Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].[I-].[K+].[C:5]1([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[O:16]=[C:12]([CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:13]([O-:15])=[O:14].[Na+:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C([O-])C(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A 3N aqueous solution (4 ml) of sodium hydroxide, 10 ml of tetrahydrofuran, 100 mg of potassium iodide and 100 mg of triethylbenzylammonium chloride were added to 0.83 g (5.0 mmoles) of phenylpyruvic acid to form a solution. Then, 0.8 ml of p-chlorobenzyl chloride was added, and the mixture was stirred at room temperature for 36 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with 100 ml of ether. The ether layer was dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellowish white oil. A 1N aqueous solution of sodium hydroxide was added to the product, and the mixture was concentrated under reduced pressure. Ether was added to the resulting semi-soid mixture, and the precipitated sodium 2-oxo-3-phenyl-4-(p-chlorophenyl)butanoate was isolated by filtration as a white solid (yield 37 %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:8].[CH:25]1([C:28]2[S:32][C:31]([NH2:33])=[N:30][N:29]=2)[CH2:27][CH2:26]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:33][C:31]2[S:32][C:28]([CH:25]3[CH2:27][CH2:26]3)=[N:29][N:30]=2)=[CH:14][CH:13]=1)=[O:8]
Reactant: Nc1nnc(C2CC2)s1
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)Nc2nnc(C3CC3)s2)cc1
Temperature: 115 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
1.1 g 4-[2-(5-Chloro-2-methoxy-benzoylamino)-ethyl]-benzenesulfonyl chloride, 483 mg 5-Cyclopropyl-[1,3,4]thiadiazol-2-ylamine and 35.0 mg 4-dimethylaminopyridine were dissolved in 5 ml pyridine and stirred under microwave irradiation at 115° C. for two hours. The pyridine was removed in vacuo and the residue coevaporated three times with portions of 20 ml toluene. The residue was purified by RP-HPLC to obtain 590 mg 5-Chloro-N-{2-[4-(5-cyclopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-ethyl}-2-methoxy-benzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][O:20][CH3:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:19][O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
A mixture of 4-(benzyloxy)-3-hydroxybenzaldehyde (912 mg, 4 mmol), chloro(methoxy)methane (480 mg, 6 mmol), and DIPEA (1.03 g, 8 mmol) in 20 mL DCM was stirred at rt under Ar atmosphere for 15 h. It was diluted with ether (100 mL) and washed with 0.5 M HCl(2×50 mL) and water (2×80 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (hexane/EtOAc) to afford 4-(benzyloxy)-3-(methoxymethoxy)benzaldehyde as a clear oil (960 mg, 88%). MS (ESI) m/z 273 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:34](O)[CH2:35][OH:36].C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:18][CH2:34][CH2:35][OH:36])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(OCCO)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 300 mg, 0.864 mmol), p-toluenesulfonic acid monohydrate (8.2 mg, 0.043 mmol) and ethylene glycol (1.45 mL) was stirred at rt overnight. The resulting suspension was treated with NaHCO3 (aq) and diluted with water. The precipitate was collected by filtration, washed with water and dried to provide 4-bromo-7-(2-(2-hydroxyethoxy)propan-2-yl)-9H-carbazole-1-carboxamide as a white solid (324 mg, 96%). 1H NMR (400 MHz, methanol-d4) δ 8.65 (1 H, d, J=8.58 Hz), 7.77 (1 H, d, J=1.10 Hz), 7.75 (1 H, d, J=8.14 Hz), 7.44 (1 H, dd, J=8.36, 1.54 Hz), 7.40 (1 H, d), 3.69 (2 H, t, J=5.17 Hz), 3.32-3.34 (2 H, m), 1.68 (6 H, s). Mass spectrum m/z 413, 415 (M+Na)+.
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)=[N:8][CH:9]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C([O-])(O)=O.[Na+].Cl>C1COCC1>[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:36](=[O:38])[CH3:37])[CH2:18][CH2:17]3)[N:15]=2)=[N:8][CH:9]=1
Reactant: Brc1cnc(Nc2nc(C3CCNCC3)cs2)c(Oc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
A 20 mL vial was charged with 5-bromo-3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine dihydrochloride (80 mg, 0.159 mmol), triethylamine (0.088 mL, 0.64 mmol) and THF (2 mL). Acetic anhydride (0.015 mL, 0.16 mmol) was added and stirred at ambient temperature for 30 minutes. The reaction was poured into saturated aqueous NaHCO3 and extract with EtOAc (2×20 mL). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (5% methanol in EtOAc) to afford the title compound (47.6 mg, 58.8% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.00 (bs, 1H), 8.23 (d, 1H), 7.44 (m, 2H), 7.40 (d, 1H), 7.21 (t, 1H), 7.11 (d, 2H), 6.70 (s, 1H), 4.41 (d, 1H), 3.12 (m, 1H), 2.83 (tt, 1H), 2.62 (td, 1H), 2.50 (m, 1H), 2.00 (s, 3H), 1.93 (m, 2H), 1.55 (qd, 1H), 1.42 (qd, 1H). Mass spectrum (apci) m/z=475.2 (M+H—HCl).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:5])[CH3:2].[OH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[OH:18])=[O:30])[CH2:8][N:7]1[CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](N)CN1CC1CCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCC1

Procedure:
(2S,4S)-1-Cyclopentylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-amino-1-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C24H31N2O4 [(M+H)+] 411.0, obsd. 411.2.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]([CH3:61])[C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:39][N:40]([CH3:61])[C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=1
Reactant: CN(C)c1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with N-(3-(dimethylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (145 mg, 0.43 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (42 mg, 0.05 mmol) and sodium carbonate (45 mg, 0.42 mmol) in DME (1.6 ml) and water (0.4 ml). The reaction mixture was submitted to vacuum-argon cycles and stirred at 70° C. for 1.5 h. The reaction mixture was cooled down to room temperature and poured into ice-water, basified with potassium carbonate and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by normal phase using SP1® Purification System (0% to 10%, hexane-ethyl acetate) to obtain 89.5 mg (73% yield) of the title compound. Purity: 100%.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]=[O:9].[NH4+].[Cl-]>C1COCC1>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]([OH:9])[CH2:2][CH3:1]
Reactant: O=Cc1c(F)cccc1Br
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1c(F)cccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of EtMgBr (35 mL, 35 mmol) in TH-F (1 M) is added dropwise to a solution of 2-bromo-6-fluoro-benzaldehyde (7 g, 34.5 mmol) in THF at −78° C. The mixture is stirred for 1 hour at −78° C. Saturated NH4Cl is added dropwise to the mixture which is subsequently warmed to room temperature and stirred for 1 hour. The organic layer is separated, extracted with THF (3×100 mL. The combined organic layers are washed with brine, dried and solvent is removed in vacuo. The crude product is purified by flash chromatography (5% EtOAc/hexanes) to obtain 1-(2-bromo-6-fluoro-phenyl)-propan-1-ol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:19][C:20]2[CH:25]=[CH:24][C:23](/[C:26](/[NH:35]C(OC(C)(C)C)=O)=[N:27]/C(OC(C)(C)C)=O)=[CH:22][CH:21]=2)[C:16]([O-:18])=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26](=[NH:27])[NH2:35])=[CH:24][CH:25]=2)[C:16]([O:46][CH3:45])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)c1ccc(NC(C(=O)[O-])c2cccc(OCc3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(Nc1ccc(C(=N)N)cc1)c1cccc(OCc2ccccc2)c1
Reaction time: 0.83 h

Procedure:
655 mg of methyl (E)/(Z)-(RS)-(3-benzyloxy-phenyl)-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-phenylamino]-acetate were treated in 3 ml of methylene chloride with 3 ml of trifluoroacetic acid and left to stand for 50 min. at room temperature. The solution was evaporated in a vacuum and the residue was chromatographed on silica gel. There were obtained 440 mg of methyl (RS)-(3-benzyloxy-phenyl)-(4-carbamimidoyl-phenylamino)-acetate trifluoroacetate, m.p. 162° C., MS: 390 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3]
Reactant: CNC
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: Cl
Product: CN(C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1

Procedure:
8-Dimethylsulfamoyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is prepared according to synthesis 178, from 326 mg (1 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid and 85 mg (1.05 mmol) of dimethylamine hydrochloride to give, after purification by precipitation and trituration in water, 210 mg (62%) of 8-dimethylsulfamoyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a gray solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (4.66 g, 34.2 mmol) in diethyl ether (100 ml) was added sodium borohydride (2.59 g, 68.4 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and a solution of ethyl 3-(3-chlorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (7.40 g, 17.1 mmol) in diethyl ether (30 ml) was added to the filtrate at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to the reaction solution to stop the reaction. Then, water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective substance (6.6 g, 89%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:31])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:37]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]4[N:23]=[CH:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][N:27]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]2=[O:31])=[CH:7][CH:8]=1)=[O:37]
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(SC)cc4)c(=O)c3)CC2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
To a stirring solution of 1-(4-(methylthio)phenyl)-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (51.4 mg, 0.118 mmol) in CH2Cl2 (15 mL) at 0° C. was added a solution of 3-Chloroperoxybenzoic acid (26.4 mg, 0.118 mmol) in 5 mL CH2Cl2. The reaction was stirred at 0° C. for 15 min and then quenched with Na2SO3 (sat. solution in H2O). The organic layer was washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0 to 10% MeOH in CH2Cl2) to yield 50 mg of desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (s, 2 H), 7.77 (d, J=8.31 Hz, 2 H), 7.57 (d, J=8.31 Hz, 2 H), 7.23 (d, J=7.34 Hz, 1 H), 5.94-6.11 (m, 2 H), 4.44-4.64 (m, 1 H), 4.07-4.31 (m, 2 H), 3.50-3.74 (m, 2 H), 2.77 (s, 3 H), 2.40 (t, J=7.58 Hz, 2 H), 1.98-2.17 (m, 2 H), 1.73-1.93 (m, 2 H), 1.50-1.64 (m, 2 H), 0.93 (tr=7.34 Hz, 3 H). MS (ESI) 453 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]([Mg]Br)=[CH2:12].[Cl-].[NH4+]>C(OCC)C.O1CCCC1.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH:11]=[CH2:12]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(Cl)cc1Cl

Procedure:
A solution of 20.0 g (114 mmol) of 2,4-dichlorobenzaldehyde in 200 ml of diethyl ether was slowly added dropwise to 137 ml (137 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran at RT under argon. After heating under reflux for 1 h, the reaction mixture was added to saturated aqueous ammonium chloride solution and diluted with diethyl ether and water. The phases were separated, and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5/1) to result in 18.8 g (81% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>[NH4+].[Cl-]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[OH:16])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(C(O)c2ccc(Br)cn2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (1.0 eq.) in Tol (0.1M) at −78° C. was added n-BuUi (1.05 eq.). The mixture was stirred for 2 h at −78° C. then 4-methoxy-benzaldehyde (1.1 eq.) was added. The final mixture was warmed 0° C., poured in saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 3:2) and stirring in Hex:Et2O afforded the title compound as a white solid after filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].C[N+](C)(C)CC1C=CC=CC=1.[CH3:43][S:44]([CH2:46][S:47][CH3:48])=[O:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:28])[C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[C:46](\[S:44]([CH3:43])=[O:45])/[S:47][CH3:48])=[CH:19][C:18]=3[CH:25]3[CH2:27][CH2:26]3)=[CH:14][CH:15]=2)=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Reactant: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CS/C(=C/c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1)S(C)=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
N-(4-Chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 0.381 mmol) was diluted with THF (3 mL) followed by the addition of N,N,N-trimethyl(phenyl)methanaminium hydroxide (0.0866 ml, 0.191 mmol) and methylsulfinyl(methylthio)methane (94.7 mg, 0.762 mmol). The reaction was heated to 70° C. and stirred for 2 hours. The reaction was cooled and loaded directly onto a silica gel column, eluting with ethyl acetate to yield (Z)-N-(4-chlorophenethyl)-4-(2-cyclopropyl-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)benzamide (100 mg, 49.9% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][C:13](OC(C)=O)=[O:14]>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:1][C:13](=[O:14])[CH3:12])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2ccccc2cn1
Product: CC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C

Procedure:
3-Aminoisoquinoline (495 mg, 3.44 mmol) was stirred in Ac2O (9 mL) at 60° for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:9]=2[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:25][CH2:26][CH2:27][CH2:28]Br>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:28][CH2:27][CH2:26][Br:25])[C:9]=2[C:10]=1[CH:11]1[CH2:12][CH2:13]1)=[O:5])[CH3:2]
Reactant: BrCCCBr
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-cyclopropyl-4-hydroxy-benzofuran-2-carboxylic acid ethyl ester (92 mg) and potassium carbonate (62 mg) in N,N-dimethylformamide (1.5 ml) was added 1,3-dibromopropane (190 μl) and the reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution (5 ml) and diluted with ethyl acetate (8 ml). The organic layer was washed with water (5 ml twice) and brine, dried over anhydrous sodium sulfate, then concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate to give 4-(3-bromo-propoxy)-3-cyclopropyl-benzofuran-2-carboxylic acid ethyl ester (120 mg) as a white solid. EI-MS: m/z 368 (M+); 1H-NMR (CDCl3): δ 0.91-0.95 (4H, m), 1.37 (3H, t, J=7.26 Hz), 2.36 (2H, quintet, J=7.26 Hz), 2.47-2.51 (1H, m), 3.60 (2H, t, J=7.26 Hz), 4.16 (2H, t, J=7.26 Hz), 4.37 (2H, q, J=7.26 Hz), 6.58 (1H, d, J=8.25 Hz), 7.07 (1H, d, J=8.25 Hz), 7.24 (1H, dd, J=8.25 Hz, 8.25 Hz).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[C:3]=1[S:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25]C)=[O:24]>[OH-].[Na+]>[OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[C:3]=1[S:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1ccccc1SC1=C(O)CC(CCC(C)C)(c2ccccc2)OC1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Sc2ccccc2C(=O)O)C(=O)O1

Procedure:
A solution of 0.3 mmol of the compound prepared in Example 77 in 15 mL of 1N sodium hydroxide was stirred at room temperature for 3 hours. The solution was washed with ether and then acidified to pH 2.0 with 6N hydrochloric acid. The solution was extracted with ethyl acetate, and the extract was washed with brine, dried over magnesium sulfate, and concentrated to give the title compound (m.p. 99°-101° C.). 1H NMR (DMSO-d6) δ0.80 (m, 6H), 0.95 (m, 1H), 1.15 (m, 1H), 1.43 (m, 1H), 1.91 (m, 2H), 3.4 (2H+H2O), 6.05 (d, 1H), 6.85 (bt, 1H), 7.03 (t, 1H), 7.42 (m, 5H), 7.79 (dd, 1H).