Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][C@@H:38]([O:42][Si](C(C)(C)C)(C)C)[CH2:39][O:40][CH3:41])=[CH:32][N:31]=4)[C:26](=[O:50])[N:25]([CH3:51])[N:24]=3)[C:18]=1[CH2:52][OH:53])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.[Na+].[Cl-]>C1COCC1.CCOC(C)=O.CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][C@@H:38]([OH:42])[CH2:39][O:40][CH3:41])=[CH:32][N:31]=4)[C:26](=[O:50])[N:25]([CH3:51])[N:24]=3)[C:18]=1[CH2:52][OH:53])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[C@@H](COc1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC[C@H](O)COc1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Yield: 61.9 %

Procedure:
In a 100 mL round-bottomed flask, (S)-6-tert-butyl-2-(3-(5-(5-(2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one (214 mg, 287 μmol, Eq: 1.00) was combined with THF (6.0 ml) to give a yellow solution. TBAF (500 μl of a 1M solution in THF, 500 μmol) was added and the resultant solution was stirred at 25° C. for 1 h. The reaction was complete by LCMS. The reaction mixture was poured into 75 mL H2O and extracted with EtOAc (1×75 mL). An emulsion resulted. Saturated NaCl was added and the EtOAc layer was separated. Extracted 2 times with DCM. No product left in aqueous phase by LCMS. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0.5% to 4% MeOH in DCM) to afford a glass. The glass was taken up in EtOAc/hexane and conc. to give a semisolid, which was triturated with ether. The resulting white solid was washed with ether/hexanes to give 112 mg of pure product as a white powder. (M+H)+=631 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 3.44 (s, 3H) 3.53-3.64 (m, 2H) 3.91 (s, 3H) 4.03-4.11 (m, 2H) 4.13-4.22 (m, 1H) 4.42 (s, 2H) 6.98 (d, J=8.69 Hz, 1H) 7.28-7.35 (m, 1H) 7.43-7.62 (m, 4H) 7.64-7.69 (m, 1H) 8.06 (d, J=3.02 Hz, 1H) 8.27-8.32 (m, 2H) 8.48 (s, 1H)
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH2:16][CH3:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:23][OH:24]>CO.O>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[N:23][OH:24])[CH2:16][CH3:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)CC)c2C1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCN(CCC)C1CCc2cccc(C(CC)=NO)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a solution of 2-di-n-propylamino-8-propionyl-1,2,3,4-tetrahydronaphthalene (0.7 g, 2.4 mmol) (prepared as in Example 21) in methanol (40 ml) was added a solution of hydroxylamine hydrochloride (1.7 g, 24 mmol) in water (10 ml). The solution was stirred at room temperature overnight. The reaction was poured into water, the pH was adjusted to 12 and then extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give 760 mg of crude 2-di-n-propylamino-8-(1-oximinopropyl)-1,2,3,4-tetrahydronaphthalene sufficiently pure to be used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[C:16](=[O:23])[NH:15][N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH2:24]([N:15]1[N:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[C:16]1=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OCC
Reactant: ClCc1ccccc1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: CCOc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OCC

Procedure:
Prepared from compound 7 and benzylchloride as described for compound 78. Crystallized from petroleum ether (60°-95° C.). M.p. 91°-92° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:27][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCC3CCOC(C)(C)C3)c2n1
Yield: 99.1 %

Procedure:
To a solution of N2-butyl-9-[2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethyl]-8-(methyloxy)-9H-purine-2,6-diamine (135 mg, 0.359 mmol) in methanol (10 ml) was added 4M HCl solution in dioxane (2.241 ml, 8.96 mmol) and the mixture was left standing at 20° C. After 6 hours the solvent was evaporated under a stream of nitrogen. The residue was loaded in methanol onto a 10 g aminopropyl SPE cartridge and eluted with methanol. The solvent was removed by evaporation to give the title compound (129 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:23][C:24]4[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4cccc(C#N)c4)ccc3o2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a cooled solution of 4-tert-butyl 2-(5-hydroxybenzofuran-2-yl)thiazole (0.33 g) in N,N-dimethylformamide (5 ml), sodium hydride ((60% in mineral oil) 55 mg) was added below 10° C. After being stirred for 10 minutes, 3-bromomethylbenzonitrile (0.26 g) was added to the mixture. After being stirred at ambient temperature for 2 hours, the resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was crystallized with diisopropyl ether and filtered to give crystals of 4-tert-butyl-2-[5-(3-cyanophenylmethoxy)benzofuran-2-yl]thiazole (0.38 g).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: COc1cc(-c2nc3ccc(OCCN4CCCCC4)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 1-(2-chloroethyl)piperidine hydrochloride essentially as previously described. mp 167° C., NMR, IR, MS 570.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.CN(C)C=O>CCOCC.O>[O:3]=[S:1]1(=[O:2])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:5](=[O:6])[N:4]1[CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: BrCCCCBr
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Temperature: 50 °C

Procedure:
The general procedure of J. D. Commerford and H. B. Donahue J. Org. Chem. 1956, 21, 583-4 was modified: A mixture of 6 g of sodium saccharin, 100 mL of 1,4-dibromobutane, and 5 mL of N,N-dimethylformamide was heated at 50° C. overnight. After cooling to ambient temperature, the mixture was diluted with 250 mL of ether and 50 mL of water. The aqueous layer was extracted with two additional 50 mL portions of ether and the combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The excess 1,4-dibromobutane was removed by short path vacuum distillation and the oily residue purified by crystallization from ether-hexane, mp 71-2° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Mg]Br)[CH2:24][CH2:25][CH2:26][CH3:27].O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[CH:18][CH:19]=[CH:20][CH:21]([OH:22])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC[Mg]Br
Reactant: O=CC=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)C=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(1-benzylindol-3-yl)-2,4-pentadienal (2 g, 7 mmol) in 25 ml of tetrahydrofuran, stirred in a dry ice-acetone bath, was added in one portion 7 mmol of n-pentyl magnesium bromide (3.9 ml of 1.8M solution in ether). The resulting mixture was stirred at -78° C. for 90 min. and then mixed with 50 ml of water after warming up to about 0° C. Ethyl acetate, 50 ml, was added and the layers were separated. The organic layer was washed with water, dried (MgSO4) and concentrated on rotary evaporator to give the crude mixture. This substance was purified on a silica gel dry column (25% ethyl acetate in hexane) to afford 0.4 g of the produce as an oil. NMR spectrum shows a singlet at 5.12 and a multiplet centered at 4.05 ppm.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][CH2:9][C@@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:23])[CH2:11]1.S([O-])([O-])(=[O:26])=S.[Na+].[Na+]>O1CCCC1>[F:8][CH2:9][C@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:23])[C@@H:11]1[OH:26]
Reactant: C[C@H](c1ccccc1)N1C[C@@H](CF)CC1=O
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@H](c1ccccc1)N1C[C@H](CF)[C@@H](O)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
In an atmosphere of nitrogen and at −78° C., 1.66 N n-butyllithium-hexane solution (7.08 ml) was added dropwise to a tetrahydrofuran (20 ml) solution of diisopropylamine (1.65 ml, 11.75 mmol), and the mixture was stirred at 0° C. for 5 minutes. The reaction solution was cooled to −78° C. and added dropwise to a tetrahydrofuran (20 ml) solution of 4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone (2.00 g, 9.04 mmol) at −78° C. in an atmosphere of nitrogen. After 15 minutes of stirring at the same temperature, degassing was effected under a reduced pressure, the atmosphere in the reaction container was replaced with oxygen gas and then the reaction mixture was stirred at the same temperature in an atmosphere of oxygen. After completion of the reaction, the reaction solution was mixed with 5% sodium thiosulfate aqueous solution, tetrahydrofuran was evaporated, the thus obtained residue was extracted with ethyl acetate (150 ml×3) and then the resulting organic layers were combined and dried over sodium sulfate. The solvent was evaporated and the thus obtained residue was subjected to a silica gel chromatography to give 1.57 g (73%) of the title compound from the eluate of 3% methanol-chloroform in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=NC(C2C[C@H](C)N[C@H](C)C2)=C(C)C=1.BrC1C=C2C(=CC=1)[C:38](=[O:42])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:42][CH3:38]
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Reactant: Cc1cc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cnc1C1C[C@@H](C)N[C@@H](C)C1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 900 mg (86% yield) of solid is obtained from 630 mg (2.23 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, and 0.14 g (0.608 mmol) of 6-[(2R,6S)-2,6-dimethylpiperidin-4-yl]-5-methylpyridin-3-yl}amine; mp: 194-195° C.;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)=[CH:14]2)=O.O.[Cl-].[NH4+]>C1COCC1>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:21][CH2:20][C:15]1[NH:16][C:17]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:9][OH:8])=[CH:19][CH:18]=2
Reactant: COC(=O)c1ccc2[nH]c(CCOC3CCCCO3)cc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2[nH]c(CCOC3CCCCO3)cc2c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (3.38 g, 89.0 mmol) in anhydrous THF (100 mL) was cooled to −30° C. 2-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-5-carboxylic acid methyl ester (13.5 g, 44.5 mmol) in anhydrous THF (100 mL) was added dropwise. The reaction mixture was stirred at −20° C. for 1 hour and then at room temperature for 4 hours. The reaction mixture was cooled to 0° C. and water (6 mL) was added slowly. Ammonium chloride solution (200 mL) was added and extracted with ethyl acetate (2×200 mL). The organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated to give {2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indol-5-yl}-methanol as a white solid. Yield: 11.50 g (94%).
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([N:23]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:33]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: Cc1cccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 257A (0.038 g, 0.083 mmol) in tetrahydrofuran (1.7 mL) and methanol (0.007 mL, 0.166 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.065 mL, 0.130 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.35 (s, 3 H) 3.87 (s, 2 H) 6.05 (t, J=6.62 Hz, 1 H) 7.12 (m, 2 H) 7.31 (m, 5 H) 7.56 (t, J=7.54 Hz, 2 H) 7.70 (dd, J=11.95, 7.91 Hz, 2 H) 8.10 (d, J=7.72 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z459 (M−H)−.
Reaction SMILES: C(OC([N:8]([C:19]1[CH:20]=[C:21]([CH:25]([O:29][P:30]([CH:33]([NH:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH:34]([CH3:36])[CH3:35])([OH:32])=[O:31])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)[C:9]([NH2:18])=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]([C:19]1[CH:20]=[C:21]([CH:25]([O:29][P:30]([CH:33]([NH:37][C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[CH:34]([CH3:35])[CH3:36])([OH:32])=[O:31])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)[C:9]([NH2:18])=[NH:10]
Reactant: CC(C)C(NC(=O)OCc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NC(=O)OCc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of 2-(3-(N,N′-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid in 10 mL of CH2Cl2 was added 5 mL of TFA. After stirring for 2 hours at ambient temperature, the solution was concentrated in vacuo and azeotrope with CH2Cl2 and MeOH. Purification by preparatory HPLC separated the two diastereomers and provided 72.9 mg (8%) of one diastereomer and 90.1 mg (10%) of 2-(3-guanidinophenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyloxy)ethanoic acid, NMR (DMSO-d6) 0.85 (m, 6), 2.05 (m, 1), 3.70 (m, 1), 4.80 (AB q, 2: doublets at 4.70, 4.90), 5.65 (d, 1), 7.20 (d, 1), 7.25-7.50 (m, 14), 9.85 (s, 1) ppm.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([N+]([O-])=O)=[CH:23][C:18]=2[N:17]([CH3:27])[C:16]1=[O:28]>CO.[Pd]>[CH3:27][N:17]1[C:18]2[CH:23]=[CH:22][C:21]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=3)=[CH:20][C:19]=2[N:15]([CH3:14])[C:16]1=[O:28]
Reactant: Cn1c(=O)n(C)c2cc([N+](=O)[O-])ccc21
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)n(C)c2cc(NCCc3ccc(C(F)(F)F)nc3)ccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
A solution of (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (223 mg, 1.21 mmol, prepared as per example 1, step 1) and 1,3-dimethyl-5-nitro-1,3-dihydro-benzoimidazol-2-one (240 mg, 2.41 mmol, commercially available) in MeOH (10 mL) was treated with NH4OAc (13.00 mmol) and 10% Pd/C (200 mg) and stirred at 60° C. for 72 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (216 mg, 25%) as a light yellow oil. MS m/e: 351.1 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=2)=[N:26]1.CCN(C(C)C)C(C)C.[F:48][C:49]([F:62])([F:61])[C:50]1[NH:51][C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([CH2:59][NH2:60])=[CH:54][CH:53]=2>CN(C=O)C>[NH:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([NH:60][CH2:59][C:55]3[CH:56]=[C:57]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([C:49]([F:62])([F:48])[F:61])=[CH:58]4)=[O:36])=[CH:37][CH:38]=2)=[N:26]1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(-c2cc[nH]n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(-c2cc[nH]n2)cc1
Reaction time: 24 h

Procedure:
To a solution of HATU (0.200 mmol) in DMF (0.5 ml) was added 4-(1H-pyrazol-3-yl)benzoic acid (Apollo Scientific Ltd.) (0.12 mmol) in DMF (0.5 ml), followed by DIPEA (0.300 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 0.025 g, 100 μmol) in DMF (0.25 ml). The experiment was carried out in an array form using a Bohdan mini block. The block was shaken for 24 hours. The compound was purified using an amino propyl column which was pre-conditioned with DMF. The column was washed with DMF (×2). The washings were evaporated to dryness and the resulting residue was then purified by MDAP to give the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[F:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[C:3]([N:28]2[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:23][CH2:22][F:21])[CH2:27]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: FCCNCC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CCC(CNCCF)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A suspension of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-(2-fluoroethylaminomethyl)pyrrolidine (165 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU, 100 mg) in absolute acetonitrile (2 ml) was refluxed for an hour. After cooling, the reaction mixture was concentrated and to the residue was added acetonitrile-ether (1:1, 5 ml). The solution was allowed to stand overnight at 5° C., then the resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-ether to give the title compound (40 mg), mp 138°-142° C.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)C1SC=CN=1.C([Sn](Cl)(CCCC)CCCC)CCC.C[Si](C)(C)[C:31]1[S:32][C:33]([Sn:36]([CH2:45][CH2:46][CH2:47][CH3:48])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:34][N:35]=1>CCOCC.C(Cl)(Cl)Cl.CO>[CH2:45]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[C:33]1[S:32][CH:31]=[N:35][CH:34]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C)(C)C)s1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)c1nccs1
Agent: [Li]CCCC
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCC[Sn](CCCC)(CCCC)c1cncs1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (1.6M, 4.95 mL, 7.88 mmol) was added to a solution of 2-trimethylsilylthiazole (826 mg, 5.25 mmol) in anhydrous ether (45 mL) stirred at −78° C. under nitrogen. After 20 min, tri-n-butylstannyl chloride (2.57 g, 7.88 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue. The residue of 2-trimethylsilyl-5-tributylstannyl-thiazole was passed through a column of neutral alumina eluting with a gradient of ammoniated methanol in chloroform to give the sub-title compound as a yellow oil (1.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([CH:15]=O)=[CH:14][C:5]2=1.O.NN.[OH-].[K+]>C(O)CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([CH3:15])=[CH:14][C:5]2=1
Reactant: O=Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Temperature: 150 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Following a published procedure (Tetrahedron, 2002, 5251) 6-bromo-9H-pyrido[3,4-b]indole-3-carbaldehyde (40 mg, 0.145 mmol), hydrazine hydrate (51 mg, 1.02 mmol) and KOH (29 mg, 0.509 mmol) were combined in 0.5 mL of ethylene glycol and heated to 150° C. overnight. The reaction was cooled to room temperature. Ice chips were added and the mixture was stirred in an ice bath for 1 hour. White precipitate formed which was filtered and dried to afford the desired compound in 73% yield.