NH4Cl and brine, dried over MgSO4, and concentrated under reduced pressure to give pink oil. The residue oil was purified on silica gel eluting with MeOH/CH2Cl2 to give the title compound F34 as a colorless oil (0.079 g, 58%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O>[CH2:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1I
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of 4-iodo-3-nitrophenol (5.00 g, 18.9 mmol) in acetone (50 ml) were added potassium carbonate (3.39 g, 24.6 mmol) and benzyl bromide (2.92 ml, 24.6 mmol), and the mixture was stirred at 50° C. for 6 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 4-benzyloxy-1-iodo-2-nitrobenzene. The obtained crude product (6.20 g) was used for Step 2 without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10].C(N(CC)CC)C.S=[C:19]1[CH2:23][S:22][C:21](=[O:24])[NH:20]1>C(O)C>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][C:19]2[CH2:23][S:22][C:21](=[O:24])[N:20]=2)[C:4]1=[O:10]
Reactant: CN1CCCC(N)C1=O
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCCC(NC2=NC(=O)SC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing 3-amino-1-methylpiperidin-2-one hydrochloride obtained in C) and triethylamine (3 mL) in ethanol (15 mL) was added 4-thioxothiazolidin-2-one (666 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (220 mg).
Reaction SMILES: Cl.Cl.Cl.S1C(C2C=CN=C([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)N=2)=CC2C=CC=CC1=2.Cl[C:31]1[N:36]=[C:35]([C:37]2[S:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:45]([OH:46])[C:39]=3[CH:38]=2)[C:34]([CH3:47])=[CH:33][N:32]=1.NCCCN1CCN(C)CC1>>[CH3:47][C:34]1[C:35]([C:37]2[S:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:45]([OH:46])[C:39]=3[CH:38]=2)=[N:36][C:31]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[N:32][CH:33]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(O)cccc2s1
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2c(O)cccc2s1

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 2-(2-chloro-5-methylpyrimidin-4-yl)benzo[b]thiophen-4-ol and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a solid. ES+(m/z) 398 [M+H].
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+]([O-])=O)[C:13]=1[O:14][CH3:15])[CH:9]=[O:10].Cl.C#N>O.O1CCOCC1.CCOCC>[OH:10][CH:9]([C:8]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:6]([O:5][CH3:4])[CH:7]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Agent: C#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(C(O)C#N)cc1OC
Reaction time: 0.5 h

Procedure:
A solution of 14.68 g of potassium cyanide in 20 ml of water is added to a solution of 10.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde in 100 ml of dioxane. 18.81 ml of 37 percent hydrochloric acid are now added dropwise thereto within 30 minutes while stirring vigorously. After the addition of 120 ml of ether, the excess hydrogen cyanide gas is driven off by passing argon through the mixture. The reaction mixture is filtered a siliceous earth filter aid, and the organic phase is washed with water dried over sodium sulfate and evaporated. The α-hydroxy-3,4-dimethoxy-phenylacetonitrile (yellowish oil) which is formed is dissolved in 200 ml of ether, whereupon the solution is treated with 20 ml of ethanol, cooled to 0° and hydrochloric acid gas is passed in for 30 minutes. After 3 hours, the separated colorless precipitate is filtered under suction and recrystallized from ethanol/ether. There is obtained ethyl (3,4-dimethoxy-5-nitrophenyl)hydroxy-acetimidate hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH:12]1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.C1(C)C=CC=CC=1.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[N:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH:12]1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Agent: [Ti+4]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1CC(=Nc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 141.7 %

Procedure:
To a solution of 2-Methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (9 g), triethylamine (24.65 g), aniline (5.7 g) in dichloromethane (110 ml), cooled at −5° C. in an ice/sodium chloride bath, a solution of titanium chloride in toluene 1 mol/l was dropwise added for 10 minutes. The mixture was stirred over night at room temperature and then washed with dichloromethane and an aqueous solution of potassium carbonate. The organic layer was separated, dried over sodium sulfate and the solvent was removed under reduced pressure to give a brown oil (16 g) which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:20]=CC)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6]2.O.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:20]([C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([CH3:12])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:33]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC=Cc1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 5-methoxy-7-methyl-4-(prop-1-en-1-yl)-1H-indole-1-carboxylate (0.29 g, 0.97 mmol) was dissolved in dioxane (7.27 mL) and water (2.4 mL) and 2,6-lutidine (0.23 mL, 1.94 mmol) was added followed by osmium tetroxide (0.24 mL, 0.019 mmol) and sodium periodate (0.83 g, 3.88 mmol) at 0° C. The reaction was removed from the ice bath and let stir at room temperature for 1 hour. The reaction was diluted with methylene chloride and water. The organic layer was separated, dried over sodium sulfate and then concentrated. The resulting residue was absorbed onto silica and then purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 290.1 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[C:14](=[O:15])[C:6]2[S:7][CH:8]=[C:9]([S:10](Cl)(=[O:12])=[O:11])[C:5]=2[CH2:4][CH2:3]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][CH3:26])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][N:25]([CH3:26])[S:10]([C:9]2[C:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[C:14](=[O:15])[C:6]=3[S:7][CH:8]=2)(=[O:12])=[O:11])=[CH:21][CH:22]=1
Reactant: CC1CCc2c(S(=O)(=O)Cl)csc2C1=O
Reactant: CNCCc1ccc(F)cc1
Product: CC1CCc2c(S(=O)(=O)N(C)CCc3ccc(F)cc3)csc2C1=O

Procedure:
From 6-methyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 13) (140 mg) and [2-(4-fluorophenyl)ethyl]methylamine (the compound of Preparation Example 14) (98 mg), the title compound (152 mg) was obtained as an orange oily substance, in the same way as Preparation Example 41.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.[F:27][C:28]1([F:39])[C:32](F)=[C:31](F)[C:30]([F:36])([F:35])[C:29]1([F:38])[F:37]>C1COCC1.CCOCC>[F:27][C:28]1([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:11][CH:12]=3)[S:4][C:3]=2[C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:21][CH:22]=2)=[C:32]1[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Reactant: CC(C)(C)c1ccc(-c2cc(Br)c(-c3ccc(C(C)(C)C)cc3)s2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(-c2cc(C3=C(c4cc(-c5ccc(C(C)(C)C)cc5)sc4-c4ccc(C(C)(C)C)cc4)C(F)(F)C(F)(F)C3(F)F)c(-c3ccc(C(C)(C)C)cc3)s2)cc1
Reaction time: 0.25 h

Procedure:
A solution of (30) in anhydrous THF/ether cooled to −45° C. and treated with nBu—Li-(2.5 M in hexanes, 35 mL, 87 mmol) dropwise under a n argon atmosphere. The reaction mixture was stirred for a further 15 minutes followed by addition of octafluorocyclopentene (5.6 mL, 41.5 mmol) using a cooled gas tight syringe. The reaction was allowed to stir until the temperature reached −10° C., quenched by the addition of 10% HCl (50 mL). The aqueous layer was separated and extracted with ether. The organic phases were separated and pooled, dried over MgSO4, filtered and solvent removed by rotary evaporation. The crude product was stirred in MeOH for 3 hours, and the resulting precipitate filtered, dried and purified using flash chromatography (hexanes), affording 2 fractions—F1 was pure S006 (TLC), F2 contained S006 along with a fluorescent byproduct by TLC. F1, 5.35 g, 14.8%) and F2, 10.4 g (˜75% pure, 22%) as light yellow, powdery solids. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.5 Hz, 4H), 7.30 (d, J=8.5 Hz, 4H), 7.05 (d, J=8.4 Hz, 4H), 6.92 (d, J=8.4 Hz, 4H), 6.13 (s, 2H), 1.34 (s, 18H), 0.91 (s, 18H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:5][CH:4]=1.[OH-].[Li+].Cl>O1CCCC1.CO>[OH:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1ccc(CO)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(CO)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-[5-(hydroxymethyl)-2-thienyl]acetate in tetrahydrofuran (10 mL) and methanol (10 mL) was added 1 N aqueous solution of lithium hydroxide (11.83 mL) and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and acidified to pH 1 with 2 N aqueous solution of HCl. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an orange solid (1.02 g, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=1[F:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[F:18]
Reactant: CCOC(=O)C(C)C(=O)Nc1ccc(Cl)c(F)c1
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1ccc(Cl)c(F)c1

Procedure:
The acid was prepared according to Procedure B using ethyl 3-(4-chloro-3-fluorophenylamino)-2-methyl-3-oxopropanoate (2.75 g, 10.1 mmol) in THF (10.1 mL) to give 3-(4-chloro-3-fluorophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=245.9 (M+1).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54](Cl)=O)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>CC(=O)OCC>[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[O:1][N:2]=[C:3]([C:5]4[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:11](=[O:21])[C:12]5[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=5)=[CH:30][CH:31]=4)[N:4]=3)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc([N+](=O)[O-])cc5)cc4)no3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Prepared using General Procedure 20. To a stirred solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-nitrobenzamido)acetate (7.25 g, 16.6 mmol) INT-57 in dioxanes (25 mL) was added DIEA (3.19 mL, 18.24 mmol) then 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (3.83 g, 16.6 mmol). The reaction mixture was stirred at room temperature for 30 mins then at 120° C. for 3 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (400 mL) and washed with brine (500 mL). The organics were pre-absorbed onto silica gel and purified by chromatography (MeCN/DCM) to provide 7.35 g (73%) of tert-butyl 2-(N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-58 as a white powder. LCMS-ESI (m/z) calculated for C35H32N4O6: 604; found 549 [M-t-Bu+H]+, tR=3.24 min (Method 10).
Reaction SMILES: C(OCC)(=O)C.[C:7]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:15]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C:16]([C:26]([O:28]CC2C=CC=CC=2)=[O:27])=[C:17]([CH2:21][O:22][CH2:23][CH2:24][Cl:25])[NH:18][C:19]=1[CH3:20])=[O:13])#[N:8]>[H][H].[C].[Pd]>[C:7]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:15]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C:16]([C:26]([OH:28])=[O:27])=[C:17]([CH2:21][O:22][CH2:23][CH2:24][Cl:25])[NH:18][C:19]=1[CH3:20])=[O:13])#[N:8]
Reactant: [H][H]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCc2ccccc2)=C(COCCCl)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)O)=C(COCCCl)N1

Procedure:
5 ml of ethyl acetate and 10% palladium carbon were added to 340 mg (0.640 mmol) of 2-(2-chloroethoxy) methyl-4-(3-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-benzyl ester 5-(2-cyanoethyl) ester. The obtained solution was stirred at room temperature in hydrogen atmosphere under normal pressure for 8 hours. After filtering the reaction mixture, the filtrate was evaporated under reduced pressure to obtain the title compound.