Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([OH:43])[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:44])[CH:31]=1)([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].O([Si:53]([CH3:56])([CH3:55])[CH3:54])S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:25])([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([O:43][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39][CH2:40][CH2:41][CH2:42]2)=[C:32]([CH3:44])[CH:31]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
2,6-Lutidine (1.24 mL, 10.6 mmol) was added to a solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclopentanol (Example 32-(3); 1.04 g, 2.13 mmol) in dichloromethane (10.7 mL). Trimethylsilyl triflate (0.92 mL, 5.13 mmol) was added at 0° C., and the mixture was directly stirred for one hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% ethyl acetate/hexane) to give the title compound (1.04 g, 87%).
Reaction SMILES: C([C@H]1CC[C@H]2[C@@H]1CC(=O)O2)=O.O1CCCC1.[Li].[O:18]=[C:19]([CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)/[CH:20]=[CH:21]/[C@H:22]1[C@H:29](OC(=O)C2C=CC=CC=2)[CH2:28][C@H:27]2[C@@H:23]1[CH2:24][C:25](=[O:39])[O:26]2>C(O)(=O)C>[O:18]=[C:19]([CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)/[CH:20]=[CH:21]/[C@H:22]1[CH2:29][CH2:28][C@H:27]2[C@@H:23]1[CH2:24][C:25](=[O:39])[O:26]2
Reactant: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1ccccc1
Agent: O=C[C@H]1CC[C@@H]2OC(=O)C[C@@H]21
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(/C=C/[C@H]1CC[C@@H]2OC(=O)C[C@@H]21)COc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.06 g. of (1S,5R,6S)-6-formyl-2-oxabicyclo[3,3,0]octan-3-one [E.J. Corey et al., J. Org. Chem. 39: 256 (1974)] in 450 ml. of absolute tetrahydrofuran is combined with 13.3 g. of the lithium salt of dimethyl-2-oxo-3-phenoxypropyl phosphonate (preparation: see Example 1). The mixture is stirred at room temperature under argon for 2 hours, then neutralized with glacial acetic acid, concentrated under vacuum, combined with 300 ml. of methylene chloride, and the mixture is extracted with 30 ml. of 5% sodium bicarbonate solution and then twice with respectively 30 ml. of water, dried with magnesium sulfate, and evaporated under vacuum. Recrystallization of the residue from isopropanol yields 11.0 g. (84.5% of theory) of the title compound in the form of colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]([CH2:27][CH2:28][NH2:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:20]([CH2:27][CH2:28][NH:29][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCOc1ccccc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCOc3ccccc3)s2)c(C)[nH]c1=O
Yield: 78 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-phenoxy-ethylamine as described in Step 5, Example 24 to give the title compound as a yellow-orange solid (78% yield). LC/MS: RT 3.00 min; m/e 419 (M+H); 1H NMR (δ, ppm): 11.82 (1H, s), 8.18 (1H, m), 7.58 (1H, dd), 7.23-7.29 (3H, m), 7.15 (1H, dd), 6.86-6.94 (3H, m), 3.99 (2H, t), 3.28 (2H, t), 2.40 (2H, q), 2.29 (3H, s), 1.09 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[O:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:18]N1C(=O)CCC1=O>ClCCl>[Cl:18][CH2:1][C:2]1[N:3]=[C:4]([NH2:17])[O:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc(N)oc1-c1cccc2ccccc12
Solvent: ClCCl
Product: Nc1nc(CCl)c(-c2cccc3ccccc23)o1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of 4-methyl-5-naphthalen-1-yl-oxazol-2-ylamine (3, 800 mg), N-chlorosuccinimide (480 mg) and dichloromethane (30 mL) were irradiated with a 150W (tungsten/halogen) lamp at reflux for 8 hours. After cooling to room temperature, the solution was diluted with dichloromethane (50 mL) and washed with a saturated solution of sodium hydrogen carbonate (50 mL), water (50 mL) and brine (50 mL). The solvent was removed under reduced pressure and the resultant residue was purified by column chromatography affording 4-chloromethyl-5-naphthalen-1-yl-oxazol-2-ylamine (27) (411 mg, 45%) as an orange foam, 1H NMR (DMSO-D6): 4.45 (2H, s), 6.95 (2H, br s), 7.5-7.6 (4H, m), 7.95-8.00 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=O>C(OCC)(=O)C>[C:5]([NH:7][CH:13]([NH:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=1)[C:12]([O:16][CH3:17])=[O:15])(=[O:6])[CH3:4]
Reactant: NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(C)=O)NC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 15.4 %

Procedure:
A mixture of 3,5-dichlorobenzamide (19.0 g) and methyl glyoxylate (8.8 g) in ethyl acetate (300 ml) was heated under reflux for 8 hours. The solvent was removed and the residual adduct was crystallised from chloroform-light petroleum. A portion (4.0 g) of the adduct was dissolved in a mixture of glacial acetic acid (30 ml) and acetonitrile (10 ml) with stirring, and then concentrated sulphuric acid (4 ml) was added. The mixture was kept at room temperature overnight when water (100 ml) was added. The precipitated solid was washed with water, dried, and crystallised from ethanol to give the product (2.45 g) as a colourless crystalline solid, m.p. 235°-237°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.COC(C)(C)C>[Cl:9][C:6]1[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: COCCOC
Solvent: O
Product: Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Temperature: 80 °C
Yield: 87.7 %

Procedure:
Step 2) To a suspension of 2-(3,5-Dichloro-4-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (119 g; 414.64 mmoles) in 1,2-dimethoxyethane (240 mL) under nitrogen, add p-bromofluorobenzene (57 mL; 518.54 mmoles), water (120 mL), potassium carbonate (115.7 g; 828.79 mmoles), triphenylphosphine (2.72 g; 10.37 mmoles) and Pd(OAc)2 (0.47 g; 2.09 mmoles). Heat the mixture at 80° C. for 12 h and then allow to cool to room temperature. To the mixture, add 240 mL of t-butyl methyl ether and 480 mL of water, and then separate the layers. Wash the organic layer with an aqueous solution of TMT (Trithiocyanuric acid, trisodium salt hydrate, 5 g) in 120 mL, followed by saturated aqueous NaCl (120 mL). Solvent exchange the organic layer into approximately 600 mL of isopropanol to afford a slurry. Add water (120 mL) and cool the slurry to 3° C. Collect the solid by filtration and wash with 120 mL of cold methanol. Dry the solid under vacuum to afford 92.8 g of 3,5-dichloro-4′-fluoro-4-methyl-biphenyl as a light yellow solid. 1H NMR (CDCl3, 500 MHz) δ 2.49 (3H, s), 7.13 (2H, t, J=9 Hz), 7.46 (2H, s), 7.49 (2H, dd, J=9, 5 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:20][C@H:21]1[C@H:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[O:26][CH2:25][CH2:24][N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]1)[C:12](=[O:19])[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:35][C:30]1[CH:29]=[C:28]([C@@H:27]2[O:26][CH2:25][CH2:24][N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22][C@H:21]2[CH2:20][N:11]([CH2:10][CH2:9][OH:8])[C:12](=[O:19])[CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN(CCO[Si](C)(C)C(C)(C)C)C(=O)CN2CCCC2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN(CCO)C(=O)CN2CCCC2)C1
Yield: 0.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-{[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)(pyrrolidin-1-ylacetyl)amino]methyl}-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (118 g) in THF (0.6 ml) was added, under ice-cooling, a solution (1.0 M, 0.219 ml) of tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (NH, hexane/ethyl acetate/methanol) to give the title compound (81.3 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:28]=3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:28]=3)[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3cccc(N4CCCCC4)c3)ncc2[N+](=O)[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCc3cccc(N4CCCCC4)c3)ncc2[N+](=O)[O-])CC1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
(4-{[5-Nitro-2-(3-piperidin-1-yl-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (176 mg, 0.33 mmol) was dissolved in CH2Cl2 (6 mL). To this solution was added TFA (3 mL) and the reaction was stirred for 1 h. The volatiles were removed and the crude was re-dissolved in 90:9:1 (CH2Cl2:CH3OH:NH4OH), then concentrated again to afford a solid. The resultant solid was purified via flash chromatography (SiO2, 10-75% CH2Cl2-(90:9:1-CH2Cl2:CH3OH:NH4OH)) to afford 131 mg (91%) of the target compound , m/z 440.72 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@:12]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of (1S,4S)-4-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopent-2-ene-1-carboxylic acid (9.78 g, 36.3 mmol) in ethanol (250 mL) was added 10% palladium on carbon (550 mg). The mixture was shaken under hydrogen at 55 psi overnight and filtered through celite. The filtrate was evaporated in vacuo to afford the title compound (9.45 g, 96%). MS calculated for C14H25NO4: (M+H)+272; found 172.1 (M−Boc+H)+.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C1COCC1.CCOC(C)=O>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1COC2(CCNCC2)OC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC2(CC1)OCCCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 1,5-dioxa-9-aza spiro[5.5]undecane (15.0 g, 95.4 mmol) and triethylamine (17.6 mL, 126 mmol) in THF (140 mL) cooled to 0° C. was added dropwise a solution of benzyl chloroformate (14 mL, 97.5 mmol) dissolved in THF (30 mL). The resulting mixture was stirred at room temp for 18 h. After diluting with EtOAc, the mixture was washed with water and brine and dried (Na2SO4). Concentration gave yellow oil that was purified by flash chromatography eluting with 20%-50% EtOAc/hexane to give the title compound as colorless oil (18.9 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ: 7.36-7.27 (5H, m), 5.09 (2H, s), 3.89-3.85 (4H, m), 3.51-3.47 (4H, m), 1.87-1.66 (6H, m). LCMS (M+H) calcd for C16H22NO4: 292.15; found: 292.00.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([OH:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[CH2:22][C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([O:20][CH2:22][C:23](=[O:25])[CH3:24])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(=O)CCl
Reactant: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1C#N
Yield: 22 %

Procedure:
1.5 g of 3-chloro-2-(4-cyano-3-hydroxyphenyl)-5-trifluoromethyl-pyridine, 1.0 g of chloroacetone, 1.5 g of potassium carbonate, 0.8 g of sodium iodide and 200 ml of acetone were refluxed for 8 hours. The reaction mixture was then concentrated, after which the residue was stirred in 20 ml of water. The insoluble portion was separated off and washed well with water. The crude product was then stirred in succession with n-hexane and with ether. After drying in a vacuum drying oven, 0.4 g of white crystals having a melting point of 146°-147° C. were finally obtained. Yield: 22%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[F:22])[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(3-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-23) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=367.0 (M+H)+
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.C([O:16][CH2:17][C:18]([OH:20])=O)(=O)C.O[N:22]=[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH3:43])=[C:29]([NH:31][C:32]([C:34]2[N:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]3=[N:36][CH:35]=2)=[O:33])[CH:30]=1)[NH2:24].O.[OH-].[Li+]>CN1C(=O)CCC1.C1COCC1.CO.O>[OH:20][CH2:18][C:17]1[O:16][N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:43])=[C:29]([NH:31][C:32]([C:34]3[N:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][CH:35]=3)=[O:33])[CH:30]=2)[N:24]=1
Reactant: CC(=O)OCC(=O)O
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 125 °C
Reaction time: 0.33 h

Procedure:
Carbonyl diimidazole (CDI) (324 mg, 2.0 mmol) was added to a stirred solution of 2-acetoxyacetic acid (236 mg, 2.0 mmol) in NMP. After 20 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (310 mg, 1.0 mmol) was added in one portion and the resulting solution was stirred for 1 hour before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was hydrolyzed by lithium hydroxide monohydrate (252 mg, 6.0 mmol) in THF/MeOH/H2O (3:2:1). After removal of all solvents 2M NaHCO3 (10 mL) was added. The precipitate was filtered and dried in air to afford N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (43). 1H NMR (400 MHz, d6-DMSO) δ 10.02 (s, 1H), 9.46 (d, J=6.8 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.82 (m, 2H), 7.53 (m, 2H), 7.18 (m, 1H), 6.08 (m, 1H), 4.80 (d, J=6.0 Hz, 2H), 2.37 (s, 3H). MS m/z 350.1 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:29])[C:6]([NH:20][C:21]2([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[C:26]([C:21]1([NH:20][C:6]2[C:5]([F:29])=[CH:4][C:3]([C:1]([NH2:2])=[O:36])=[C:8]([NH:9][C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:27])[NH2:28]
Reactant: CC(=O)O
Reactant: N#Cc1cc(F)c(NC2(C(N)=O)CCCC2)nc1Nc1cnc2ccccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1cc(F)c(NC2(C(N)=O)CCCC2)nc1Nc1cnc2ccccc2c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)cyclopentanecarboxamide in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred for 1 h. HOAc (0.5 mL) was added. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (41 mg). MS 409.4 (M+H); UV 224.1, 243.7, 302.6, 324.8 nm; t 0.495 min.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(I)cc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(I)cc1
Yield: 79.6 %

Procedure:
This compound was prepared according to the procedure of Example 56. A mixture of 22.0 g (0.1 mole) of 4-iodophenol (Aldrich) and 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate in 100 ml of toluene gave 23.8 g (80%) of the title compound as a white solid, mp 146°-147° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH:25]=[O:26]>>[CH:25]([C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:20][C:19]=1[CH3:18])=[O:26]
Reactant: Cc1cc(B(O)O)ccc1C=O
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Product: Cc1cc(-c2cccc(CN(C)C(=O)OC(C)(C)C)c2)ccc1C=O
Yield: 84.2 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 1.1 g (3.5 mmol) of tert-butyl (3-bromo-benzyl)-N-methylcarbamate obtained in Example 79(b) with 750 mg (4.6 mmol) of 3-methyl-4-formylbenzene-boronic acid, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (7/3), 1 g (87%) of the expected product is obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[C:17]4[C:22]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[CH:29]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=1.CC(C)([O-])C.[Na+]>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]>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([N:15]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:16]2[C:17]3[C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH:29]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:33][CH:32]=1
Reactant: c1ccc2c(c1)cc(Nc1cc3ccccc3c3ccccc13)c1ccccc12
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2cc3ccccc3c3ccccc23)c2cc3ccccc3c3ccccc23)cc1
Reaction time: 12 h
Yield: 44 %

Procedure:
Diphenanthren-9-ylamine (4.50 g, 12.18 mmol), 1,4-dibromobenzene (3.02 mL, 25.12 mmol), Pd2(dba)3 (307 mg, 0.355 mmol), tris-o-tolyphosphine (0.255 mL, 0.837 mmol), sodium tert-butoxide (3.2 g, 33.49 mmol) were put in a 250 mL two-neck flask and dissolved in toluene. The solution was refluxed and stirred for 12 hours. After completion of the reaction, the solution was extracted with DI water/methylenechloride and distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of n-hexane and methylenechloride (7:1). The resultant was distilled under reduced pressure and re-crystallized such that the wax compound was obtained, (2.8 g, yield: 44%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][NH:28][N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]O>>[Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][N:28]([CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])[N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1
Reactant: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: CN(C)CCO
Product: CN(C)CCn1cnc(-c2c(Cl)csc2NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)n1

Procedure:
The title compound was prepared from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (125 mg, 275 umol) and 2-(dimethylamino)ethanol (311 mg, 3.49 mmol) using the procedures described in Example 1.76 except that the reaction was run at 60° C. (rather than 0° C.). The residue was purified by HPLC to yield N-(4-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide. Method [7] Retention time 4.40 min by HPLC (M+=525 and 527) and (M+Na=547 and 549). 1H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.28 (s, 1H), 8.22 (d, J=9.3 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7, 1H), 7.16 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 5.32 (s, 2H), 4.28 (t, J=6.0 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.15 (s, 6H).