Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[C:5]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:27][OH:28]>C(O)C.ClC(Cl)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[N:27][OH:28])[CH3:9])[C:5]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])=[CH:4][N:3]=1
Reactant: CC(=O)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(Cl)Cl
Product: CC(=NO)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Temperature: 70 °C

Procedure:
A mixture of 1-(2-chloro-5-((5-fluoro-2-methylphenyl)ethynyl)pyridin-4-yl)ethanone (700 mg, 2.0 mmol), sodium acetate (320 mg, 3.9 mmol), and hyroxylamine hydrochloride (254 mg, 3.65 mmol) in ethanol (11 mL) and dichloroethane (1.6 mL) was heated at 70° C. for 15 minutes. The cooled reaction mixture was evaporated in vacuo to afford a residue that was redissolved in ethyl acetate (150 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a white solid that was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@H:5]([CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[NH2:6].[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])(=[O:21])[CH3:20]>CO>[CH3:2][O:3][C:4](=[O:18])[C@H:5]([CH2:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[NH:6][C:25](=[O:26])[CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:23][S:22][C:19](=[O:21])[CH3:20]
Reactant: COC(=O)[C@@H](N)CSCc1ccc(OC)cc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CSCc1ccc(OC)cc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-(4-methoxybenzyl)-L-cysteine methyl ester hydrochloride (1.85 g) and 3-acetylthio-2-benzylpropionic acid (1.95 g) in the manner described in Example 1, Step 1 to give an amber oil. Chromatograph this oil on a column of silica gel (2L, 60-200 mesh) and elute with ethyl acetate:hexane 5:20 to give Isomer A, a clear oil (0.63 g), [α]D26 =-66.5° (MeOH), overlap Isomer A and Isomer B (0.28 g); and Isomer B, a clear oil (0.67 g), [α]D26 =+3.0° (MeOH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16]C)=[O:15])[CH:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1(O)C=CC=CC=1>C(OCC)(=O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=[C:2]2[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[CH3:18]
Reactant: Cc1ccccc1CN
Reactant: COC(=O)c1cc(Cl)c2cccc(OC)c2n1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: COc1cccc2c(NCc3ccccc3C)cc(C(=O)O)nc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A mixture of 54 g (=215 mmol) of methyl 4-chloro-8-methoxyquinoline-2-carboxylate, 33.7 g (=278 mmol) of 2-methylbenzylamine and 243 g (=2.58 mmol) of phenol was heated at 140° C. in an autoclave for 4 hours. The cooled reaction mixture was added dropwise to 4 1 of ethyl acetate, and the resulting precipitate was filtered off with suction. The solid was dissolved in 1 1 of THF and the pH was adjusted to 10 with 10% NaOH. The mixture was stirred at 50° C. for 1 hour, maintaining the pH constant, cooled to 10° C. and adjusted to pH 5-6 with dilute HCl. This resulted in the product crystallizing. 18.85 g of 8-methoxy-4-(2-methylbenzylamino)quinoline-2-carboxylic acid of melting point 276-277° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O>Cl.O=[Pt]=O>[CH:8]1([N:7]2[C:2]([NH2:1])=[C:3]([NH2:15])[C:4](=[O:14])[NH:5][C:6]2=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CCCC1
Agent: O=[Pt]=O
Agent: Cl
Product: Nc1c(N)n(C2CCCC2)c(=O)[nH]c1=O

Procedure:
12.9 g of 6-amino-1-cyclopentyl-5-nitroso-2,4-(1H,3H)-pyrimidinedione (XV) was catalytically hydrogenated in 30 ml of 2N HCl and in the presence of 0.1 g PtO2 for 3 hours and at room temperature and at a pressure of 200 kPa. The catalyst was filtered off and the filtrate was neutralized with 5N NaOH. The crystals were filtered off. Yield 6.1 g (50%) (XV).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH3:22])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)[CH2:9][CH2:8]1>O>[OH:3][CH:4]([CH3:22])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)[CH2:11][CH2:12]1
Reactant: CC(=O)CCN1CCC(c2cc3ccccc3o2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(O)CCN1CCC(c2cc3ccccc3o2)CC1

Procedure:
A solution of 6.0 g of sodium borohydride in 25 ml of water is added dropwise, with stirring and external cooling, to a solution of 6.0 g of 1-(3-oxobutyl)-4-(2-benzofuranyl)-piperidine (cp. Example 8), the manner of addition being such that the reaction temperature does not exceed 30°. The mixture is subsequently stirred for 15 hours at room temperature. The methanol is then evaporated off in vacuo, the aqueous phase remaining being extracted twice with 250 ml of chloroform each time, the chloroform solution dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 500 ml of 2N hydrochloric acid, and the acid solution washed with ether. The aqueous solution is subsequently adjusted by addition of 10% sodium hydroxide solution to have a pH value of 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 1-(3-hydroxybutyl)-4-(2-benzofuranyl)-piperidine (4-(2-benzofuranyl)-α -methyl-1-piperidinepropanol). The hydrochloride of this is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon it melts at 194°-195°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:22](O)(=[O:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[C:22]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:24])[CH3:23]
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (101.2 mg, 0.312 mmol), acetic acid (56.2 mg, 0.936 mmol), HBTU (355 mg, 0.936 mmol) and N,N-diisopropylamine (326 μl, 1.872 mmol) in 5 ml of dimethylformamide in a test tube, equipped with a magnetic bar, is stirred for 20 hours at room temperature. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated. The residue obtained is taken up in ethyl acetate and purified on a Varian flash cartridge containing 5 g of silica of porosity 15-35μ, with a mixture of 1% methanol in dichloromethane. After evaporating off the solvent, 66 mg of 4-fluorobenzenesulfonic acid 2-acetylaminobenzothiazol-6-yl ester are obtained (yellow oil) in a yield of 58%. LC/MS (method A1): [M+H]+: 367.14, retention time: 3.50 min.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25](O)=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[C:59]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)(=[O:62])[NH:60][NH2:61]>CN(C=O)C>[C:13]([O:17][C:18]([CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25]([NH:61][NH:60][C:59]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])=[O:26])=[O:19])([CH3:15])([CH3:16])[CH3:14]
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)O)cc1OCC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1OCC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g) was added to a mixture of the product of step (c) (3.82 g), HOBT (1.71 g), diisopropylethylamine (1.75 ml) and DMF (30 ml) at ambient temperature and stirred for 30 minutes. Benzyl carbazate (1.66 g) in DMF (10 ml) was added and the mixture was stirred for 20 hours at ambient temperature. The solvent was removed by evaporation. The residue was dissolved in ethyl acetate (160 ml) and the solution was washed with 1M citric acid solution (25 ml), water (2×25 ml), 1M sodium hydroxide solution (20 ml), water (25 ml) and with saturated sodium chloride solution (25 ml) and dried (MgSO4). The solvent was removed by evaporation to give benzyl 3-(3,4-di-t-butoxycarbonylmethoxybenzoyl)carbazate as a gum; NMR Spectrum (d6 -DMSO) 1.43 (s, 18H), 4.70 (s, 2H), 4.75 (s, 2H), 5.11 (s, 2H), 6.96 (d, 1H), 7.34 (br s, 5H), 7.4 (d, 1H), 7.49 (dd, 1H), 9.28 (br s, 1H), 10.17 (br s, 1H); Mass Spectrum (+ve FAB, DMSO/GLYCEROL) 530 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:30])[C:20]3[C:25]([C:26](=[O:29])[C:27]=2[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C1COCC1.CCOCC>[C:37]([O:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:18]1[C:19](=[O:30])[C:20]2[C:25]([C:26](=[O:29])[C:27]=1[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(CCCCC(=O)NO)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(CCCCC(=O)NOC(C)=O)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
6-(4-Methoxyphenyl)-6-(3-methyl-1,4-naphthoquinon-2-yl)hexanohydroxamic acid (215 mg) and pyridine (125 mg) were dissolved in THF (1 ml) followed by addition of acetic anhydride (56 mg), and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with ether, washed serially with 1N HCl, saturated aqueous NaCl solution, and saturated aqueous NaHCO3 solution, dried, and concentrated under reduced pressure. The residue was applied to a silica gel column and developed with hexane-ethyl acetate (1:1) to provide the title compound (150 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:23]([O:25][C:26](=[O:29])[C:27]#[N:28])[CH3:24].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:28]=[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:29])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#N
Reactant: Cc1ccc(C(=O)Nc2ccccc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccc(C)cc2)nc2ccccc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-N-phenylbenzamide (6 g, 28.40 mmol, 1.00 equiv) in toluene (60 mL) and PCl5 (7.13 g, 34.24 mmol, 1.20 equiv). The mixture was stirred for 2 h at 65° C. The mixture was concentrated under vacuum. The residue was diluted with 30 mL of PhCl. To the mixture was added 2-ethoxy-2-oxoacetonitrile (3.37 g, 34.01 mmol, 1.20 equiv), SnCl4 (12.5 g, 1.70 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 125° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4×100 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 2.64 g (32%) of ethyl 2-(4-methylphenyl)quinazoline-4-carboxylate as a light green solid. MS (ESI) m/z 293 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:16]([CH3:15])[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: CN(Cc1ccccc1)C(=O)c1ccc2cc(O)ccc2c1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and N-methylbenzylamine (commercially available) according to the procedure described for Example A. MS (m/e): 290.1 (MH−, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]([OH:31])CO)[N:11]=1>CC(C)=O.O.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]=[O:31])[N:11]=1
Reactant: Cc1cccc(C)c1Nc1nn(CCC(O)CO)c2nc(Nc3ccccc3)ncc12
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cccc(C)c1Nc1nn(CCC=O)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 114 mg (0.3 mmol) of 4-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butane-1,2-diol 34 (Example 2) in 10 mL of acetone and 7 mL of water was treated with 585 mg (2.7 mmol) of NaIO4. The resulting tan slurry was stirred at room temperature for 6 h. The reaction mixture was diluted with CH2Cl2, filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2 (75 mL) and washed with water (50 mL). The aqueous layer was extracted with more CH2Cl2 (2×75 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated to give the title compound 36, which was used without further purification. 1H-NMR (CDCl3) δ 2.27 (s, 6H), 3.05 (t, J=6.7 Hz, 2H), 4.52 (t, J=6.7 Hz, 2H), 5.30 (s, 1H), 5.89 (s, 1H), 7.06 (t, J=7.6 Hz, 1H), 7.13-7.19 (m, 3H), 7.34 (t, J=7.7 Hz, 2H), 7.42 (s, 1H), 7.64 (d, J=7.7 Hz, 2H), 9.89 (s, 1H). Mass Spectrum (ESI) m/e=387.2 (M+1).
Reaction SMILES: O.[CH:2]12[CH2:8][CH:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:30])[C:14]([C:27]([OH:29])=[O:28])=[CH:15][N:16]2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:11][C:10]=1[F:31].C(=O)(O)[O-].[Ca+2].C(=O)(O)[O-].Br[CH2:42][C:43]1[O:44][C:45](=[O:49])[O:46][C:47]=1[CH3:48].C(OCC)(=O)C>CN(C=O)C.O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:16]1[C:17]2[C:12](=[CH:11][C:10]([F:31])=[C:9]([N:3]3[CH2:4][CH:5]4[CH2:8][CH:2]3[CH2:7][N:6]4[CH2:42][C:43]3[O:44][C:45](=[O:49])[O:46][C:47]=3[CH3:48])[CH:18]=2)[C:13](=[O:30])[C:14]([C:27]([OH:29])=[O:28])=[CH:15]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3CC4CC3CN4)c(F)cc2c1=O
Reactant: Cc1oc(=O)oc1CBr
Agent: O=C([O-])O
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CN1CC2CC1CN2c1cc2c(cc1F)c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 27.5 %

Procedure:
To 188 mg (0.434 m Mol) of 7-(2,5-diazabicyclo(2.2.1)hept-2-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-di-hydro-4-oxoquinoline-3-carboxylic acid monohydrate (Example 11) was suspended in 20 ml dry DMF was added 96 mg (0.95 m Mol) anhydrous calcium bicarbonate and 92 mg (0.48 m Mol) 4-bromomethyl-5-methyl-1,3-dioxolen-2-one. The resultant suspension was stirred at room temperature for 10 hrs. Then the suspension was treated with 150 ml of ethyl acetate and 50 ml of water. The organic phase was separated and washed with 5×30 ml water, dried over sodium sulfate, filtered the volatiles were removed at room temperature under reduced pressure. Recrystallization from ethyl acetate gave 63 mg (27.5%) of the desired material.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[CH:13][O:14][C:10]=2[C:9]([OH:15])=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6](C)[O:7]2.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][O:15][C:9]2[C:10]3[O:14][CH:13]=[CH:12][C:11]=3[C:2]([OH:1])=[C:3]3[C:8]=2[O:7][CH:6]=[CH:5][C:4]3=[O:17])=[CH:23][CH:24]=1
Reactant: Cc1cc(=O)c2c(O)c3ccoc3c(O)c2o1
Reactant: Fc1ccc(CCCBr)cc1
Product: O=c1ccoc2c(OCCCc3ccc(F)cc3)c3occc3c(O)c12
Yield: 66 %

Procedure:
4,9-Dihydroxy-7-methyl-5H-furo[3,2-g]chromen-5-one (2.32 g, 10 mmol) was reacted with 1-bromo-3-(4-fluorophenyl)propane (1.0 eq) according to General Procedure A to give 9-(3-[4-fluorophenyl]propoxy)-4-hydroxy-5H-furo[3,2-g]chromen-5-one (2.4 g, 66%), that was further reacted according to General Procedure D (Step 1) to provide the corresponding triflate derivative in 80% (2.6 g) yield. The triflate (2.5 g, 5.0 mmol), ZnBr2.2H2O (3.92 g, 15.0 mmol), CuI (47.5 mg, 0.25 mmol), PdCl2(PPh3)2 (105 mg, 0.15 mmol) and MeLi (9.4 mL of 1.6 M in diethylether, 15.0 mmol) were reacted according to General Procedure D (Step 2) and the crude material was purified by silica-gel flash chromatography, eluting with dichloromethane to afford the title compound as a off-white solid (1.2 g, 65%). 1H NMR (300 MHz, CDCl3): δ 2.06-2.15 (m, 2H), 2.36 (s, 3H, Me), 2.89 (t, J=7.6 Hz, 2H, CH2), 2.96 (s, 3H), 4.37 (t, J=6.3 Hz, CH2), 6.05 (s, 1H), 6.92-6.99 (m, 3H), 7.15-7.20 (m, 2H), 7.64 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]ncc12
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(Cn2ncc3c(Cl)nccc32)cc1

Procedure:
To 4-chloro-1H-pyrazolo[4,3-c]pyridine (60 mg, 0.40 mmol) in 2 ml DMF was added 4-Fluorobenzylbromide (0.060 ml, 0.48 mmol) then add NaH (20 mg, 0.4 mmol) and stir at room temperature overnight. Work up by adding water and EtOAc and extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 38 mg of major isomer A and 15 mg of minor isomer B.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 86 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(2-fluoro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 111 mg (83%) of a white solid. MS (ISP) 429.6 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].[CH:15]([OH:19])([CH2:17][CH3:18])[CH3:16].C(N(CC)CC)C>C(OCC)C>[CH:15]([O:19][C:3](=[O:4])[C:2](=[CH2:1])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: C=C(CCCc1ccccc1)C(=O)Cl
Reactant: CCC(C)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(CCCc1ccccc1)C(=O)OC(C)CC
Temperature: 25 °C

Procedure:
27 g of 2-methylene-5-phenylvaleric acid chloride are added dropwise to a solution of 100 ml of sec.-butanol and 20 ml of triethylamine in 300 ml of diethyl ether at 25° to 30°. When the addition is complete, the obtained mixture is stirred at room temperature for another hour; 500 ml of ice water are then added and the mixture is shaken thoroughly. The organic phase is collected, dried over sodium sulfate and concentrated. 19.5 g of 2-methylene-5-phenylvaleric acid sec.-butyl ester (b.p. 115° to 126° under 0.01 mm Hg) are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])[CH:2]=1.[Li+].[OH-].O>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])[CH:2]=1
Reactant: COC(=O)c1ccccc1SCc1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1SCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of compound 3 (55.0 g, 0.212 mol) in MeOH/H2O (300 mL/50 mL) was added LiOH. H2O (17.8 g, 0.425 mol) in portions at 0° C. The reaction mixture was stirred at room temperature overnight and TLC showed the starting material was consumed. The solvent was removed under reduced pressure. The residue was diluted with water, and extracted with Et2O (2×1 L) to remove neutral impurities. The aqueous layer was adjusted to pH 3-4 with 1 N aq. HCl (50 mL) and extracted with EtOAc (2×1 L). The combined organic phases were washed with water (2×200 mL), brine (300 mL), dried over Na2SO4 and concentrated to afford compound 4 (35.0 g, 67%). This was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[N:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[N:19][CH:18]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:21]2[CH:22]=[N:17][CH:18]=[N:19][CH:20]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: OB(O)c1cncnc1
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cncnc2)c(C(F)(F)F)cc1N
Yield: 40.8 %

Procedure:
To a solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 4.35 mmol) in DME (50 mL) were added pyrimidine-5-boronic acid (538.7 mg, 4.35 mmol), Pd(dppf)Cl2.CH2Cl2 (355 mg, 0.43 mmol), Cs2CO3 (2.8 g, 8.7 mmol) and the resultant mixture was stirred at reflux temperature for 36 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (120 g silica gel, hexanes→EtOAc/hexanes (3:7 to 1:1)) to furnish the title product (528 mg, 41%) as a beige solid. API-ES: m/z 298 [M+H]+, rt 4.06 min.