Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:54]([C:55](O)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[C:54]([C:55]([N:1]3[CH2:5][CH2:4][CH:3]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:2]3)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:48][CH:49]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A solution of 3-pyrrolidin-3-ylpyridine (6 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1479.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.[H-].[Na+].Cl>CN(C)C=O.O>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([NH:19][C:20]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.27 g, 2.0 mmole), 3-(trifluoromethyl) phenyl isocyanate (0.55 ml, 4.0 mmole), and 60% sodium hydride in mineral oil (0.088 g, 2.2 mmole) in dimethylformamide (100 mL) was stirred at 0° C. for 1 hour and then heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N aqueous HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified with by chromatography on silica gel (40% dichloromethane/hexane) to give a clear oily liquid as the expected product. The oily product was crystallized with ethyl acetate/hexane in a dry ice bath to afford the title compound as a white solid, mp=68–69° C.; MS (−) ESI m/z=324 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:30])[C:11]([CH:28]=[O:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4].[O-:31]Cl=O.[Na+].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:30])[C:11]([C:28]([OH:31])=[O:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C=O)c(=O)n21
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)[C@@H]1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C(=O)O)c(=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2 (100 mg, 0.239 mmol) in dimethylsulfoxide (2.40 mL), NaH2PO4 (66.0 mg, 0.478 mmol), dissolved in water (0.960 mL), was added dropwise at room temperature. The mixture was then kept on ice and NaClO2 (86.0 mg, 0.956 mmol) dissolved in water (0.480 mL), was added dropwise during 30 min. A white precipitate formed. The reaction mixture was stirred in room temperature for 1 h and then poured into a separation funnel containing ice-cooled 1M HCl. The aqueous phase was extracted with CH2Cl2 and the combined organic phases concentrated. The residue was dissolved in H2O:MeCN, 8:2 and freeze dried to yield 5 as a white powder (102 mg, yield: 98%). 1H-NMR (400 Mhz, CDCl3) δ 14.60 (s, 1H, CO2H), 8.21 (d, J=8.32 Hz, 1H, ArH), 7.85 (d, J=7.68 Hz 1H, ArH), 7.67 (d, J=8.14 Hz, 1H, ArH) 7.61-7.45 (m, 2H, ArH) 7.30-7.21 (m, 1H, ArH), 6.69 (d, J=6.72 Hz, 1H, ArH), 5.78 (d, J=8.42 Hz, 1H, ArH), 5.51 (d, J=14.55 Hz, 1H, Nph-CH2) 5.37 (d, J=14.55 Hz, 1H, Nph-CH2) 3.87 (s, 3H, CH3) 3.82-3.72 (m, 1H, SCH2) 3.63-3.54 (m, 1H, SCH2) 1.44-1.32 (m, 1H, CH-cyclopropyl) 0.81-0.64 (m, 2H) 0.56 (sd, 2H, CH2-cyclopropyl) 13C-NMR (100 Mhz, CDCl3) δ 167.59, 165.24, 165.09, 163.75, 154.33, 134.92, 133.84, 132.16, 128.83, 126.78, 126.15, 125.76, 125.51, 123.40, 123.23, 118.68, 112.72, 64.10, 53.84, 33.35, 31.58, 12.10, 8.35, 7.67.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=O)=[C:15]([O:24][CH3:25])[CH:14]=1.[NH2:26][C:27]1[C:31]([CH3:32])=[C:30]([CH3:33])[O:29][N:28]=1>>[CH3:32][C:31]1[C:27]([NH:26][C:20](=[O:22])[CH:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)=[CH:14][C:15]=2[O:24][CH3:25])[CH3:23])=[N:28][O:29][C:30]=1[CH3:33]
Reactant: Cc1onc(N)c1C
Reactant: COc1cc(Oc2ccnc3ccc(F)cc23)ccc1C(C)C(=O)O
Product: COc1cc(Oc2ccnc3ccc(F)cc23)ccc1C(C)C(=O)Nc1noc(C)c1C
Yield: 11 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-[4-(6-fluoroquinolin-4-yloxy)-2-methoxyphenyl]propionic acid was reacted with 3-amino-4,5-dimethylisoxazole. The resultant mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound as a solid in 11% yield; 1H NMR: (DMSOd6) 1.43 (s, 3H), 1.77 (s, 3H), 2.3 (s, 3H), 3.81 (s, 3H), 4.16 (q, 1H), 6.72 (d, 1H), 6.87 (m, 1H), 7.0 (d, 1H), 7.4 (d, 1H), 7.75 (m, 1H), 7.97 (m, 1H), 8.12 (m, 1H), 8.7 (d, 1H), 10.16 (s, 1H); Mass Spectrum: M+H+ 436.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:10])=[O:9].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.CCCCCC.CCOC(C)=O>O1CCOCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([N:11]2[C:23](=[O:25])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2N)cc1OC
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)Nc3ccccc3S2(=O)=O)cc1OC
Yield: 46.2 %

Procedure:
A mixture of 2-amino-N-(3,4-dimethoxyphenyl)benzenesulfonamide (0.8 g, 2.6 mmol) and triphosgene (0.99 g, 3.4 mmol) in anhydrous 1,4-dioxane was heated in a sealed tube at 100° C. overnight with TLC monitoring (hexane:EtOAc, 1:1). After concentration in vacuo H2O (30 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 20-25% EtOAc in hexane yielded the title compound (0.4 g, 1.20 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([C:15]=2[C:16](=[NH:18])[O-])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.[NH2:27][NH2:28]>CCO.CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[C:9]3[C:14]([C:15]=2[C:16](=[N:27][NH2:28])[NH2:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: NN
Reactant: Cc1noc(C)c1-c1c(C(=N)[O-])c2ccccc2n1-c1ccc(O)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1c(C(N)=NN)c2ccccc2n1-c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carbimidate (Example 184) was dissolved in EtOH and 10 eq hydrazine was added. The resulting mixture was stirred at 90° C. for 10 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic phase was evaporated to dryness in vacuo and then purified using reversed phase preparative HPLC. Fractions were combined, concentrated and the final product was identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 362.21 (M+H), 360.28 (M−H); 1H NMR (methanol-d3, 500 MHz): 7.81 (m, 1H), 7.36-7.32 (m, 3H), 7.08 (m, 2H), 6.90 (m, 2H), 2.16 (s, 3H) and 1.96 (s, 3H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@H:23]3[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:19][C:20]=2[CH2:21][CH2:22]3)=[CH:9][CH:8]=1.[C:33]([O-])(=[S:35])[CH3:34].[K+]>>[C:33]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@H:23]3[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:19][C:20]=2[CH2:21][CH2:22]3)=[CH:9][CH:8]=1)(=[S:35])[CH3:34]
Reactant: C[C@]12C[C@H](c3ccc(OCCCCI)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CC([O-])=S
Agent: [K+]
Product: CC(=S)CCCCOc1ccc([C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1
Yield: 82.2 %

Procedure:
The operation is carried out as in Stage E of Example 8 starting with 1.18 g of the product obtained in Stage D and 460 mg of potassium thioacetate. 850 mg of expected product is obtained. M.p. #90° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:40]([N:43]([CH3:73])[NH:44][C:45](=[O:72])[C@H:46]([N:54]([CH3:71])[C:55](=[O:70])[C@H:56]([NH:68][CH3:69])[CH2:57][C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=[O:42])[CH3:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:68]([C@@H:56]([C:55](=[O:70])[N:54]([C@H:46]([CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:45]([NH:44][N:43]([C:40](=[O:42])[CH3:41])[CH3:73])=[O:72])[CH3:71])[CH2:57][C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=1)[CH3:69])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NN(C)C(C)=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.1 g, 0.42 mmol) in methylene chloride (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.06 g, 0.42 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.08 g, 0.42 mmol) and the mixture was cooled to 0° C. Then (2R)-N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (0.13 g, 0.28 mmol) and diisopropylethylamine (0.062 ml, 0.36 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo. The product was chromatographed on silica (40 g) with heptane:ethyl acetate (1:1) to give 0.12 g (63%) of ((3E)-4-[N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:3]=2[OH:2])[CH2:14][CH2:15]1)[CH2:20][CH3:21]
Reactant: CCCN1CCC(c2cccc(C(F)(F)F)c2OC)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2O)CC1
Reaction time: 2 h

Procedure:
4-[2-methoxy-3-(trifluoromethyl)phenyl]-1-propylpiperidine (0.18 g, 0.6 mmol) and pyridine hydrochloride (2 g) was heated to 190° C. and stirred for 2 h. Aqueous sodium carbonate (10%, 50 ml) and ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phase was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate/methanol, 1:1) gave the title compound: 0.17 g (98%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 218-220° C. MS m/z (relative intensity, 70 eV) 287 (M+, 10), 259 (14), 258 (bp), 238 (15), 195 (19).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.C(N(S(F)(F)[F:24])CC)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:24])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: O=C1COCC(CO)(c2cc(Br)ccc2F)N1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2cc(Br)ccc2F)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(5-bromo-2-fluoro-phenyl)-5-hydroxymethyl-morpholin-3-one (1.6 g, 5.26 mmol) in 30 ml THF was added dropwise diethylaminosulfur trifluoride (0.97 ml, 7.34 mmol) and stirred for 2 h. The colorless solution was slowly added to an ice cooled Na2CO3 solution (10%, aqueous) and extracted with TBME. The organic layer was washed with brine, dried with MgSO4 and evaporated. The crude product was purified by chromatography on silica gel (heptane/EtOAc 3/1) to provide the title compound as a slightly yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([NH:28]C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:36])[C:10]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:17]([NH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([O:37][C:38]3[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=3)[C:11]=1[F:36])=[O:18])=[CH:27]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
Trifluoroacetic acid (5 mL, 64.9 mmol) was added to a solution of 1,1-dimethylethyl (2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)carbamate (1.36 g, 2.39 mmol) in dichloromethane (40 mL). The reaction mixture was stirred at RT overnight. The solvent was evaporated to give the title compound as a beige foam (1.35 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (s, 1H), 9.92 (br. s., 2H), 9.13 (t, 1H), 7.75-7.85 (m, 1H), 7.62 (d, 1H), 7.44-7.57 (m, 4H), 7.40 (t, 1H), 7.23 (d, 1H), 7.16 (dd, 1H), 4.57 (d, 2H). ES-LCMS: m/z 469 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11](=[O:13])[CH3:12].[OH-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[NH2:1])(=[O:13])[CH:12]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1oc2ccccc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(C(=O)C=Cc2ccccc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of 1A (114 mmol) in MeOH (200 mL) was added NaOH (18.2 g, 445 mmol). The reaction was exothermic. After cooled to room temperature, benzaldehyde (14.5 g, 137 mmol) was added. The mixture was stirred overnight under N2. TLC monitored the reaction. After the reaction completed, the reaction mixture was poured into ice-water under stirring. The solids precipitated out and were collected by filtration, and dried to give 1B (26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[SH:11][CH2:12][CH2:13][OH:14]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OCCS
Reactant: N#Cc1ccc(F)cc1Cl
Product: N#Cc1ccc(SCCO)cc1Cl

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 2-chloro-4-(2-hydroxyethylthio)benzonitrile. 1 g of 2-chloro-4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-hydroxyethylthio)benzoic acid. 1 g of 2-chloro-4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 451.0(M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:18][C:19](=[O:21])[CH3:20])[NH:11][C:10]=2[CH3:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[C:19]([NH:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[C:10]([CH3:22])[N:11]2[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:21])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Nc1cccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-4-yl]acetamide (1.0 g, 3.0 mmol), anhydrous potassium carbonate (0.63 g, 4.6 mmol), acetone (10 mL) and ethyl bromoacetate (0.50 mL, 4.5 mmol) was heated under reflux for 1.5 h then cooled to r.t. and left stirring at this temperature overnight. After heating under reflux for an additional 1 h, the mixture was cooled to r.t. Water (2×10 mL) was added, the solid product was collected by filtration, washed with water (10 mL), then dried in a vacuum oven at 40° C. to afford the title compound as an off-white solid; 1.16 g (92%); purity 95.4 area % by HPLC; m/z: 417/419 (MH+); 1H-NMR: 9.52 (1H, s), 7.45 (1H, d, J=7.9 Hz), 7.33 (1H, d, J=8.2 Hz), 7.29 (2H, d, J=8.6 Hz), 7.11 (1H, t, J=8.0 Hz), 6.97 (1H, d, J=8.6 Hz), 5.24 (2H, s), 4.18 (2H, q, J=7.1 Hz), 2.39 (3H, s), 1.86 (3H, s), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[NH:6][C:5]2=[O:13].[Cl:14][C:15]1[C:20]([CH:21]=O)=[C:19]([O:23][CH3:24])[N:18]=[CH:17][CH:16]=1>CO.CC(O)=O.O>[Cl:14][C:15]1[CH:16]=[CH:17][N:18]=[C:19]([O:23][CH3:24])[C:20]=1[C:21]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:12])[NH:6][C:5](=[O:13])[C:4]=3[CH:3]=[C:2]2[N:1]=1
Reactant: COc1nccc(Cl)c1C=O
Reactant: Nc1cc2c(cc1N)C(=O)NC2=O
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)NC3=O
Reaction time: 8 h
Yield: 87.5 %

Procedure:
5,6-Diaminoisoindoline-1,3-dione (2.88 g, 16.26 mmol) and 4-chloro-2-methoxynicotinaldehyde (2.79 g, 16.26 mmol) were suspended in MeOH/HOAc (200 mL, 3/1 v/v) at rt under air. The reaction mixture was stirred under air overnight and diluted with 200 mL of water. The solid was filtered, washed with acetone and recrystallized from hot EtOAc to give a pale-yellow solid product, 4.67 g, 87.5% yield. MS: 329.0 [M+H]+. 1H NMR (DMSO-d6, 500 MHz): δ 13.23 (s, 1H), 8.36 (d, 1H, J=5.5 Hz), 8.02 (S, 2H), 7.39 (d, 1H, J=6.0 Hz), 3.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]1=2>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:14]1[S:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: c1ccc2sccc2c1
Product: Brc1cccc(Cc2cc3ccccc3s2)c1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 4 using 3-bromobenzaldehyde and benzo[b]thiophene.
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C([Cl:16])(=O)C>II>[Cl:16][CH2:2][CH2:1][O:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(OCC)OCC
Agent: II
Product: CCOC(=O)COCCCl
Temperature: 50 °C
Yield: 101.8 %

Procedure:
20 mL (112 mmol) of ethyl diethoxyacetate, 16 mL (224 mmol) of acetyl chloride and 60 mg (0.2 mmol) of iodine are placed in a round-bottomed flask and heated at 50° C. for 24 hours. The reaction progress is monitored by NMR. The excess acetyl chloride is removed by evaporation under vacuum. 19 g (100%) of ethyl chloroethoxyacetate are obtained in the form of a liquid colored brown by the residual iodine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.CS([Cl:16])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Cl:16])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc2c(c1)CCCC2Cl
Yield: 31.6 %

Procedure:
To 7.02 g of 3-methyl-5,6,7,8-tetrahydroquinoline was added dropwise 9.62 g of methanesulfonyl chloride under ice-cooled condition. The reaction mixture was stirred under ice-cooling condition for 2 hours, then further stirred at 80° C. for 3 hours. To the reaction mixture was added water, and this solution was made alkaline by adding sodium carbonate, then extracted with diethyl ether. The diethyl ether layer was washed with an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation, then thus obtained residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol=100/1) to obtain 2.74 g of 3-methyl-8-chloro-5,6,7,8-tetrahydroquinoline.