Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:63]([O:65][CH2:66][CH:67]1[C:79]2[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=2)[C:73]2[C:68]1=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])[C@H:2]([C:24]([NH:26][CH2:27][C:28]([NH:30][C@H:31]([C:40]([NH:42][C@@H:43]([C:51]([N:53]([CH3:62])[C@H:54]([C:58]([O:60][Na])=[O:59])[CH:55]([CH3:57])[CH3:56])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41])[CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:29])=[O:25])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:23])[NH:8][S:9]([C:12]1[C:21]([CH3:22])=[C:19]([CH3:20])[C:16]([O:17][CH3:18])=[CH:15][C:13]=1[CH3:14])(=[O:11])=[O:10].N(C)[C@H](C(O)=O)C(C)C.N[C@@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)CC(=O)OC(C)(C)C.NCC(O)=O.N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CCCNC(=N)NS(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O.C(O)(C(F)(F)F)=O.ClCCl>>[NH:1]([C:63]([O:65][CH2:66][CH:67]1[C:79]2[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=2)[C:73]2[C:68]1=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])[C@H:2]([C:24]([NH:26][CH2:27][C:28]([NH:30][C@H:31]([C:40]([NH:42][C@@H:43]([C:51]([N:53]([CH3:62])[C@H:54]([C:58]([OH:60])=[O:59])[CH:55]([CH3:56])[CH3:57])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41])[CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:29])=[O:25])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:23])[NH:8][S:9]([C:12]1[C:21]([CH3:22])=[C:19]([CH3:20])[C:16]([O:17][CH3:18])=[CH:15][C:13]=1[CH3:14])(=[O:11])=[O:10]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)NCC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](Cc2ccccc2)C(=O)N(C)[C@H](C(=O)O[Na])C(C)C)c(C)c1C
Agent: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: CN[C@H](C(=O)O)C(C)C
Agent: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)NCC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](Cc2ccccc2)C(=O)N(C)[C@H](C(=O)O)C(C)C)c(C)c1C

Procedure:
Fmoc-Arg(Mtr)-Gly-Asp(OBut)-DPhe-NMeVal-ONa (SEQ ID NO 41) is synthesized using solid-phase Merrifield-type procedures by sequentially adding NMeVal, DPhe, Asp(OBut), Gly and Fmoc-Arg(Mtr) in a step-wise manner to a 4-hydroxymethyl-phenoxymethyl-polystyrene resin (Wang type resin) (customary Merrifield-type methods of peptide synthesis are applied as described in Houben-Weyl, l.c., Volume 15/II, Pages 1 to 806 (1974). The polystyrene resin and amino acid residues precursors are commercially available from Aldrich, Sigma or Fluka chemical companies). After completion of sequential addition of the amino acid residues, the resin is then eliminated from the peptide chain using a 1:1 mixture of TFA/dichloromethane which provides the Fmoc-Arg(Mtr)-Gly-Asp(OBut)-DPhe-NMeVal-OH product (SEQ ID NO 42). The Fmoc group is then removed with a 1:1 mixture of piperidine/DMF which provides the crude Arg(Mtr)-Gly-Asp(OBut)-DPhe-NMeVal-OH (SEQ ID NO 43) precursor which is then purified by HPLC in the customary manner.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][C:12]=3[C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1)(=O)=O.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:35])[C:33]=1[F:34].[OH-].[NH3+]N>O.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:22]([CH:19]1[CH2:18][C:12]2[C:13](=[O:17])[O:14][C:15]3[C:10]([C:11]=2[CH2:21][CH2:20]1)=[CH:9][CH:8]=[C:7]([C:30]1[CH:29]=[C:28]([F:27])[C:33]([F:34])=[C:32]([F:35])[CH:31]=1)[CH:16]=3)[CH2:23][CH3:24]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: CCCC1CCc2c(c(=O)oc3cc(OS(=O)(=O)C(F)(F)F)ccc23)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N[NH3+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCc2c(c(=O)oc3cc(-c4cc(F)c(F)c(F)c4)ccc23)C1

Procedure:
10 g (25.6 mmol) of 6-oxo-8-propyl-7,8,9,10-tetrahydro-6H-benzo[c]-chromen-3-yl trifluoromethanesulfonate, 4.50 g (25.6 mmol) of 3,4,5-trifluorobenzeneboronic acid, 10.6 g (38.4 mmol) of sodium metaborate octahydrate, 360 mg (0.51 mmol) of bis(triphenylphosphine)palladium chloride and 50 μl of hydrazinium hydroxide are dissolved in 15 ml of water and 250 ml of THF, and the mixture is refluxed overnight. Water is added to the batch, which is extracted three times with dichloromethane. The combined org. phases are dried over sodium sulfate, the solvent is removed under reduced pressure, and the residue is filtered through silica gel and recrystallised, giving 8-propyl-3-(3,4,5-trifluorophenyl)-7,8,9,10-tetrahydrobenzo[c]chromen-6-one.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8]C(=O)[N:6]3[N:13]=[CH:14][N:15]=[C:5]3[C:4]=2[CH:3]=1.[OH-].[Na+]>C(O)CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][N:13]=[CH:14][N:15]=2)[CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)cc2c2ncnn12
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Nc1ccc(Br)cc1-c1ncn[nH]1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a well stirred slurry of 9-bromo-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one (32.0 g, 171 mmol) in ethylene glycol (146 mL) which was heated at 100° C., was added aqueous NaOH (32%, 22.4 ml, 241 mmol). The slurry was heated at 140° C. for 17.5 h. The resulting solution was cooled to 27° C. and the product began to crystallize. Water (146 mL) and 1-octanol (1.73 mL) were added and the pH of the suspension was adjusted to 6.5 by the slow addition of glacial acetic acid (14 mL). The resulting slurry was stirred for 30 min, the solid was collected by filtration and washed with water and 2-propanol. Drying in vacuo afforded the title compound (25.2 g, 87%) as a light yellow solid. MS: m/e=239.0/241.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=O)=O)[N:3]=1.[F:13][C:14]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23]C(S)=[CH:21][CH:20]=1)=[O:17]>C(O)(C)(C)C>[F:13][C:14]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:15]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:12]([S:9][C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[N:5]=2)=[CH:23][CH:24]=1)=[O:17]
Reactant: O=C(Nc1ccc(S)cc1)c1c(F)cccc1F
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Solvent: CC(C)(C)O
Product: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 34.8 %

Procedure:
A 250ml round bottom flask equipped with a condenser was charged with 4,6-dichloro-2-methanesulfonyl pyrimidine (4.2 g, 18.8 mmol), 2,6-difluoro-N-(4-mercapto-phenyl)-benzamide (4.98 g, 18.8 mmol) and tert-butanol (75 ml) under nitrogen. The reaction mixture was degassed thoroughly and then heated at 90° C. for 2 h. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The solid residue was taken up in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution and brine. The organic was dried over magnesium sulfate, filtered and concentrated until the product began to precipitate. The mixture was then cooled and aged for 12 hrs. The product was collected by filtration, washed with cold ethyl acetate and dried. This gave the title compound as an off-white solid (2.7 g, 35%). 1H NMR (DMSO) 7.32 (2H, m), 7.61 (3H, m), 7.79 (1H, s), 7.82 (2H, d), 10.9 (1H, s). MS (ES+): 412.19
Reaction SMILES: O.[C:2]1([CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-]S([O-])(=O)=O.[Cu+2]>[CH2:8]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]1=[CH:6][CH:7]=[C:2]2[C:3]1[CH2:8][C:2]2[C:7]([CH:4]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: Cc1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: C=c1cccc2c1=CC=C2C1=Cc2ccccc2C1

Procedure:
The alcohol is added to the suspension of CuSO4 in toluene. After 90 minutes at 110° C. the mixture is poured into water and extracted with ethyl ether. After washing the organic extracts to neutrality with water and anhydrifying on Na2SO4, the solvent is evaporated. 1.8 g of 4-methylene(2-indenyl)indene are obtained, after purification on a silica gel column (eluant: hexane/ethyl acetate=99/1).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:15]([C:26]([O:28][CH2:29][CH2:30][C:31]#[N:32])=[O:27])=[C:14]([CH3:33])[NH:13][C:12]=1[CH3:34])=[O:10])C1C=CC=CC=1.C(O)=O>C(Cl)(Cl)Cl.[Pd]>[C:31]([CH2:30][CH2:29][O:28][C:26]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:34])[NH:13][C:14]=1[CH3:33])=[O:27])#[N:32]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(C)N1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
A solution of 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine (3.24 g, 7.02 mmol) in 160 ml of 4.4%(w/w) formic acid/NeOH mixture was stirred with Pd/C (10%, 3.24 g) for 30 min., the reaction was quenched by addition of 10 ml of CHCl3. The mixture was filtered and concentrated to give a yellow powder, which was dissolved in CHCl3 (100 ml), washed with water (25 ml) and aqueous 1N HCl (25 ml). After drying (Na2SO4) and evaporation of solvent, 3-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid was obtained as a yellow powder (1.94 g, 75%).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[O:15]C)[CH2:7][CH2:6]1>ClCCl>[NH2:12][C:11]1[CH:13]=[CH:14][C:8]([CH:5]2[CH2:7][CH2:6]2)=[C:9]([OH:15])[CH:10]=1
Reactant: COc1cc(N)ccc1C1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(C2CC2)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A solution of BBr3 in dichloromethane (4.47 mL of 1 M, 4.47 mmol) was added to a solution of 4-cyclopropyl-3-methoxyaniline (243 mg, 1.49 mmol) in dichloromethane (15 mL) at 0° C. under N2 atmosphere. The reaction was stirred for 30 min at 0° C. then diluted with dichloromethane (10 mL). The reaction mixture was washed with aqueous NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by HPLC (10-99% CH3CN. 0.05% TFA) to provide 5-amino-2-cyclopropylphenol (115 mg, 52% yield). LC/MS m/z 150.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cc(C(=O)O)c(N)c1C
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C)c(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 2-amino-5-bromo-3,4-dimethylbenzoic acid (73.9 g) in DMF (750 mL) was added cesium carbonate (148 g), and the mixture was stirred at room temperature for 30 min. To this reaction mixture was added dropwise methyl iodide (22.7 mL) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (56.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([NH2:19])[CH:9]=1.[H-].[Na+].[C:22]([C:26]1[C:27]([Cl:35])=[C:28]([C:32](O)=[O:33])[N:29]([CH3:31])[N:30]=1)([CH3:25])([CH3:24])[CH3:23].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([NH:19][C:32]([C:28]2[N:29]([CH3:31])[N:30]=[C:26]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:27]=2[Cl:35])=[O:33])[CH:9]=1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Reactant: COc1nc(-c2ccccc2Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-(2-chloro-phenyl)-2-methoxy-3-nitro-pyridin-4-ylamine (8.10 g, 29.0 mmol, prepared as described in the previous step) in THF (200 mL) was treated with NaH (3.47 g, 86.8 mmol, 60% dispersion in oil) at 0° C. for 1 h. Simultaneously a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6.90 g, 31.8 mmol, prepared as described in Example B) in DCM (200 mL) was treated with oxalyl chloride (3.2 mL, 36 mmol) and DMF (50 μL) at 0° C. and stirred at room temperature for 1 h. The volatile components were removed in vacuo, and the resulting residue was dried in vacuo for 15 min taken up in THF (20 mL) and added to the above sodium anilide solution at 0° C. The resulting mixture was stirred at room temperature for 30 min, quenched with saturated aqueous NH4Cl (20 mL), and extracted with EtOAc (3×100 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The resulting solid was suspended in hexane (200 mL) and sonicated for 10 min and collected by suction filtration to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-(2-chloro-phenyl)-2-methoxy-3-nitro-pyridin-4-yl]-amide as a tan-colored solid.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:14]([CH3:17])([CH3:16])[CH3:15].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1>[F:6][C:7]1[C:12]([F:13])=[C:11]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:10]=[CH:9][C:8]=1[Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)c1cccc(F)c1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2F)OC1(C)C
Temperature: -75 °C
Yield: 60.1 %

Procedure:
A solution of sec-butyllithium (1.4 M in cyclohexane; 19.17 mL, 26.8 mmol) was added to THF (53.7 mL) cooled to −75° C. To this solution was added (2,3-difluorophenyl)-trimethylsilane (prepared as in Heiss, C. et al. Eur. J. Org. Chem. 2007, 4, 669-675; 5.0 g, 26.8 mmol) dropwise keeping the temperature below −70° C. The resulting reaction mixture was stirred at −75° C. for 45 min after which time 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.49 g, 29.5 mmol) was added dropwise keeping the temperature below −70° C. The reaction mixture was then allowed to warm to 25° C. and was partitioned between Et2O and H2O. The aqueous phase was acidified to pH 3 with 12 Normal (N) HCl. The product was extracted with Et2O, and the organic phase was dried and concentrated under vacuum to provide the title compound as a white solid (5.03 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.42 (ddd, J=7.3, 4.4, 0.7 Hz, 1H), 7.09 (ddd, J=7.3, 4.1, 0.9 Hz, 1H), 1.36 (s, 12H), 0.32 (d, J=0.9 Hz, 9H); EIMS m/z 312.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[CH2:34](O)[CH2:35][OH:36].O.Cl>CN(C)C1C=CN=CC=1.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:34][CH2:35][OH:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: OCCO
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCCO)c[nH]4)c3)cc2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (50 mg, 0.11 mmol), ethylene glycol (1 ml), 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl, 25 mg, 0.13 mmol) and 4-dimethylaminopyridine (DMAP, 5 mg, 0.04 mmol) in anhydrous THF (10 ml) was stirred at 60° C. for 16 hours. The mixture was poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography with a gradient of 3-5% MeOH/CHCl3 to give 2-hydroxyethyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 36 mg, 67%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:39][C:40]1[CH:57]=[CH:56][C:43]2[O:44][C:45]([S:47]([N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)(=[O:49])=[O:48])=[CH:46][C:42]=2[CH:41]=1>CN(C)C=O>[Cl:39][C:40]1[CH:57]=[CH:56][C:43]2[O:44][C:45]([S:47]([N:50]3[CH2:51][CH2:52][N:53]([C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[CH:15][CH:14]=4)[CH2:54][CH2:55]3)(=[O:48])=[O:49])=[CH:46][C:42]=2[CH:41]=1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2o1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CC1
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A stirred suspension of 4-(4-pyridyl)benzoic acid (133 mg, 0.67 mmol) in dimethylformamide (5 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (HOBT, 108 mg, 0.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC, 153 mg, 0.8 mmol) and 1-(5-chlorobenzo[b]furan-2-ylsulphonyl)piperazine (201 mg, 0.67 mmol). After stirring overnight the solvent was removed in vacuo and the residue chromatographed (Merck Art 9385 silica, eluting with dichloromethane containing 2% v/v of methanol) to yield 1-(5-chlorobenzo[b]furan-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine as a colourless solid (40 mg), 1H NMR (CDCl3) 3.2-3.4 ppm (broad s, 4H), 3.6-4.0 ppm (broad s, 4H), 7.35 ppm (s, 1H), 7.5 ppm (m, 6H), 7.7 ppm (m, 3H), 8.7 ppm (d, 2H), MS (M+H)+ 482/484.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1>C1COCC1.[Zn].C1COCC1.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>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:9][C:5]2[C:4]([F:11])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[F:8])[N:14]=1
Reactant: Fc1cc(Br)cc(F)c1CBr
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(F)c1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (from Step B above, 18.5 g, 65.17 mmol) in THF (400 mL) was added 100 mL of Zn/THF solution (5 g Zn/100 mL, 76.46 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes. To this reaction was added 2,6-dibromo pyridine (15.44 g, 65.17 mmol) and tetrakis(triphenylphosphine)palladium (7.51 g, 6.51 mmol), and heated to 90° C. for 1 hr. The reaction was monitor by LCMS. After cooling to room temperature, the reaction was quenched with aqueous NH4Cl, and diluted with EtOAc. The organic layer was washed with water (3×), brine (3×), dried over MgSO4, and condensed in vacuo to yield a yellow oil. The crude residue was purified via silica gel chromatography to give the title compound (16 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([Sn](CCCC)(CCCC)CCCC)[CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[CH:23]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:27]=[CH:26][N:25]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccccc2)ccn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(-c3ccccc3)ccn2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.3 g, 1.21 mmol), 4-phenyl-2-(tributylstannyl)pyridine (0.591 g, 1.33 mmol), palladium tetrakistriphenylphosphine (0.140 g, 0.12 mmol) in toluene (2 mL) to give 4-chloro-5,7-difluoro-3-methyl-2-(4-phenylpyridin-2-yl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=367.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=1>C([O-])(O)=O.[Na+]>[CH3:38][O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:12](=[O:14])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[C:42]([C:47]([F:48])([F:49])[F:50])[CH:41]=1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc(CC(=O)Nc2ccc(OC)cc2C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 20.2 %

Procedure:
Prepared using General Procedure 6: To a stirring solution of 2-(4-(methoxycarbonyl)phenyl)acetic acid (300 mg, 1.54 mmol) were added HOBt (417 mg, 3.09 mmol), EDC (593 mg, 3.09 mmol) and DIEA (539 μL, 3.09 mmol). After 1.5 h, 4-methoxy-2-(trifluoromethyl)aniline (325 mg, 1.70 mmol) was added. After stirring for 14 h, the mixture was diluted with NaHCO3 and extracted with EA. The combined organic extracts were dried (Na2SO4), concentrated, and purified by chromatography (EA/hexanes) to provide 114 mg (31%) of methyl 4-(2-((4-methoxy-2-(trifluoromethyl)phenyl)amino)-2-oxoethyl)benzoate INT-54. LCMS-ESI (m/z) calculated for C18H16F3NO4: 367; found 368 [M+H]+, tR=3.27 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.40 (t, J=14.6 Hz, 2H), 7.13 (s, 1H), 7.09-6.96 (m, 2H), 3.92 (d, J=10.8 Hz, 3H), 3.81 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].C(C1C=CC(OC2C(OC)=CC=CC=2F)=C(C=1)N)=O.NC1SC=CN=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[O:10][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1cccc(F)c1O
Agent: COc1cccc(F)c1Oc1ccc(C=O)cc1N
Agent: Nc1nccs1
Product: COc1cccc(F)c1Oc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 68.7 %

Procedure:
4-(2-Fluoro-6-methoxy-phenoxy)-3-nitrobenzaldehyde (1.0 g, 70%) was prepared from 2-fluoro-6-methoxyphenol (0.78 g, 5.5 mmol) and 4-fluoro-3-nitrobenzaldehyde (0.84 g, 5.0 mmol) following the general procedure A. This was reduced to 5-formyl-2-(2-fluoro-6-methoxy-phenoxy)-aniline (0.57 g, 62%) following general procedure B. 1-[2-(2-Fluoro-6-methoxy-phenoxy)-5-fonnyl-phenyl]-3-thiazol-2-yl-urea (265 mg, 69%) was prepared from 5-formyl-2-(2-fluoro-6-methoxy-phenoxy)-aniline (261 mg, 1.0 mmol) and 2-aminothiazole (100 mg, 1.0 mmol) following the general procedure D.