Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:20]1(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1.C1C=CC2C(=NO[N+]=2[O-])C=1.C(OCC)(=O)C>CO.C(#N)C>[CH:14]1([N:13]2[C:12]3[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=3[N:1]=[C:26]2[C:23]2[CH:24]=[CH:25][C:20](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccc(/C=C/c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Agent: [O-][n+]1onc2ccccc21
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(/C=C/c3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Ethyl 3-amino-4-cyclohexylaminobenzoate (500 mg) obtained in Example 1, Step 3, was dissolved in methyl alcohol (6 ml) and trans-4-stilbenecarbaldehyde (397 mg) was added under ice-cooling. The mixture was stirred overnight at room temperature. The reaction mixture was ice-cooled and benzofuroxan (259 mg) dissolved in acetonitrile (2 ml) was added. The mixture was stirred for 7 hr at 50° C., The reaction mixture was ice-cooled. After 1N sodium-hydroxide was added, ethyl acetate was added and the mixture was extracted. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate=4:1) to give the title compound (540 mg, yield 63%).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([S:27]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)(=[O:29])=[O:28])[CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:22]=[N:23][CH:24]=[C:25]([S:27]([N:30]3[CH2:33][C:32]([F:35])([F:34])[CH2:31]3)(=[O:29])=[O:28])[CH:26]=2)[CH:11]=1)#[N:16]
Reactant: O=S(=O)(c1cncc(Br)c1)N1CC(F)(F)C1
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: N#Cc1ccc(OCC(=O)O)c(C#Cc2cncc(S(=O)(=O)N3CC(F)(F)C3)c2)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 3-bromo-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]pyridine (Intermediate 34), the title compound was obtained as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[Li+].[OH-].Cl>C1COCC1.CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2c(F)cccc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of ethyl 2-(2,6-difluorophenyl)thiazole-4-carboxylate (1.0 eq.) in 2:1 THF/MeOH (0.17 M) was added 1.0 M LiOH (2.0 eq.). After standing for 16 hours, 1.0 M HCl (2.0 eq.) was added and the THF/MeOH was removed in vacuo. The resulting solid was filtered, rinsed with H2O and dried, yielding 2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (88%) as a crusty solid. LCMS (m/z): 251.1 (MH+); LC Rt=2.68 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:37])=[CH:34][CH:33]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(Cl)cc1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 4-(8-cyclohexyloctylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated an the residue is crystallized from diisopropyl ether.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([CH2:34][OH:35])=[N:4]1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([CH:34]=[O:35])=[N:4]1)[CH3:2]
Reactant: CCn1nc(CO)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nc(C=O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a suspension of 1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy) cinnolin-4(1H)-one (1.6 g, 3.36 mmol) in dichloromethane (DCM) (50 mL) at room temperature was added Dess-Martin periodinane (1.709 g, 4.03 mmol). The white suspension turned into a dark green solution. The reaction was stirred at room temperature for 1 h, treated with sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with ethyl acetate/hexanes (0-100%) to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde (0.9 g, 1.897 mmol, 56.5% yield) as a yellow solid. LCMS: (M+H)+: 475.2
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Ni].CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(SCCCc2ccccc2)cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc(SCCCc2ccccc2)cc1

Procedure:
90 g of 4-(3'-phenyl-propylthio)-nitrobenzene is catalytically hydrogenated in 300 ml. of dimethylformamide with Raney nickel. After completion of the hydrogen absorption and removal of the catalyst and the solvent, there is obtained 4-(3'-phenyl-propylthio)-aniline as an oily residue, which can be used without purification in the next reaction stage.
Reaction SMILES: ClCC([O:5][C@@H:6]1[C@@H:19]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:18]([F:27])[C@@H:17]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:16][C@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.C[O-].[Na+]>CO>[F:27][C@@H:18]1[C@@H:17]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:16][C@@H:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:6]([OH:5])[C@H:19]1[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(=O)CCl)[C@@H](OC(=O)C(C)(C)C)[C@@H]1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](O)[C@@H](OC(=O)C(C)(C)C)[C@@H]1F
Temperature: -15 °C
Yield: 74 %

Procedure:
Compound (20) (625 mg, 1.21 mmols) was dissolved in methanol (24.2 ml), and sodium methoxide (13.1 mg, 0.6 mmol) was added to the solution with stirring under an argon stream at −15° C. Disappearance of the material was confirmed by TLC 30 minutes later, and the reaction mixture was neutralized (pH 6-7) with a cation-exchange resin IR-120(+). After the resin was filtered off, the filtrate was concentrated in a vacuum. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4), giving Compound (21) (in an amount of 395 mg, yield 74%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:3]=1[CH3:22].[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[NH:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[N:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:3]=2[CH3:22])[CH2:25]1
Reactant: Cc1c(Cc2cccc(F)c2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(Cc2cccc(F)c2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
4-Chloro-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinoline (41.4 mg, 0.129 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (30 mg, 0.129 mmol), Pd2dba3 (11.8 mg, 0.013 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.3 mg, 0.026 mmol), sodium tert-butoxide (37.1 mg, 0.386 mmol), and toluene (1.29 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.63 (1H, ddd, J=9.4, 2.5, 1.4 Hz), 7.51-7.54 (1H, m), 7.27-7.30 (1H, m), 7.05 (1H, ddd, J=7.9, 1.3, 1.2 Hz), 6.86-7.01 (3H, m), 5.55 (1H, dd, J=2.2, 0.4 Hz), 4.42 (2H, s), 3.79-3.86 (1H, m), 3.68-3.78 (4H, m), 3.57 (1H, d, J=9.2 Hz), 2.86-2.98 (4H, m), 2.19 (3H, s), 1.52 (3H, s), 1.47 (3H, s). Mass Spectrum (ESI) m/e=519.1 (M+1).
Reaction SMILES: C([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)(=O)C.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(C#N)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-acetamidobenzonitrile (9.40 g) in concentrated sulfuric acid (80 ml) was added potassium nitrate in small portions at a temperature not exceeding 10° C. The reaction mixture was stirred at 5°-10° C. for 2 hours and poured into ice-water and the separated crystals were collected by suction. To the crystals was added 4N hydrochloric acid (100 ml) and the mixture was refluxed for 2 hours. After cooling to room temperature, the crystals were recovered by filtration, washed with water and dried under reduced pressure to give 7.22 g of 4-amino-3-nitrobenzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:19]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.5 g (2.6 mmol) of 1H-Indole-2-carboxylic acid ethyl ester was dissolved in DMF and 116 mg (2.9 mmol) of sodium hydride (60% dispersion in mineral oil) was added. The solution was stirred for 30 min at room temperature, then cooled to −78° C. A solution of 0.82 g (2.6 mmol) of toluene-4-sulfonic acid 2-(4-chloro-phenyl)-ethyl ester in DMF was added to this cooled solution. The solution was warmed to RT and was stirred for 16 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed once with saturated aqueous sodium bicarbonate, once with water, and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of n-heptane/ethyl acetate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl.Cl[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].O>CN(C=O)C>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][CH2:18][O:15][C:11]1[CH:10]=[C:9]([CH2:8][OH:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCCCl
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCOc1cccc(CO)c1
Temperature: 80 °C

Procedure:
Cesium carbonate (15.4 g) was added to a solution of 3-hydroxymethyl-phenol (3 g) in DMF (80 mL). To this mixture was added (3-chloro-propyl)-dimethyl-amine hydrochloride (4 g). The mixture was heated at 80° C. for 20 hours then allowed to cool. The reaction mixture was poured into water and extracted with ethyl acetate.
Reaction SMILES: [C:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)=[C:9](N)[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(ON=O)CCCC.[I:43]CI.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)=[C:9]([I:43])[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: ICI
Reactant: CC(C)C(=O)Nc1nc(N)c2ncn([C@H]3C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O3)c2n1
Agent: CCCCCON=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1nc(I)c2ncn([C@H]3C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O3)c2n1
Temperature: 60 °C
Yield: 34.4 %

Procedure:
2-isobutyrylamino-6-amino-9-(2-deoxy-3,5-di-O-isobutyryl-β-D-ribofuranosyl]purine (17) [Babara L. Gaffney, Luis A. Marky and Roger A. Jones, Tetrahedron, 40, 3-13 (1984)] 2.38 g (5 mmol) was heated at 60° C. under argon atmosphere. n-pentylnitrite 13.5 ml (0.10 mol) and diiodomethane 25 ml (0.31 mol) were rapidly added and suspended. The mixture was irradiated by visible light using 200 W halogen tungsten lump at the distance from light source 2 cm for 3 hours under well stirring at 60° C. To the reaction mixture, saturated aqueous sodium sulfite 30 ml was added and stirred at room temperature for 3 hours. Thereafter, saturated aqueous sodium sulfite 120 ml and chloroform 150 ml were added to separate the layers. The aqueous layer was extracted twice with chloroform. The thus obtained organic layer was dried with anhydrous magnesium sulfate and concentrated. The residue was purified by short column (developer: ethyl acetate:dichloromethane=1:4) to obtain the product (18) 1.01 g (1.72 mmol) (34.4%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[N:24]1([S:30]([NH2:33])(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]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>O1CCOCC1.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].CO.C(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6]([NH:33][S:30]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:32])=[O:31])=[N:7]2
Reactant: NS(=O)(=O)N1CCCCC1
Reactant: Fc1ccc2c(Cl)nc3ccnc(Cl)c3c2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1nc2ccnc(Cl)c2c2cc(F)ccc12)N1CCCCC1
Temperature: 80 °C

Procedure:
To a solution of 1,6-dichloro-9-fluorobenzo[c]-1,6-naphthyridine (30 mg, 0.11 mmol) in dioxane (3 mL) were added cesium carbonate (128 mg, 0.39 mmol), piperidine-1-sulfonamide (18.4 mg, 0.11 mmol), Xantphos, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), (10 mg, 0.02 mmol), and Pd2(dba)3 (5.14 mg, 5.62 μmol). The solution was degassed by bubbling N2 for 5 min and heated 80° C. overnight and worked up with EtOAc and H2O. The organic layers were dried with MgSO4, filtered, and concentrated by rotary evaporation to afford an oily residue. Silica gel column chromatography 100% CH2Cl2 to 25% MeOH afforded N-(1-chloro-9-fluorobenzo[c]-1,6-naphthyridin-6-yl)piperidine-1-sulfonamide. This intermediate was taken up in 6 N HCl (2 mL) and THF (2 mL) and heated to 85° C. for 2 hr. The reaction mixture was concentrated and purified by reverse phase HPLC 100% H2O to 100% MeCN to afford N-(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-6-yl)piperidine-1-sulfonamide. LRMS (ESI) calc'd for (C17H18FN4O3S) [M+H]+, 377.1; found 377.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-:18].[Na+].[Na+]>C(OC(=O)C)(=O)C>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[CH:8]=[CH:7]2
Reactant: [O-][n+]1cccc2cc(OC(F)(F)F)ccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=c1ccc2cc(OC(F)(F)F)ccc2[nH]1

Procedure:
A solution of 6-trifluoromethoxy-quinoline 1-oxide of Step B (4.58 g, 20 mmol) in acetic anhydride (20 mL) is heated at 135° C. under nitrogen for 4 hours. The mixture is poured onto ice, carefully basified with sodium carbonate and extracted with ethyl acetate. The extracts are washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica Merck-60 using a gradient of methanol (0–3%) in hexane-ethyl acetate (1:1). The appropriate fractions are combined and evaporated. The residue is triturated with diethyl ether. The insoluble is collected, washed with hexane and dried to provide the title compound as a pale brown crystalline solid (1.086 g), m.p. 215–217° C.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:23])[CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:24])=[CH:4][CH:3]=1.[OH-].[Na+:28]>CCO>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:23])[CH2:19][C:20]([O-:22])=[O:21])=[C:8]2[CH3:24])=[CH:4][CH:3]=1.[Na+:28]
Reactant: COc1ccc2c(c1)c(C(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)c(C(C)CC(=O)[O-])c(C)n2Cc1ccc(Br)cc1
Yield: 99.8 %

Procedure:
A suspension of the acid from Step 5 (870 mg, 2.09 mmol) in 15 mL EtOH was treated with 1.00N NaOH (2.1 mL, 2.1 mmol), and stirred until the solid dissolved. The solution was concentrated to dryness, then dissolved in a minimum amount of water and freeze-dried to provide 914 mg of the title compound.
Reaction SMILES: [C:1]([CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:23]>O>[Ag+:23].[C:1]([CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[C:9]([O-:11])=[O:10])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C(CCCCN)C(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)C(CCCCN)C(=O)[O-]
Yield: 87.6 %

Procedure:
Boc-6-aminohexanoic acid (0.85 g, 3.68 mmol) was added to water (4 mL) and cooled in ice bath. To this suspension 1N NaOH was added with constant stirring until the pH of solution was about 7 and the mixture became a clear solution. To this solution, silver nitrate (0.63 g, 3.68 mmol) in water (2 mL) was added slowly. The resulting precipitate was filtered and washed with water. The solid was dried in vacuum over phosphorus pentoxide to yield a white solid (1.09 g) (yield, 88%).
Reaction SMILES: N#N.[NH2:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].C[O-].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1.CO>[C:17]([NH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:8][CH3:9])[O:10][CH3:11])(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: CO[Si](CCCN)(OC)OC
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CC(=O)NCCC[Si](OC)(OC)OC
Temperature: 0 °C

Procedure:
A one liter, three-necked flask equipped with a thermometer, stirring paddle, air tight stirring sleeve, N2 inlet and dropping funnel was charged with aminopropyltrimethoxysilane (100.0 g, 0.558 moles), toluene (160.1 g), sodium methoxide (33.16 g, 0.614 moles) and methanol (10.11 g). The mixture was stirred under N , atmosphere and cooled to 0° C using a dry ice/isopropanol bath. To this, 55.37 g (0.614 moles) of acrylyl chloride dissolved in 100 g of toluene was added gradually over a period of 30 minutes. The mixture was agitated for another 30 minutes. By-product sodium chloride was removed by filtration and the solvent was removed under reduced pressure to obtain acrylamidopropyltrimethoxysilane in essentially quantitative yield. Sodium nitrite (0.001 g) was added as an inhibitor.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.[NH2:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[C:45](=[O:55])[C:46]([CH3:54])=[CH:47][N:48]2[CH3:53]>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:42][C:43]3[CH:52]=[CH:51][CH:50]=[C:49]4[C:44]=3[C:45](=[O:55])[C:46]([CH3:54])=[CH:47][N:48]4[CH3:53])[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)(=[O:37])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: Cc1cn(C)c2cccc(N)c2c1=O
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3c(=O)c(C)cn4C)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (99.5 mg, 0.219 mmol) and 5-amino-1,3-dimethylquinolin-4(1H)-one (Compound 299A, 49.2 mg, 0.261 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 14.66 (s, 1H), 8.88 (s, 1H), 8.60 (br s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.43-7.63 (m, 2H), 7.18 (d, J=8.6 Hz, 1H), 7.05 (s, 1H), 6.90 (d, J=7.8 Hz, 1H), 3.95-4.05 (m, 4H), 3.80 (s, 3H), 3.76 (s, 3H), 3.28 (d, J=21.5 Hz, 2H), 1.98 (s, 3H), 1.20 (t, J=6.9 Hz, 6H). MS (ES+): m/z 606.16 (60) [MH+]. HPLC: tR=1.46 min (TOF, polar—3 min).