Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[N:7]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[C@H:22]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=1)=[O:5])C.O.[OH-].[Li+].CO>O1CCCC1>[Cl:39][C:38]1[C:33]([CH2:32][N:21]([CH2:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH2:13][N:7]2[CH:6]([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][S:8]2(=[O:12])=[O:11])[C@H:22]([CH2:28][N:29]([CH3:30])[CH3:31])[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[C:34]([F:42])[C:35]([O:40][CH3:41])=[CH:36][CH:37]=1
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(CN(Cc2c(Cl)ccc(OC)c2F)[C@H](CN(C)C)CC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (0.865 g, 1.4 mmol) was dissolved in tetrahydrofuran (5.6 mL). Water (5.6 mL) and lithium hydroxide (0.050 g, 2.07 mmol) and methanol (1.2 mL) were added. The reaction was stirred at room temperature for 2.5 hours after which the reaction was concentrated under reduced pressure. To the residue was added dichloromethane and aqueous hydrochloric acid (pH˜7) resulting in an emulsion. The reaction was then concentrated to dryness under reduced pressure. The crude material was purified by supercritical fluid chromatography into the corresponding Epimer 1 and Epimer 2 of 2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (0.084 g (Epimer 1) and 0.089 g (Epimer 2), respectively, 99% (combined yield)).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:25](O)=[O:26])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:32]1([NH:34][C:25]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:26])[CH2:33][CH2:31]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2/C=C/c2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 176.6 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-[(E)-2-phenylvinyl]-1H-1,2,3-triazole-4-carboxylic acid (264 mg, 0.728 mmol) obtained in Example 106b), HOBt (49.7 mg, 0.364 mmol, 0.5 eq.) and cyclopropylamine (0.068 ml, 0.947 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (3:1, 4 ml), WSC (171 mg, 0.874 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 13 hr. Water (10 ml) was added to the reaction mixture and the mixture was stirred. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (258 mg, 0.643 mmol, 88.3%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:12]O[CH2:14][C:15]4[C:16]=3[C:17]=2[CH:18]=[CH:19][CH:20]=4)[CH2:3]1.BrC1C=CC2C[S:27]CC3C=2C=1C=CC=3>>[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:12][S:27][CH2:14][C:15]4[C:16]=3[C:17]=2[CH:18]=[CH:19][CH:20]=4)[CH2:3]1
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)COC3)CCN1
Reactant: Brc1ccc2c3c(cccc13)CSC2
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CSC3)CCN1

Procedure:
The procedure used for the synthesis of (3R)-3-methyl-1-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazine (Example 5b)) was followed, using 6-bromo-1H,3H-naphtho[1,8-cd]thiopyran as starting material and making non-critical variations, to obtain the title compound (3R)-3-methyl-1-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazine as brown solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25][Si](C(C)(C)C)(C)C)[CH:23]=4)[N:18]([CH3:33])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([OH:25])[CH:23]=4)[N:18]([CH3:33])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(O[Si](C)(C)C(C)(C)C)cc34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(O)cc34)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
In a round-bottomed, 2-[5-(tert-butyl-dimethyl-silanyloxy)-1-methyl-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (50 mg, 0.108 mmol) was suspended in THF (1.2 ml) and tetrabutylammonium fluoride (1.0 M in THF, 0.11 ml, 110 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered and the solid was washed with hot water and ethyl acetate then dried under high vacuum to provide 33 mg (83%) of 2-(5-hydroxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a yellow powder. MS: (M+Na)+=373; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.77 (br. s., 1H), 9.25 (s, 1H), 9.06 (s, 1H), 8.38 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 7.10 (dd, J=9.1, 2.3 Hz, 1H), 4.23 (dq, J=13.6, 6.7 Hz, 1H), 4.13 (s, 3H), 1.35 (d, J=6.8 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:30])=[CH:4][C:5]([Cl:29])=[C:6]([C:8]2[C:9](=[O:28])[N:10]([CH2:26][CH3:27])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:29][C:5]1[C:6]([C:8]2[C:9](=[O:28])[N:10]([CH2:26][CH3:27])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[C:3]([F:30])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)CC3)cc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC3CCN(C)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpiperidin-4-ylamino)-1,6-naphthyridin-2(1H)-one (200 mg, 0.465 mmol) and pyridine (70 mg, 0.95 mmol) in DCM (5 mL) was treated drop-wise with phenyl isocyanate (112 mg, 0.93 mmol) and stirred at RT under nitrogen overnight. The mixture was quenched with MeOH (5 mL), concentrated under reduced pressure and purified by prep-TLC separation to give 1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (120 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.72 (s, 1H), 8.39 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.51 (d, J=10.8 Hz, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.26 (t, J=8.0 Hz, 2H), 7.02-6.94 (m, 2H), 6.33 (s, 1H), 4.11-4.05 (m, 2H), 3.81-3.78 (m, 1H), 2.78-2.75 (m, 2H), 2.20 (s, 3H), 2.12-2.05 (m, 2H), 1.90-1.88 (m, 2H), 1.52-1.47 (m, 2H), 1.21-1.18 (m, 3H); MS (ESI) m/z: 549.3 [M+H]+.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=2)[N:39]=[C:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[C:37]=1[CH3:53].[NH2:54][C:55]1[CH:56]=[C:57]([NH:67][C:68]([CH:70]2[CH2:72][CH2:71]2)=[O:69])[CH:58]=[C:59]([N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)[CH:60]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:46][C:42]1[CH:41]=[C:40]2[C:45]([C:36]([NH:54][C:55]3[CH:56]=[C:57]([NH:67][C:68]([CH:70]4[CH2:71][CH2:72]4)=[O:69])[CH:58]=[C:59]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)[CH:60]=3)=[C:37]([CH3:53])[C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[N:39]2)=[CH:44][CH:43]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(NC(=O)C2CC2)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(NC(=O)C2CC2)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure X by stirring palladium (II) acetate (1.1 mg, 4.78 μmol), XPhos (6.8 mg, 0.014 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.026 g, 0.096 mmol), N-(3-amino-5-morpholinophenyl)cyclopropanecarboxamide (0.025 g, 0.096 mmol), potassium carbonate (0.033 g, 0.239 mmol), and tert-butanol (1 mL) at 110° C. for 1 hour. Purification by column chromatography (silica; 0-10% methanol in DCM) afforded N-(3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)phenyl)cyclopropanecarboxamide as a yellow amorphous solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.68 (1H, d, J=4.3 Hz), 8.26 (1H, br. s.), 7.86 (2H, td, J=7.7, 1.7 Hz), 7.74 (1H, d, J=7.0 Hz), 7.62 (1H, dd, J=10.0, 2.0 Hz), 7.33-7.42 (1H, m), 7.24 (1H, br. s.), 7.14-7.21 (1H, m), 6.15 (2H, br. s.), 6.02 (1H, br. s.), 3.69-3.87 (4H, m), 3.05-3.20 (4H, m), 2.29 (3H, s), 1.27 (1H, t, J=7.1 Hz), 0.92-0.99 (2H, m), 0.57-0.73 (2H, m). Mass Spectrum (ESI) m/e=498.2 (M+1).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([NH2:21])=[O:20])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:8]=1)=[N+]=[N-].CO.[Cl-].[NH4+]>[Zn].O1CCCC1>[NH2:1][C:4]1[S:5][C:6]([C:19]([NH2:21])=[O:20])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[N:8]=1
Reactant: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(N)=O)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1sc(N)nc1-c1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To a solution of 0.9035 g (2.884 mmole) of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide, 27 mL of methanol and 27 mL of tetrahydrofuran, was added 1.91 g (29.21 mg-atom) of zinc and 3.82 g (71.42 mmole) of ammonium chloride. The mixture was stirred vigorously for 1 hour, and then filtered through Diatomaceous earth, washing the filter pad with methanol and tetrahydrofuran. The filtrate was concentrated under reduced pressure, diluted with 350 mL of ethyl acetate and washed three times with 100 mL of water, twice with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 0.8527 g of 2-amino-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.48).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:2]=1.C(O[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C1(C)C=CC=CC=1>CCN(CC)CC.CCOC(C)=O.CCCCCC>[CH3:13][C:1]1[CH:6]=[CH:5][C:4]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:2]=1
Reactant: Cc1cccc(-c2ccccn2)c1
Reactant: CC(=O)OC=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(C=Cc2ccccc2)c(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 50 h
Yield: 98 %

Procedure:
A Teflon-coated magnetic stirring rod was placed in a 10 mL two-necked flask which was then equipped with a reflux condenser. The reflux condenser was connected to a pressure reduced/nitrogen line and the whole apparatus was dried with heating under reduced pressure. Thereafter, N2 gas was charged in the reaction apparatus and the whole reaction apparatus was purged with nitrogen. The reaction vessel was left to cool to room temperature, then, Ru(cod)(cot) complex (0.05 mmol, 15.8 mg), 2-m-tolylpyridine (1 mmol, 169.2 mg), styryl acetate (3 mmol, 486.6 mg) and toluene (1.5 mL) were added. The mixture was heated by an oil bath and reacted under reflux condition for 50 hours. 50 hours after, the reaction solution was left to cool to room temperature, then, triethylamine (0.3 mL) was added. Isolation of the product was carried out by silica gel column chromatography (i.d.=30 mm; length=170-250 mm; hexane:EtOAc:Et3N=9:1:0.1; 25 mL each). A subject substance 2-(5-methyl-2-styrylphenyl)-pyridine was obtained with a yield of 98%.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C@H:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:19]=O>[Pd].CO>[CH3:19][N:13]1[CH2:14][CH2:15][C@H:10]([CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C@@H:12]1[C:16]([NH2:18])=[O:17]
Reactant: CCOP(=O)(C[C@H]1CCN[C@@H](C(N)=O)C1)OCC
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(C[C@H]1CCN(C)[C@@H](C(N)=O)C1)OCC
Reaction time: 16 h

Procedure:
A mixture of 500 mg of cis-4-diethylphosphonomethyl-2-piperidinecarboxamide, 3 ml of 37% aqueous formaldehyde, 50 ml of methanol and 500 mg of 10% palladium on carbon catalyst is hydrogenated at 3 atmospheres pressure for 16 hours. The solvent is removed and the residue chromatographed on silica gel with 10% methanol/methylene chloride as the eluant to afford cis-1-methyl-4-diethylphosphonomethyl-2-piperidinecarboxamide. This product is refluxed for 16 hours in 6N hydrochloric acid followed by treatment with propylene oxide to yield cis 1-methyl-4-phosphonomethyl-2-piperidinecarboxylic acid, m.p. 256°-260°.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:8]([C:12]#[N:13])[C:9]=2[CH3:11])[C:4](=[O:26])[N:3]1[C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[OH:33].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[OH:33][C@@H:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@H:27]1[N:3]1[CH2:2][C:10]2[C:5](=[CH:6][C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:8]([C:12]#[N:13])[C:9]=2[CH3:11])[C:4]1=[O:26]
Reactant: Cc1c(C#N)c(Cc2ccc(-n3cccn3)cc2)cc2c1C(O)N([C@@H]1CCCC[C@H]1O)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C#N)c(Cc2ccc(-n3cccn3)cc2)cc2c1CN([C@@H]1CCCC[C@H]1O)C2=O
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a solution of rac-3-hydroxy-2-(trans-2-hydroxycyclohexyl)-4-methyl-1-oxo-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindole-5-carbonitrile (0.10 g) in dichloromethane (2.00 mL) was added trifluoroacetic acid (0.31 mL) under ice-cooling. After 15 min, triethylsilane (0.50 mL) was added thereto, and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (×2). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by prep-HPLC, then lyophilized to give the title compound (0.02 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=[C:8]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.I(O)(=O)(=O)=[O:29]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:29]
Reactant: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c(SC)cccc32)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c2cccc3S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirring suspension of compound 98 (100 mg, 0.266 mmol) and iron (III) chloride (1.296 mg, 7.99 μmol) in acetonitrile (2 mL) after 5 minutes was added periodic acid (66.8 mg, 0.293 mmol) in one portion. The reaction mixture was left to stir at room temperature overnight then quenched with saturated sodium thiosulfate solution and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, filtered and solvent evaporated. Purification via ISCO (0-40% EtOAc/Hexanes; 40 g silica gel column) afforded title compound 99 (60 mg, 57%) as a yellow solid. LRMS (ESI): (calc) 391.09 (found) 392.4 (MH)+.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH2:34]O>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:34][C:33]2[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=2[O:31][CH3:30])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: COc1ccc(OC)c(CO)c1
Agent: Cl
Product: COc1ccc(OC)c(CN2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)c1
Yield: 23.8 %

Procedure:
The compound (0.20 g) obtained in Example 1 and 2,5-dimethoxybenzyl alcohol (0.12 g) were reacted and treated in the same manner as in the method described in Example 16 to obtain the title compound as colorless oil (0.060 g, 23%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:23]=[CH:22][C:14]3=[N:15][CH:16]=[C:17]([C:19]([OH:21])=O)[CH:18]=[C:13]3[C:12](=[O:24])[C:11]=2[CH:25]=1)(=[O:5])=[O:4].[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OC(=O)C)C>[CH3:1][N:2]([CH3:26])[S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:23]=[CH:22][C:14]3=[N:15][CH:16]=[C:17]([C:19]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[O:21])[CH:18]=[C:13]3[C:12](=[O:24])[C:11]=2[CH:25]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)Nc1ccc2ccc3ncc(C(=O)O)cc3c(=O)c2c1
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)Nc1ccc2ccc3ncc(C(=O)Nc4nccs4)cc3c(=O)c2c1
Reaction time: 18 h

Procedure:
The crude 7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylic acid (21 mg, 0.056 mmol), 2-aminothiazole (8 mg, 0.084 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (16 mg, 0.084 mmol), 1-hydroxybenzotriazole hydrate (11 mg, 0.084 mmol) and 4-dimethylaminopyridine (spatula tip) were dissolved in 2 mL of DMF and stirred for 18 h. The mixture was diluted in ethylacetate and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate and concentrated. The residue was purified via reverse phase HPLC (20-100% acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, DMSO-d6) δ 13.06 (br s, 1H); 10.59 (br s, 1H); 9.47 (d, 1H); 9.13 (d, 1H); 8.02 (d, 1H); 7.81 (d, 1H); 7.61 (dd, 1H); 7.57 (d, 1H); 7.50 (d, 1H); 7.27-7.33 (m, 2H); 2.74 (s, 6H); LRMS (APCI) calc'd for (C20H17N5O4S2) [M+H]+, 456.1; found 456.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl.CCOCC>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c(c1C#CCCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperidine-1-carboxylate (0.0507 g, 0.0961 mmol) in methylene chloride (4 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (4 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with ether, and the precipitated solid was collected by filtration, and washed with ether. The resulting solid was dissolved in a small volume of water, and the solution was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonatewas. The solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[4-(piperidin-4-yl)but-1-ynyl]benzofuran-3(2H)-one (0.0372 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC(C)C)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.67 (br s, 1H, NH), 8.45 (d, 1H, J=1.8 Hz), 7.75 (d, 1H, J=8.8 Hz), 7.68 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (d, 2H, J=9.0 Hz), 7.50 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.32 (d, 1H, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 4.43 (septet, 1H, J=6 Hz), 2.65 (s, 3H), 1.28 (d, 3H, J=6 Hz). MS: m/z 445 (M+1).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=1.ClC1C=C(C=CC=1)C(O)=[O:20]>C(Cl)Cl>[OH:1][CH2:2][CH:3]1[O:20][CH:4]1[C:5]1[CH:14]=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: O=C1OCc2cc(/C=C/CO)ccc21
Solvent: ClCCl
Product: O=C1OCc2cc(C3OC3CO)ccc21
Reaction time: 2 h

Procedure:
A solution of 5-[(1E)-3-hydroxyprop-1-en-1-yl]-2-benzofuran-1(3H)-one (2.0 g, 10.5 mmol) in 50 mL of DCM was cooled to 0° C. and meta-chlorobenzoic acid (2.14 g, 10.53 mmol) in DCM (100 mL) was added dropwise. The temperature of the reaction mixture was then allowed to rise to RT. After 2 hours, the mixture was filtered and the filtrate was partitioned between DCM and water. The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified with silica gel chromatography (petrol ether/EtOAc=2:1) to give the title product.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.ClC1C=C(C2[NH:31][C:32](=[S:42])NC=2C2C=CC(F)=CC=2)C=CN=1>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[NH:31][C:32](=[S:42])[NH:2][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1
Reactant: CC(C)Oc1cc(C(N)C(=O)c2ccc(F)cc2)ccn1
Agent: Cl
Product: CC(C)Oc1cc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)ccn1

Procedure:
24c was prepared from 23c (2.5 g; 7.6 mmol) using the method described in the synthesis of 24a.