Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([CH2:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)/[CH:10]=[CH:11]/[CH:12]=[C:13]1[C:17](=[O:18])[C:16]([S:19][CH3:20])=[CH:15][C:14]1([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:21][Si](C)(C)C)(C(C)(C)C)(C)C.C(O)(=O)C.O1CCCC1>O>[OH:8][CH:9]([CH2:37][CH2:38][CH2:39][OH:40])/[CH:10]=[CH:11]/[CH:12]=[C:13]1[C:17](=[O:18])[C:16]([S:19][CH3:20])=[CH:15][C:14]1([OH:21])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(=C/C=C/C(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Yield: 63.3 %

Procedure:
To 255 mg of 5-[(E)-4,7-bis(t-butyldimethylsilyloxy)-2-heptenylidene]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 75 was added 20 ml of a mixture of acetic acid:tetrahydrofuran:water=3:1:1, and the mixture was stirred at room temperature for 26 hours. After concentration with an addition of toluene, saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 94 mg (yield 63%) of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:21]=[C:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:19][N:18]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:20]1[O:19][N:18]=[C:17]([CH3:16])[N:21]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
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: Cc1noc(-c2ccccc2C(=O)N2CCCC[C@H]2CNC(=O)OC(C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformamide (10 ml containing diisopropylethylamine (2.4 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (3.55 g) and stirred at 90° C. for 16 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ether eluant) to give the title compound (3.4 g).
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1>CO.[O-2].[O-2].[Mn+4]>[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:1])=[O:15])=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: CC(=O)Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: COC(=O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 28 %

Procedure:
Acetyl chloride (5 mL) was added to an ice-cooled solution of 4-(hydroxymethyl)phenylacetic acid (5.78 g, 34.8 mmol) in methanol (200 mL). The reaction mixture allowed to warm to RT at stirred at this temperature for 42 hours. The solvent was evaporated at reduced pressure and the residue dissolved in DCM (100 mL). Manganese dioxide (29.47 g, 339 mmol) was added and the resultant suspension stirred at RT for 18 hours. The suspension was filtered through celite and the filter cake washed with further DCM. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0-25% ethyl acetate in iso-hexane to afford the title compound (1.72 g, 28%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1O.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[O:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4]
Reactant: Oc1cc(F)ccc1F
Reactant: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](COc1cc(F)ccc1F)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(2-Hydroxy-1-methylethyl)-1H-isoindole 1,3(2H)-dione (Becker, Y. J. J. Org. Chem. 1980, 45, 2145–51) was diluted with 40 mL THF then treated in order with 7.0 g triphenyl phosphine, 4.0 g of 2,5-difluorophenol and finally with 5.0 mL of diethylazocarboxylate. The reaction became warm to the point of reflux and was allowed to cool to room temperature and stirred at room temperature overnight. The solvent was removed in vacuo and the resulting brown oil was taken up in ethyl acetate (EtOAc). The solution was washed sequentially with aqueous sodium bicarbonate, aqueous ammonium chloride, and brine. Removal of the solvent gave an oil which was chromatographed on silica gel, eluting with 10% ethyl acetate-hexane, to afford 5.4 g of the title compound of Step A as a clear colorless oil: 1H NMR (CDCl3) δ 1.57 (d, 3H), 4.22 (dd, 1H), 4.57 (t, 1H), 4.82 (m, 1H), 6.55 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.72 (m, 2H), 7.82 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:10]C(=O)[O:8][C:7](=O)[C:6]=2[CH:13]=1.C(O)(=O)C.[CH3:19][NH2:20].O>C(#N)C>[NH2:10][C:5]1[C:4]([CH3:14])=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:20][CH3:19])=[O:8]
Reactant: CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)c1cc(Cl)cc(C)c1N
Temperature: 5 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (211.6 g, 1000 mmol) in acetonitrile (700 mL) was added acetic acid (7.3 g, 122 mmol). Then 40% aqueous methylamine (104 mL) was added dropwise over 30 minutes at 25-30° C. Stirring was continued for 2 h, and then water (700 mL) was added slowly. The resulting suspension was cooled to 5° C., and stirred for 30 minutes at this temperature. The suspension was then filtered, and the solids were washed with water (3×200 mL) and dried under nitrogen to afford the title compound as off-white needles, 172.8 g (87.0% yield), m.p. 141-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
3-Bromo-4-hydroxybenzaldehyde (250 mg) was dissolved in 5 ml of acetic acid. Nitric acid (52 μl) was added and the mixture was stirred for 3 h during which a solid formed. The solid was filtered off, washed with water and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[O:15][CH:16]=[C:17]([C:19](O)=[O:20])[N:18]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:17]3[N:18]=[C:14]([CH3:13])[O:15][CH:16]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1nc(C(=O)O)co1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)co1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methyloxazole-4-carboxylic acid (276 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 4 hours. Next, 2M LiOH.H2O (3 mL) was added, and after 30 minutes water (10 mL) was added. The solid formed was filtered, washed with water (2×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide (165 mg, 56% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.15 (s, 1H), 9.68 (s, 1H), 8.63 (s, 1H), 8.37 (d, 1H), 7.67 (s, 1H), 2.52 (s, 3H); LCMS (APCI+) m/z 338.9, 341.0 (M+H)+, Retention time=3.21 minutes (Method 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@H:11]2[CH2:17][O:16][C@@H:13]([CH:14]=[O:15])[C@@H:12]2[OH:18])=[CH:5][CH:4]=1.[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@@H:11]2[C@@H:12]([OH:18])[C@H:13]([CH2:14][OH:15])[O:16][CH2:17]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](C=O)[C@@H]2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CS[C@H]2CO[C@@H](CO)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a room temperature solution, under argon, of 10.9 g of product from Example 322 in 115 ml of absolute ethyl alcohol is added 1.57 g of sodium borohydride. The reaction is stirred at room temperature for 1 hour. Water is added dropwise with stirring and the mixture is concentrated in vacuo. The residue is extracted with methylene chloride, washed with water, dried and concentrated in vacuo to give after chromatography (Silica gel: 50-75% ethyl acetate/hexane) 7.68 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C(=O)O)c1ccc(N)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-nitrophenyl)propionic acid (2.05 g) in THF (20 mL) and EtOH (20 mL) was slowly added 10% Pd/C (0.21 g) at room temperature. After hydrogenated for 2 h with H2 balloon, the reaction mixture was filtered through celite pad and washed with EtOH. The filtrate was concentrated in vacuo to afford the product as pale brown solid. (1.75 g, quantitative)
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Yield: 84.7 %

Procedure:
A solution of 3-nitro-1H-pyrazole (Intermediate 2, 250 mg, 2.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) was treated with a 60% dispersion of sodium hydride in mineral oil (93 mg, 2.32 mmol) was added while stirring under nitrogen. After the effervescence ceased, the reaction stirred for an additional 10 min. At this time, the reaction was treated with (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (598 mg, 2.50 mmol). The reaction continued to stir under nitrogen for 2 h. At this time, the solution was diluted with ethyl acetate (200 mL), washed with water (2×75 mL), a saturated aqueous sodium chloride solution (75 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (Merck silica gel 60, 40-63 μm; 5-25% ethyl acetate/hexanes) afforded 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-nitro-1H-pyrazole (508 mg, 84%) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ 0.00 (6H, s), 0.86 (9H, s), 4.03 (2H, t, J=5.6 Hz), 4.40 (2H, t, J=5.2 Hz), 7.11 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=2.4 Hz).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([CH2:21][C:22](=O)[CH3:23])([O-:20])=[O:19].[NH2:25]/[C:26](/[CH3:32])=[CH:27]\[C:28]([O:30][CH3:31])=[O:29].C1CCCCC1.C(OCC)(=O)C>C(O)C>[CH3:23][C:22]1[NH:25][C:26]([CH3:32])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:16]([C:15]2[C:9]3[S:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=2)[C:21]=1[N+:18]([O-:20])=[O:19]
Reactant: O=Cc1cccc2nc(-c3ccccc3)sc12
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: CCO
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C([N+](=O)[O-])C1c1cccc2nc(-c3ccccc3)sc12
Yield: 25 %

Procedure:
10 mmol of 2-phenyl-benzothiazole-7-carboxaldehyde, 10 mmol of nitroacetone and 10 mmol of methyl 3-aminocrotonate are boiled in 20 ml of ethanol overnight, the mixture is concentrated and the residue is purified on a silica gel column (cyclohexane/ethyl acetate=6:4) Yield: 25% of yellow crystals M.p.: 233° C. (dec.)
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]2)=[CH:7][CH:6]=1)([O-])=O.CCOCC>[Pd].C(O)C>[ClH:1].[NH2:2][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]2)=[CH:7][CH:6]=1
Reactant: CN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN1CCc2ccc(N)cc2C1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A suspension of 3.98 g (17.5 mmol) of 7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride and 0.4 g of 10% palladium on carbon in 200 ml of ethanol was hydrogenated at 50 psi for 2 h. The catalyst was filtered and washed with a small amount of water. The filtrate was concentrated yielding an aqueous solution. Absolute ethanol was added and evaporated driving off the excess water until a solid was produced. This solid was dissolved in hot ethanol (60 ml) and ether was added slowly to induce crystallization. The product was collect to give 3.38 g (97%) of the title compound as an off-white solid, m.p. 114-9° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].N[C:29]1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2[CH:30]=1.C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C1COCC1.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][CH2:29][CH3:30])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Reactant: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCNc1cc2nc(-n3cc(C(=O)OCC)cn3)n(COCCOC)c2cc1Cl
Temperature: 23 °C
Reaction time: 7.5 h

Procedure:
To a slurry of 4 Å molecular sieves (1.2 g) and 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol), and ethanol (3 mL) was added acetaldehyde (0.500 mL, 8.91 mmol) at 0° C. in a sealable microwave tube. The tube was sealed and the reaction mixture was allowed to warm to 23° C. over 16 h. The reaction mixture was heated at 60° C. for 1 h. The molecular sieves were removed from the resulting solution by filtration and the filtrate was concentrated under reduced pressure. Sodium triacetoxy borohydride (0.242 g, 1.14 mmol), THF (3 mL), and glacial acetic acid (0.04 mL) were added to the residue and the resulting suspension was stirred for 7.5 h at 23° C. The reaction mixture was concentrated and the residue partitioned between saturated aqueous sodium bicarbonate and EtOAc (35 mL). The aqueous layer was further extracted with EtOAc (2×35 mL) and the combined organic layers were washed with brine (15 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (0.169 g, 47% crude yield). This compound was used without further purification in subsequent reactions. MS (ESI/CI): mass calcd. for C19H24ClN5O4, 421.2; m/z found, 422.1 [M+H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=[O:19])[C:15]([Cl:18])([Cl:17])[Cl:16].[N+:20]([O-])([OH:22])=[O:21]>C(O)(C)C>[CH3:8][N:9]1[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=[C:10]1[C:14](=[O:19])[C:15]([Cl:16])([Cl:17])[Cl:18]
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])O
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)C(Cl)(Cl)Cl
Temperature: -40 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
An acetic anhydride solution (200 ml) containing 3 (45.2 g, 0.200 mol) was cooled to −40° C., and then fuming nitric acid (18.5 ml, 0.360 mol) was dropped into the solution at the same temperature. After stirring the mixture for 2 hours at a room temperature, isopropanol was added to precipitate a solid. The precipitated solid was collected by filtration to obtain a nitro substance 5 (27.2 g). The filtrate was distilled under a reduced pressure, and the obtained residue was subjected to silica gel column chromatography to further obtain 5 (10.7 g) from an elusion position of ethyl acetate-hexane (1:10, v/v). (Total yield: 70%)
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[OH:16][NH:17][C:18]([NH2:20])=[O:19].ClC(Cl)(Cl)C(O)=O>CN(C=O)C.C(OCC)(=O)C>[OH:16][N:17]([CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:18]([NH2:20])=[O:19]
Reactant: NC(=O)NO
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 20 h

Procedure:
15 g (54 mmol) of 4-hydroxycyclophosphamide (that is to say 2-[bis-(2-chloroethyl)-amino]-4-hydroxytetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) and 4.4 g (58 mmol) of hydroxyurea were dissolved in 70 ml of DMF, acidified with trichloroacetic acid (pH 3-4) and left for 20 hours at 0° C. in a refrigerator. The resultant crystal sludge was diluted with 70 ml of ethyl acetate and after 2 hours was drawn off by suction, washed, dried and recrystallized from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].Cl>C(Cl)Cl>[C:12]([NH:16][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 4.0 g (16 mmol) 2-bromobenzenesulfonyl chloride in 75 mL methylene chloride at 0° C. was added 3.7 mL (35 mmol) tert-butylamine. The mixture was allowed to warm to RT and stir for 1 hour. The mixture was poured into aqueous 5% HCl and extracted three times with ether. The combined organic material was dried over MgSO4, was stripped of solvent in vacuo, then was recrystallized from hexane/acetone to give 3.19 g (70% yield) of the title compound. Rf 0.17 in 10% EtOAc/hexane, visualized by UV;
Reaction SMILES: CN(C)C=O.[CH2:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([C@@]1(O)[C@@H](CO)O[C@@](C(=O)C)([N:24]2[C:34]3[N:33]=[C:31]([NH2:32])[NH:30][C:28](=[O:29])[C:27]=3[N:26]=[CH:25]2)[C@]1(C(=O)C)O)(=O)C.Cl>CO>[CH2:6]([N:26]1[C:27]2[C:28](=[O:29])[NH:30][C:31]([NH2:32])=[N:33][C:34]=2[N:24]=[CH:25]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@@H](CO)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 22 h
Yield: 76.4 %

Procedure:
Four milliliters of N,N-dimethylformamide and 0.53 ml (2.49 equivalents) of benzyl chloride were added to 0.758 g (1.85 mmols) of triacetylguanosine, and the reaction was conducted at 60° C. for 22 hours. It was identified through liquid chromatography that 69% of the starting material remained. Accordingly, 1.60 ml (10 equivalents in total) of benzyl chloride were further added thereto, and the reaction was conducted at 60° C. for 23 hours and at 70° C. for 5 hours. The temperature was returned to room temperature, and 1.57 ml (10 equivalents) of conc. hydrochloric acid were added to the solution. The reaction was conducted for 2 hours, but the cleavage of the sugar moiety was not completed. Therefore, 1.58 ml (20 equivalents in total) of conc. hydrochloric acid were further added, and the mixture was stirred overnight at room temperature. Ten milliliters of methanol were added to the reaction solution in the slurry state. The mixture was stirred for 2 hours, and then filtered. The crystals were washed twice with 5 ml of methanol, dried at 50° C. under reduced pressure for 5 hours to give 0.444 g of 7-benzylguanine crystals in a yield of 76.4%.
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.C([Sn](CCCC)(CCCC)/C=C/[Sn](CCCC)(CCCC)CCCC)CCC.Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43](=[O:51])[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48].[Br:52]Br>C(Cl)(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Br:52]/[CH:1]=[CH:7]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43](=[O:51])[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48]
Reactant: BrBr
Reactant: Cc1ccccc1
Reactant: COC(=O)CCCC(=O)c1ccccc1Br
Agent: [Pd]
Agent: CCCC[Sn](/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCCC(=O)c1ccccc1/C=C/Br
Temperature: 120 °C

Procedure:
To 10 ml of toluene was added 6.0 g (9.9 mmol) of trans-1,2-bis(tri-n-butylstannyl)ethylene, which was prepared according to the procedure of Corey, et al., J. Org. Chem., 40, 3788 (1975), and 0.5 g (1.8 mmol) of the product of Example 3. To the solution was then added 0.040 g (0,035 mmol) of 2 mole% tetrakis(triphenylphosphine)palladium(O) and the solution was degassed with argon. The reaction mixture was heated under argon for 1 hour at 120° C. (oil bath). Thereafter the reaction mixture was cooled to -20° C. To the reaction mixture was added dropwise with stirring, a solution of 1.5 ml (29.1 mmol) of Br2 in 30ml of CCl4 until thin layer chromatography of the reaction mixture indicated that all of the product of Example 3 was consumed. The volatile components were removed in vacuo. The residue was flash chromatographed on a silica gel column. Sequential elution with hexane, 5% diethyl ether in hexane and 10% diethyl ether in hexane produced 0 48g of the titled product The product was triturated with cold hexane to give a white solid, m.p. 52-55° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A degassed solution of 6-bromoindole (1.0 g, 5.1 mmol), 4-fluorobenzeneboronic acid (0.928 g, 6.63 mmol), potassium phosphate (2.7 g, 153 mmol) and palladium (0)tetrakis-(triphenylphosphine) (0.294 g, 0.255 mmol) in dimethylacetamide (50 mL) was heated at 120° C. for 14 hours. After cooling to room temperature, the mixture was diluted with water. The suspension was filtered, the solid washed with water and then dissolved in ethyl acetate (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:4) to give 0.411 g (38.2%) of the title compound as a white crystalline solid.