Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[C:7]([N:30]2[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: OC1CCNCC1
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CCC(O)CC1
Temperature: 65 °C
Yield: 58.9 %

Procedure:
A stirred mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.120 g, 0.301 mmol), 4-hydroxypiperidine (0.0366 g, 0.362 mmol), palladium acetate (1 mg, 0.006 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6 mg, 0.009 mmol), and cesium carbonate (0.14 g, 0.42 mmol) in tetrahydrofuran (6 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and then filtered. The filtrate was washed with brine, dried over sodium sulfate and evaporated to dryness. The resulting residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane, to give the desired product (62 mg, 59%). LCMS calculated for C17H21ClN3O3 (M+H)+: m/z=350.1; Found: 350.1.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: COC1CCCCC1=O
Agent: [Pd]
Product: COc1ccccc1O

Procedure:
A suspension of 800 mg. of 5% palladium on charcoal (half of which has beenused for a previous dehydrogenation) in 100 gm. of distilled 2-methoxycyclohexanone was stirred and refluxed under a pressure of 9 psi.After 5 hours approximately 75% of the ketone was converted. The reaction was stopped and the crude product separated by filtration. Distillation afforded a high yield of o-methoxyphenol with virtually no residue in the still pot. The catalyst can be reused with no additional fresh catalyst added.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[N:27](S(C3C=CC=CC=3)(=O)=O)[C:21]3=[N:22][CH:23]=[C:24]([F:26])[CH:25]=[C:20]3[CH:19]=2)=[CH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:37].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[NH:27][C:21]3=[N:22][CH:23]=[C:24]([F:26])[CH:25]=[C:20]3[CH:19]=2)=[CH:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:6][C:5]=1[F:37]
Reactant: COC(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
A mixture of 4[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (400 mg, 0.74 mmol) and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 ml) was stirred at 25° C. for 16 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×100 mL), washed with a saturated aqueous ammonium chloride solution (3×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-fluoro-4-[1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl]-benzoic acid methyl ester (250 mg, 84%) as a solid which was used in the next step without further purification: LC/MS m/e calcd for C22H20F2N2O3 [M+H] 399.41, observed 399.0.
Reaction SMILES: [C@H:1]([NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:8]=1)([CH2:3][CH3:4])[CH3:2].[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[F:31].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][C@@H:1]([CH2:3][CH3:4])[CH3:2])=[O:20])[CH2:19][CH2:18]2)=[O:27])=[CH:24][C:23]=1[F:31]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC[C@@H](C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution of (R)—N-sec-butyl-3-(piperazin-1-ylmethyl)benzamide (5.08 mmol, 1.4 g), 4-amino-3-fluorobenzoic acid (5.08 mmol, 0.789 g) and triethylamine (15.25 mmol, 2.126 mL, 1.543 g) in dichloromethane (80 mL) was added 1-propanephosphonic acid cyclic anhydride (7.63 mmol, 2.270 mL, 2.426 g, 50% solution in ethyl acetate). The reaction mixture was stirred for 1 hour then was diluted with ethyl acetate and potassium carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. Chromatography on silica (eluting with ethyl acetate to ethyl acetate/methanol (5%)) gave the intermediate (R)-3-((4-(4-amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-sec-butylbenzamide (1.2 g).
Reaction SMILES: [CH3:1][Mg]I.[OH:4][C@H:5]1[CH2:10][C@H:9]2[CH2:11][C@@:8]32[C@H:12]2[C@H:22]([CH2:23][CH2:24][C@:6]13[CH3:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[CH:14]=[CH:13]2>C1COCC1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:4][C@H:5]1[CH2:10][C@H:9]2[CH2:11][C@@:8]32[C@H:12]2[C@H:22]([CH2:23][CH2:24][C@:6]13[CH3:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[CH2:14][C@H:13]2[CH3:1]
Reactant: C[Mg]I
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@H]3C[C@@]312
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)C[C@H]4C[C@]43[C@H]12
Temperature: -5 °C
Reaction time: 2 h

Procedure:
80 ml of THF is added to a solution of methylmagnesium iodide (prepared from 2.5 g of magnesium and 6.4 ml of methyl iodide in 80 ml of diethyl ether), it is cooled to −5° C., and 1 g of copper acetate-monohydrate, dissolved in 50 ml of THF, is added. It is cooled to −20° C., and then a solution of 5 g of 17β-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one in 80 ml of THF is added in drops. After 2 hours, it is poured onto ice water/2N sulfuric acid and extracted with 3×80 ml of ethyl acetate. The organic extract is dried and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethyl acetate 10:1). For further purification, it is recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Br:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][N:30]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=2)[CH:31]([CH3:32])[CH3:33])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccc(Br)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (100 mg, 0.35 mmol), 4-bromo-N′-isopropylbenzohydrazide (134.24 mg, 0.52 mmol) and HATU (198.5 mg, 0.52 mmol) dissolved in DMF (4.0 ml), N,N-diisopropylethylamine (DIPEA)(0.09094 ml, 0.52 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried so that ivory (E)-tert-butyl 3-(3-(2-(4-bromobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (85.5 mg, 46.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH2:10][NH:9]2)=[N:6][CH:7]=1.Cl[C:19]1[C:24]([NH:25][C:26](=O)[O:27]C(C)(C)C)=[CH:23][CH:22]=[CH:21][N:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>CC(O)C.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]=[C:11]3[C:10]([CH:15]=[CH:14][C:13]([N:17]4[C:19]5=[N:20][CH:21]=[CH:22][CH:23]=[C:24]5[NH:25][C:26]4=[O:27])=[CH:12]3)=[N:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(N2NCc3cc(N)ccc32)nc1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1ccc(-n2cc3cc(-n4c(=O)[nH]c5cccnc54)ccc3n2)nc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 34.1 %

Procedure:
Under argon atmosphere, a mixture of 1-(5-methylpyridin-2-yl)-2H-indazol-5-amine (60 mg), tert-butyl 2-chloropyridin-3-ylcarbamate (67.3 mg), Pd2(dba)3 (24.5 mg), Xantphos (31.0 mg) and sodium tert-butoxide (28.3 mg) in 2-propanol (2 mL) and toluene (0.5 mL) was stirred at 90° C. for 24 h, treated with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound as white crystals (31 mg).
Reaction SMILES: [C:1]([CH:3]([C:9]1([CH3:19])[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].O>CS(C)=O>[C:1]([C:3]([C:9]1([CH3:19])[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)([CH2:24][CH:23]=[CH2:22])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)C1(C)CC(C)(C)CC(C)(C)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC(C#N)(C(=O)OCC)C1(C)CC(C)(C)CC(C)(C)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of cyanoacetate 47 (1.25 g, 4.71 mmol) in anhydrous DMSO (10 ml) was added sodium hydride (0.284 g, 7.09 mmol; 60% mineral oil dispersion). The mixture was stirred for 30 min at 50° C., and cooled to 20° C. To this was added allylbromide (0.86 g, 7.1 mmol) and the mixture was stirred for 3 h at room temperature, then for 30 min at 50° C. The mixture was cooled, treated with water and extracted with diethyl ether. The extract was washed with water and with brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 20:1) to give 48 (0.92 g, 63.7%) as a colorless oil. 1H NMR (CDCl3, TMS): 0.98 (6H, s, 3′,5′-CH3eq); 1.11 (6H, s, 3′,5′-CH3ax); 1.00-1.85 (6H, m, ring CH); 1.31 (3H, t, 7 Hz, CH3-ethyl); 1.33 (3H, s, 1′-CH3); 2.42 and 2.86 (total 2H, both dd, 13 and 7 Hz, 3-CH2); 4.02 (2H, q, 7 Hz, OCH2); 5.05-5.37 (2H, m, ═CH2) and 5.55-6.05 ppm (1H, m, ═CH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][C@H:9]1[CH:15]=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of Compound 2b (1.33 g; 5.61 mmol) in CH2Cl2 (20 mL) was added 3,3,3-triacetoxy-3-iodophthalide (3.56 g; 8.39 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was diluted with EtOAc, and washed sequentially with saturated NaHCO3 (aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2c (0.58 g; 44% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 9.59 (d, 1H), 4.28-4.45 (m, 1H), 3.77-3.89 (m, 2H), 2.43-2.63 (m, 2H), 1.46-1.51 (m, 9H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:12]=3[F:14])[C:7](=[O:27])[CH:6]=[C:5]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1.O>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:47][CH2:46][C:45]4[CH:48]=[CH:49][C:42]([O:41][CH3:40])=[CH:43][CH:44]=4)[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:12]=3[F:14])[C:7](=[O:27])[CH:6]=[C:5]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:3][CH2:2]1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cc(=O)c2c(F)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(=O)c2c(NCc3ccc(OC)cc3)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Yield: 67 %

Procedure:
A solution of ethyl 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7-[(2-pyridylamino)ethylamino]quinoline-2-carboxylate (705 mg, 1.58 mmol) and triethylamine (0.66 mL, 4.74 mmol) and 4-methoxybenzylamine (0.600 mL, 4.62 mmol) in DMSO (15 mL) was stirred at 100° C. for 18 h. The reaction mixture was poured into water, and then extracted with EtOAc. The organic layer washed with water and brine, and dried over anhyd. Na2SO4 followed by the removal of EtOAc. The crude product was purified by column chromatography (Hexane:EtOAc 1:1) to yield ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-(4-methoxybenzylamino)-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (597 mg, 67%) as a orange amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH2:13][N:14]3[C:22]4[C:17](=[C:18]([Cl:25])[C:19]([C:23]#[N:24])=[CH:20][CH:21]=4)[CH:16]=[C:15]3[CH:26]([F:28])[F:27])=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:29][N:30](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:18]1[C:19]([C:23]#[N:24])=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[C:15]([CH:26]([F:28])[F:27])[N:14]2[CH2:13][C:11]1[O:12][C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:29]#[N:30])[CH:3]=2)=[N:9][N:10]=1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(-c3cncc(Br)c3)o2)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cncc(-c2nnc(Cn3c(C(F)F)cc4c(Cl)c(C#N)ccc43)o2)c1
Temperature: 120 °C
Yield: 61 %

Procedure:
To a solution of 1-{[5-(5-bromo-3-pyridinyl)-1,3,4-oxadiazol-2-yl]methyl}-4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile (0.015 g, 0.032 mmol) in anhydrous DMF (1.5 mL) under N2, was added Zn(CN)2 (0.002 g, 0.016 mmol) and Pd(PPh3)4 (0.004 g, 0.0032 mmol). The mixture was heated at 120° C., under N2 for 1 h. Additional Pd(PPh3)4 (0.004 g, 0.0032 mmol) was added and the mixture was heated at 120° C., under N2 for another 40 min. Upon cooling, the mixture was partitioned between Et2O and water. The organic phase was washed with water and sat'd brine. The combined aqueous phases were washed with EtOAc. The EtOAc phase was washed with water (2×) and brine. The Et2O and EtOAc phases were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (5-70% EtOAc-hexanes gradient), followed by a second purification by radial chromatography (0-3% MeOH—CH2Cl2 gradient). The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.008 g, 61% yield): MS (ES) m/z 411 (M+1).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH2:28][C:29]([O:31][C@H:32]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:52])[F:51])=[C:45]([O:53][CH2:54][CH:55]3[CH2:57][CH2:56]3)[CH:44]=2)[CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][N+:37]([O-:41])=[CH:36][C:35]=2[Cl:42])=[O:30])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:42][C:35]1[CH:36]=[N+:37]([O-:41])[CH:38]=[C:39]([Cl:40])[C:34]=1[CH2:33][C@H:32]([O:31][C:29](=[O:30])[CH2:28][O:27][C:25](=[O:26])[CH2:24][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]2[CH2:22][CH2:23]2)=[C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:14]=1)[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:52])[F:51])=[C:45]([O:53][CH2:54][CH:55]2[CH2:56][CH2:57]2)[CH:44]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(CC(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(CC(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccc1OCC1CC1
Yield: 26.9 %

Procedure:
To a solution of crude (S)-4-(2-(2-(2-(3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetoxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (theoric 0.501 mmol) in DCM (5 ml), HCl 4M in dioxane (1.309 ml, 5.23 mmol) was added and the mixture was reacted for 4 hours at RT. The solvents were evaporated to dryness, and the resulting crude was purified by preparative LC-MS recovering the desired product (102.5 mg, 0.135 mmol, 26.9% yield over two steps, MS/ESI+ 759.46 [MH]+, [αD]=+47.84, c=0.25, DCM).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:14]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(C)=O)ccc1O
Reaction time: 5 h

Procedure:
36 g of methyl 2-methoxy-benzeneacetate and 15.7 g of acetyl chloride are dissolved in 100 ml of methylene chloride, the resultant solution then being added dropwise to a suspension of 100 g of aluminum chloride in 300 ml methylene chloride. The solution is boiled for 5 hours, poured onto ice water and filtered. The crystals are washed with water and methylene chloride.
Reaction SMILES: ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH:24]1[CH:29]=[C:28]([CH2:30][C:31](O)=[O:32])[C:27]([NH:34][C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:26][CH:25]=1.CCOC(C)=O>ClCCl>[CH2:30]1[C:31](=[O:32])[N:34]([C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[C:27]2[C:28]1=[CH:29][CH:24]=[CH:25][CH:26]=2
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1Cc2ccccc2N1c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
N-Hydroxysuccinimide (0.76 mmol) and DCC (0.76 mmol) are added to a solution of the corresponding diclofenac acid derivative (0.506 mmol) dissolved in 10 ml of dichloromethane. The mixture is stirred for 1 hour and monitored by TLC (EtOAc:He, 1:1). When completion of the reaction is detected, the mixture is filtered and the solvent is evaporated under reduced pressure. The crude product is purified by column chromatography to afford the pure diclofenac amide derivative.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=2)=[O:28])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(Sc2ccc3ccccc3n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
2-(4-Aminophenylthio)quinoline (3.9 moles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisocyanate (3.9 moles, 0.85 g) were reacted according to procedure A to yield the title compound, 0.8 g, 43%. Mass Spec (FD) 463. Calculated for C23H15ClF3N3OS: C, 58.29; H, 3.19; N, 8.87. Found: C, 58.56; H, 3.43; N, 9.02. M Pt 194°-195 ° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].Cl[C:19]([O:21][CH3:22])=[O:20].Cl>C1COCC1>[CH3:22][O:21][C:19]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:20]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
was prepared as follows: A suspension of L-diphenylalanine (13.87 g, 57.5 mmol) in THF (100 mL), and saturated NaHCO3 (3 mL) being stirred at 0° C. was treated with neat methyl chloroformate (11.81 g, 125 mmol), stirred at 0° C. for 10 minutes and then at room temperature for 14 hours. 1 M HCl was then added and the mixture was extracted with DCM, dried over MgSO4, filtered and concentrated to give the title compound as a white solid, which was used without further purification. MS: m/z=322.1 (MNa+). Part B. The title compound was prepared as follows: To a mixture of N-(1-[4-(aminomethyl)thiophen-2-yl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-(3-methylbutyl)benzenesulfonamide (87 mg, 0.227 mmol), N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (75 mg, 0.250 mmol) and Hunig's base (131 μL, 0.751 mmol) in 2.3 mL DMF was added BOP reagent (111 mg, 0.25 mmol). The mixture was stirred at room temperature for 1 hour, and then quenched with saturated NaHCO3. The aqueous layer was extracted 2× with EtOAc, the EtOAc layers were combined and washed 3 times with water, once with brine and dried (MgSO4). The mixture was filtered, concentrated and purified on silica gel (EtOAc/hexanes). MS: m/z=686.2 (MNa+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:14])([F:13])[CH2:11]I.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:9][C:10]([F:14])([F:13])[CH2:11][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccccc1Br
Temperature: 25 °C

Procedure:
A solution of 0.35 g (2 mmol) of 2-bromophenol, 0.63 g (3 mmol) of 2,2,2-trifluoroethyliodide, 0.55 g (4 mmol) of potassium carbonate in 2 Ml of DMF was reacted at 150° C. in a microwave system (Personal Chemistry, Smithcreator) for 30 min. After cooling to RT, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (5%, 10% successively EtOAc:hexanes) to give the title compound.