Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]N1C(=O)CCC1=O.S(=O)(=O)(O)O.O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Br)cc1I

Procedure:
4-Bromophenol (51.9 g, 0.30 mol) and N-iodosuccinimide (67.5 g, 0.30 mol) were combined in acetic acid (360 mL). The mixture was stirred briefly, treated with concentrated sulfuric acid (5 mL, 0.09 mol) and stirred at about 22° C. overnight. The mixture was poured into water (about 800 mL) with stirring to precipitate the product. The suspension was stirred for about 1 hour and filtered. The wet cake was washed with water (50 mL, 2×) and dried under reduced pressure at about 50° C. (80.9 g, 90%). MS-DEI (M+H)+ m/z at 298; 1H NMR (CDCl3 at 400 MHz) δ 5.28 (s,1H), 6.86 (d, 1H), 7.33 (dd, 1H), 7.75 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ 86.0, 112.8, 116.0, 132.7, 139.4, 153.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[N+:24]([O-])=O)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9](=[O:10])[NH:24][C:15]3[C:14](=[CH:23][CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[NH:13]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(NC(C(=O)OC)c2ccc(F)cc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccc(F)cc1)N2
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 4-(1-(4-fluorophenyl)-2-methoxy-2-oxoethylamino)-3-nitrobenzoate (3.5 g, 9.67 mmol, 1.00 equiv), methanol (50 mL), and palladium on carbon (10%) (500 mg). Hydrogen gas was introduced to the reaction, and it was stirred overnight at 30° C. in an oil bath. Then the solids were filtered off and the filtrate was concentrated in vacuo. This resulted in 2.6 g (90%) of methyl 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a light yellow solid.
Reaction SMILES: [CH3:1][CH2:2]/[C:3](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:4](/[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=1)\[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[O:29]=[C:30]([OH:41])[C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32]>C(O)C.CC(O)C>[CH3:1][CH2:2]/[C:3](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:4](/[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=1)\[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[O:29]=[C:30]([O-:41])[C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC/C(=C(\c1ccccc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Solvent: CCO
Solvent: CC(C)O
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A particular emulsion formulation such as a cream or lotion may be obtained for example, by adding a slurry of tamoxifen free base in ethanol or 2-propanol to an aqueous solution of D-gluconic acid to form tamoxifen gluconate in situ, which mixture is then combined with the required components of the disperse phase.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[N:35][C:34]([O:33][CH3:32])=[N:39][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: COc1ncc(B(O)O)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cn1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-methoxypyrimidine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (11%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[F:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: F[B-](F)(F)F
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: Cc1ccc(F)cc1-c1ccc2c(F)c(N)ncc2c1
Reaction time: 16 h
Yield: 49.1 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (203 mg, 806 μmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (313 mg, 883 μmol) were dissolved together in acetonitrile (2.0 mL) at ambient temperature and the mixture stirred for 16 h, at which time LCMS indicated approx 40% conversion. The mixture was diluted with water, extracted three times into dichloromethane and the combined organic phases washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0-6% methanol in dichloromethane) to yield the impure title compound as a pale solid (107 mg), used without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:18]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:18]21[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC12CCCC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), cyclopentanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 2 h at 100° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate), then triturated with ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0434 g, 28%) as a yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3([C:27](=[O:30])[NH:28][CH3:29])[CH2:26][CH2:25]3)[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:23][C:24]2([C:27]([NH:28][CH3:29])=[O:30])[CH2:25][CH2:26]2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][NH:32][CH3:33])[CH:9]=1
Reactant: CNC(=O)C1(COc2cccc(S(=O)(=O)n3cc(CN(C)C(=O)OC(C)(C)C)cc3-c3ccccc3F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC3(C(=O)NC)CC3)c2)c1
Reaction time: 1 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-((1-(methylcarbamoyl)cyclopropyl)methoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 5d (100 mg, 0.18 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of 1 mL of trifluoracetic acid, and then the reaction solution was stirred for 1 h. 10 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 1-((3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)methyl)-N-methylcyclopropylcarboxamide 5 (20 mg, a yellow oil) in 24% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=O)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.C[NH+](C)C>CO.C(O)(=O)C>[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C[NH+](C)C
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a mixture of piperidine-4-carboxylic acid (0.13 g, 1.0 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.24 g, 1.0 mmol), methanol (3 mL) and acetic acid (0.3 mL) was added (polystyrylmethyl) trimethylammonium cyanoborohydride (4.1 mmol/g, 0.25 g). The reaction mixture was heated for 5 min at 120° C. using microwave single node heating. Methanol was added and then the resin was filtered off. The solvent was removed by evaporation. There was obtained 0.35 g (100%) of 1-[1-(diphenylmethyl)azetidin-3-yl]piperidine-4-carboxylic acid. 1H NMR (500 MHz, CDCl3): 1.6-1.8 (m, 2H), 1.9-2.0 (m, 4H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 2H), 2.9-3.0 (m, 3H), 3.4 (t, 2H), 4.4 (s, 1H), 7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 351 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ncoc1CSCCN
Reactant: O=C(N=C=S)c1ccccc1
Product: Cc1ncoc1CSCCNC(=S)NC(=O)c1ccccc1

Procedure:
5-[(2-Aminoethyl)thiomethyl]-4-methyloxazole is reacted with benzoyl isothiocyanate by the procedure of Example 18 to give N-benzoyl-N'-[2-((4-methyl-5-oxazolyl)-methylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-((4-methyl-5-oxazolyl)methylthio)ethyl]thiourea.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[C:9](=[O:10])[NH:8][CH2:7][CH2:6][NH:5]1.[Cl:11][CH:12]([Cl:16])[C:13](Cl)=[O:14]>O.C(Cl)Cl>[Cl:11][CH:12]([Cl:16])[C:13]([N:5]1[CH2:6][CH2:7][NH:8][C:9](=[O:10])[CH:4]1[CH3:3])=[O:14]
Reactant: CC1NCCNC1=O
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1C(=O)NCCN1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
A solution of 8 g (0.2 mole) of sodium hydroxide in 15 ml of water was added to a solution of 20 g (0.18 mole) of 2-methyl-piperazin-3-one in 150 ml of methylene chloride. 26.6 g (0.18 mole) of dichloroacetyl chloride were then added dropwise at from 10° to 15° C. The mixture was stirred at 25° C. for 10 hours and the precipitated crude product was filtered off with suction, washed with water and recrystallized from a 2:1 mixture of isopropanol and H2O to give 14.4 g (36% of theory) of 1-dichloroacetyl-2-methyl-3-oxo-piperazine of melting point 167°-168° C.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].Cl[CH:12]([B:15]1[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]1)[CH2:13][CH3:14].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>O1CCCC1>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:13]([CH:12]([B:15]1[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]1)[NH2:5])[CH3:14]
Reactant: CCC(Cl)B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
10 ml (10 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise to a solution of 2.03 g (9.9 mmol) of 2-[1(RS)-chloropropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 ml tetrahydrofuran under a nitrogen atmosphere at -78° C. The solution was then stirred overnight at room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 2.3 ml (30 mmol) of trifluoroacetic acid were added and the solution was stirred at 0° C. for 30 minutes. The resulting precipitate was filtered off and dried to give 0.5 g of a-(RS)-ethyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine trifluoroacetate as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[O:4]1.CCN(CC)CC.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:16])([CH3:2])[O:4][B:5]([C:10]2[CH2:11][CH2:12][N:13]([C:24](=[O:26])[CH3:25])[CH2:14][CH:15]=2)[O:6]1
Reactant: CC(=O)Cl
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (2.9 g, 11.8 mmol) in DCM (30 mL) were added Et3N (3.6 g, 35.4 mmol) and acetyl chloride (AcCl) (932 mg, 11.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with DCM (20 mL), washed with H2O (2.0 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered, evaporated to give the crude product (3.2 g, crude). ESI-MS (M+1): 252 calc. for C13H22BNO3 251.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[Cl:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)c(Cl)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-chloro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.35 (3H, s), 5.30 (2H, s), 5.80 (1H, d, J=1.6 Hz), 7.10 (1H, d, J=8.4 Hz), 7.25 (1H, d, J=3.2 Hz), 7.40 (2H, dd, J=1.2 Hz, 5.2 Hz), 7.58 (1H, d, J=2.4 Hz), 8.06 (1H, s), 8.71 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13ClN4O, 325. Found, 325.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
Sodium hydride (60 wt%, 0.20 g) was added to dimethyl sulfoxide (15 ml), and the mixture was stirred at room temperature for 10 min. 4-Amino-3-nitrophenol (0.77 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinazoline (1.12 g) was added thereto, and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a 1 N aqueous sodium hydroxide solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give the title compound (1.10 g, yield 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]([CH3:14])([C:12]#[N:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[SH2:15].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]([CH3:14])([C:12](=[S:15])[NH2:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: S
Reactant: Cc1cnc2c(c1)CCCC2(C)C#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cnc2c(c1)CCCC2(C)C(N)=S

Procedure:
3,8-dimethyl-8-cyano-5,6,7,8-tetrahydroquinoline is treated with H2S in pyridine in the presence of triethylamine following the general procedure of Example 5 and the title compound is isolated and recrystallised from benzene as the quarter hydrate, colorless meedles m.p. 164° C. This was converted to the hydrochloride by treatment in isopropanol with a solution of dry HCl gas in ether. The title compound hydrochloride crystallised as colorless needles m.p. 277° C.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[O:23]=[C:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:23]=[C:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH2:30][C:31]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C@@H:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH2:18][CH2:19]1)=[O:32]
Reactant: O=C(O)CCN1CCCC1=O
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)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=C1CCCN1CCC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one (0.25 mmol) in dry DMF (3 mL) was added 3-(2-oxopyrrolidin-1-yl)propanoic acid (47 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol). The mixture was stirred at room temperature for 1 h, and the reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The crude product was purified with High pH prep-LCMS to provide the title compound (53 mg, 47%) as white powders. 1H NMR (400 MHz, METHANOL-D4): δ ppm 1.26-1.51 (m, 6H), 1.55-1.73 (m, 2H), 1.75-2.08 (m, 9H), 2.19-2.37 (m, 5H), 2.56 (t, J=11.91 Hz, 2H), 2.64 (t, J=7.03 Hz, 2H), 2.87-3.14 (m, 5H), 3.43-3.55 (m, 4H), 3.55-3.69 (m, 1H), 3.99 (d, J=13.28 Hz, 1H), 4.54 (d, J=13.28 Hz, 1H). MS (M+1): 446.3
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:29])[C:27]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:20][C:4]1[N:3]=[C:2]([C:24]2[CH:23]=[C:22]([F:21])[C:27]([F:28])=[C:26]([F:29])[CH:25]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1nc(-c2cc(F)c(F)c(F)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 6.5 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 3,4,5-trifluorophenylboronic acid (107 mg, 0.609 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 30 s) for 40 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (30 mL) and washed with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 50 g, 18-32%, gradient 2.5-15% ethanol in DCM, residue dry loaded, product eluted in 15% ethanol) and by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 50% acetonitrile) afforded (2R,3R,4S,5R)-2-{6-amino-2-(3,4,5-trifluorophenyl)-9H-purin-9-yl}-5-(hydroxymethyl) tetrahydrofuran-3,4-diol 12 as a white solid (13.2 mg, 7%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23]>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CCN1CCNCC1
Solvent: CC#N
Product: CCN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-ethylpiperazine, and acetonitrile was refluxed for 5 hours. After cooling, the resulting crystals were filtered, washed with water and recrystallized from ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-ethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 236°-237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1.[CH3:19][N:20]([CH:31]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]1)[C:21]1[S:22][C:23]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH3:19][N:20]([CH:31]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]1)[C:21]1[S:22][C:23]2[CH:29]=[C:28]([NH:30][C:16]([C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=4[Cl:1])=[CH:15][CH:14]=3)=[O:18])[CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CN1CCC(N(C)c2nc3ccc(N)cc3s2)C1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)c(Cl)c1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)C5CCN(C)C5)sc4c3)cc2)c(Cl)c1

Procedure:
The title compound is prepared by following Method A, using 2′-chloro-4′-methoxy-biphenyl-4-carboxylic acid (0.26 g, 0.99 mmol), and isomer-1 of N*2*-Methyl-N*2*-(1-methyl-pyrrolidin-3-yl)-benzothiazole-2,6-diamine (0.20 g, 0.76 mmol) to afford the product (0.125 g, 32%). LC/MS: Retention time=5.27 min; (m/z): calcd for C27H27ClN4O2S. m/e: 507.1; found: 507.0.