Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.OO.C(OCC)(=O)C.[CH:29]([NH2:31])=[O:30]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:29]([NH2:31])=[O:30])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(COc2cccnc2)cc1
Reactant: NC=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 8 h

Procedure:
To 3-(4-chlorobenzyloxy)pyridine (2.19 g, 10 mmol) in formamide (10 ml) at 10° is slowly added conc. sulfuric acid. The reaction is then cooled to 5°, and FeSO4.7H2O (4.16 g, 15 mmol), finely powdered, and hydrogen peroxide (1.7 ml of 30% solution, 0.51 g of H2O2, 15 mmol) are added simultaneously over 10 minutes, with rapid stirring and cooling to 12°-18°. After addition is complete, the reaction is allowed to sit at RT overnight. Ethyl acetate and water are added to the reaction slurry. The layers are separated, and the aqueous phase is extracted with ethyl acetate (3×). The combined organic layers are washed with water and with brine and are dried over calcium sulfate. The residue is taken up in ether, leaving an oily residue. The oily residue is then taken up in chloroform, washed with sat. sodium carbonate, with water and with brine and purified by preparative thin layer chromatography (developing with 50% ethyl acetate/hexane and 0.05% ammonium hydroxide). The second band is collected, yielding 5-(4-chlorobenzyloxy)pyridine-2-carboxamide.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19]>C1COCC1>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In a three-neck flask equipped with mechanical stirrer, cooled in ice bath under nitrogen atmosphere, place a solution of 4.67 g (0.02 mole) of 4-[(methylsulfonyl)amino]benzoyl chloride in 30 ml of anhydrous THF. Add dropwise a solution of 1.77 g (0.02 mole) of N,N-dimethylethylenediamine in 10 ml of anhydrous THF; white solid precipitate forms immediately. Stir the mixture at ice temperature for one-half hour and at room temperature for one-half hour. Collect the solid by filtration, wash with dichloromethane, and recrystallize from methanol ether mixture to provide the title compound.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>>[O:19]1[CH:8]2[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][C:10]=1[CH2:9]2
Reactant: C1=CCc2ccccc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: c1ccc2c(c1)CC1OC1C2

Procedure:
Reaction of a 5,8-dihydronaphthalene of formula III or formula IV with m-chloroperbenzoic acid yields a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene having the structure ##STR6## The reaction can be carried out by mixing m-chloroperbenzoic acid with a solution of a 5,8-dihydronaphthalene in an organic solvent, e.g., ethyl acetate. The resulting mixture is added to a mixture of ethyl ether and aqueous sodium bicarbonate, and mixed to form a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene of formula V.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:5]=1)[CH3:2].O.O.Cl[Sn]Cl>CCOC(C)=O>[CH2:1]([S:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(-c2cn(C)nc2-c2ccccc2F)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 2-(ethylthio)-6(3-(2-fluorophenyl)-1methyl-1H-pyrazol-4-yl)-3-nitropyridine (2.87 g, 8.01 mmol, 1.00 eq.) and SnCl2.2H2O (9.05 g, 40.1 mmol, 5.0 eq.) in EtOAc (200 mL) was refluxed for 2 h. After cooling to room temperature, the solution was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(ethylthio)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3-amine as a yellow solid (2.31 g, 88% yield).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][CH:18]([F:34])[C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:28]4[CH:29]=[CH:30][C:25]([C:22]5[CH:23]=[N:24][C:19]([CH:18]([F:34])[F:17])=[CH:20][CH:21]=5)=[CH:26][CH:27]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(C(F)F)nc2)cc1
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)F)nc4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-[6-(difluoromethyl)-3-pyridyl]benzenecarboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[N:14]=[C:15]([C:17](=[O:20])[CH2:18][CH3:19])[CH:16]=[C:11]2[C:10]([CH3:31])=[C:9]1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33].C(N1C2=C(N3CCC4C(=CC=CC=4)C3)N=C(C(=O)CC)C=C2C(C)=C1C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[ClH:33].[CH2:1]([N:8]1[C:12]2=[C:13]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[N:14]=[C:15]([CH:17]([OH:20])[CH2:18][CH3:19])[CH:16]=[C:11]2[C:10]([CH3:31])=[C:9]1[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cc2c(C)c(C)n(Cc3ccccc3)c2c(N2CCc3ccccc3C2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(O)c1cc2c(C)c(C)n(Cc3ccccc3)c2c(N2CCc3ccccc3C2)n1
Yield: 95 %

Procedure:
In accordance with the same procedures as in Example 860, except for using 1-[1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-propan-1-one obtained by treating the compound prepared in Example 856 with a saturated sodium bicarbonate solution, the titled compound was obtained as a white solid. (Yield: 95%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[CH3:9][CH:10]([CH3:14])[C:11](Cl)=[O:12]>>[CH3:9][CH:10]([CH3:14])[C:11]([N:3]1[CH:4]([CH3:8])[CH2:5][N:6]([C:11](=[O:12])[CH:10]([CH3:14])[CH3:9])[CH2:7][CH:2]1[CH3:1])=[O:12]
Reactant: CC1CNCC(C)N1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)N1CC(C)N(C(=O)C(C)C)C(C)C1
Yield: 55.8 %

Procedure:
The reaction of 5.7 g (0.05 mole) of 2,6-dimethylpiperazine with 13.85 g (0.13 mole) of 2-methylpropionyl chloride is carried out as described in Example VI, and yields 13.3 g of crude product as a solid. Recrystallization from acetone provides 7.1 g of the pure product: mp, 160°-161° C. An additional 4.0 g of pure product is obtained by concentrating the mother liquor and adding hexane. The assigned product structure is consistent with IR and NMR data.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:4]=[N:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.O>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:19][CH:20]=1
Reactant: Cn1nnc(-c2ccccn2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
A solution of (3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-methanol (158 mg, 0.83 mmol) in THF (2.4 mL) was added dropwise at 0° C. to a suspension of NaH (60% in oil, 40 mg, 0.91 mmol) in THF (1.2 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (157 mg, 0.91 mmol) in THF (2.4 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 18 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (209 mg, 77%) as a white solid. MS: m/e=326.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)O1>>[N+:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH:11]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: Nc1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1

Procedure:
4-(4-Nitroquinolin-2-yl)aniline T492P was prepared by using general procedure A from 2-Bromo-4-nitroquinoline (50 mg, 0.2 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (44 mg, 0.2 mmol). The product was obtained as a dark brown solid (31 mg, 58%). NMR (400 MHz, CDCl3): δ 8.36 (m, 1H), 8.32 (s, 1H), 8.20 (m, 1H), 8.06 (m, 2H), 7.80 (m, 1H), 7.65 (m, 1H), 6.81 (m, 2H), 3.99 (br s, 2H); MS (ESI): 266 (M+H+).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-])=O)=[CH:12][C:11]=1[F:21]>C(O)C.O>[Br:9][C:10]1[C:11]([F:21])=[CH:12][C:13]([NH2:18])=[C:14]([O:16][CH3:17])[CH:15]=1
Reactant: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(Br)c(F)cc1N
Yield: 40.3 %

Procedure:
Sodium hydrosulfite (14.7 g, 84.4 mmol) was added to a solution of 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (9.28 g, 37.12 mmol) in ethanol (180 mL) and water (130 mL) at 80° C. in three portions. After 5 hours the organic solvent was removed and the solid in aqueous layer was collected by filtration. The solid was further washed with heptane/ethyl acetate (3:2, 400 mL). The filtrate was evaporated to give 4-bromo-5-fluoro-2-methoxyaniline (3.29 g, 40%). 1H NMR (DMSO-d6) δ 3.75 (s, 3H), 5.22 (s, 2H), 6.56 (d, J=10.68 Hz, 2H), 6.94 (d, J=6.57 Hz, 2H).
Reaction SMILES: O.Cl.[CH3:3][C:4]1([CH3:23])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]1=2>[Zn].C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:23])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCC(=O)O)ccc21
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(CCCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a mixture of 6 g zinc wool and 0.6 g of mercuric chloride, there are added 9 cm3 of water and 0.3 cm3 of 12N HCl. The mixture is stirred for 10 minutes at ambient temperature. The aqueous phase is removed by decanting. The resulting amalgam is rinsed with 20 cm3 of water. There are added 7.21 g (0.025 mole) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-oxo butyric acid, described in Example III, 10 cm3 of water, 8 cm3 of toluene and 5 cm3 of 12N HCl. The mixture is heated for 34 hours at reflux with stirring, adding 3 cm3 of 12N HCl every 6 hours. The reaction mixture is diluted by the addition of 100 cm3 of toluene, filtered (separation of residual amalgam) and rinsed with toluene. The toluene phase is separated, washed copiously with water, dried on sodium sulfate and concentrated under reduced pressure. The resulting crude oil is purified by chromatography on silica 60 gel in a 2/8/90 acetic acid/dioxan/toluene eluant mixture. After evaporation, the recovered solid is taken up in a minimum of isopropyl ether, filtered and dried under a vacuum at 70° C. 4.6 g of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) butyric acid in the form of a white solid whose melting point is 99° C. are obtained.
Reaction SMILES: ClCCC[O:5][P:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1.[CH2:12](O)[CH:13]=[CH2:14]>>[CH2:14]([P:6]1(=[O:5])[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1)[CH:13]=[CH2:12]
Reactant: CC1=CCP(OCCCCl)C1
Reactant: C=CCO
Product: C=CCP1(=O)CC=C(C)C1

Procedure:
To 8 g. (0.0448 mole) of 1-(chloropropoxy)-3-methyl-3-phospholene there was added 2.9 g. (0.05 mole) of allyl alcohol. The mixture was allowed to stand at room temperature and then distilled under reduced pressure to remove volatile material. There was thus obtained 1-allyl-3-methyl-3-phospholene-1-oxide.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.I[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]#[N:33])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]#[N:33])[CH:25]=2)=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(I)cc1C#N
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(C#N)c(C#N)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 23.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.197 g, Example 33), 4-iodo-1,2-dicyanobenzene (0.421 g, Can. J. Chem., 1985, 63, 3057), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.054 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure and the residue purified by chromatography over silica eluting with ethyl acetate. The residue was further purified by chromatography over silica gel eluting with dichloromethane:2-propanol (19:1). The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution. The HPLC fractions were concentrated under reduced pressure, the residue dissolved in dichloromethane, filtered and concentrated under reduced pressure. The residue was triturated with ether to give the title to compound as a solid (0.060 g).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24]O)[O:22][C@@H:21]([N:26]2[C:43]3[N:42]=[CH:41][N:40]=[C:30]([NH:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]=3[N:28]=[CH:27]2)[C@@H:20]1[O:44][CH3:45])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC(S(Cl)(=O)=O)=CC=1)([O-])=O.[Li][N:60]=[N+:61]=[N-:62]>>[N:60]([CH2:24][C@H:23]1[O:22][C@@H:21]([N:26]2[C:43]3[N:42]=[CH:41][N:40]=[C:30]([NH:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]=3[N:28]=[CH:27]2)[C@H:20]([O:44][CH3:45])[C@@H:19]1[O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:61]=[N-:62]
Reactant: [Li]N=[N+]=[N-]
Reactant: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CN=[N+]=[N-])O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21

Procedure:
The low selectivity in the tosylation of guanosine derivative 6 prompted us to to use 3'-hydroxyl protection in the preparation of adenosine analog. Thus, 5'-O-DMT derivative 12 was converted to 3'-O-TBDPSi derivative which was 5'-deprotected to yield 13 with TFA in CH2Cl2. The reaction of 13 with a more reactive sulfonylating agent, p-nitrobenzenesulfonyl chloride, yielded unexpectedly a 2:1 mixture of 5'-O-p-nitrobenzenesulfonyl and 5'-chloro-5'-deoxy substituted derivatives 14 and 15. The mixture was treated with LiN3 at 80° C. overnight to afford 5'-azido-5'-deoxy derivative 16 in good yield. Catalytic hydrogenation of 16 proceeded smoothly to afford 5'-amino derivative 17 which was, without purification converted to 5'-N-MMTr protected derivative 18. Cleavage of the 3'-O-TBDPSi group was achieved using tetrabutylammonium fluoride and the resulting 19 was phosphitylated under standard conditions to give the 3'-O-phosphoramidite 20 in 74% yield (FIG. 8C).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])[CH3:19].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:24]3[CH:25]=[CH:26][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Temperature: 67.5 °C
Yield: 23.1 %

Procedure:
A mixture of 1-benzyl-5-bromo-1H-indole (1.00 g, 3.49 mmol), 4-acetylphenylboronic acid (0.692 g, 4.22 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.0581 g, 0.0711 mmol), potassium carbonate (0.725 g, 5.25 mmol) in dioxane (35 mL) and water (3.5 mL) was heated at 65-70° C. for 3 hours. The reaction mixture was evaporated to dryness and partitioned in ethyl acetate and 2N hydrochloric acid. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using (1-10% ethyl acetate in hexane and 10-15% chloroform in hexane) to yield 1-[4-(1-benzyl-1H-indol-5-yl)phenyl]-1-ethanone as a buff-colored solid (0.262 g, 23%), mp: 134-135° C. 1HNMR (300 MHz, DMSO-d6): δ 7.95-8.1 (m, 3H), 7.85 (d, 2H, J=7.7 Hz), 7.5-7.65 (m, 3H), 7.2-7.4 (m, 5H), 6.6 (d, 1H, J=2.5 Hz), 5.5 (s, 2H), and 2.6 ppm (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:15])=[O:5])[CH3:2].Br[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=1[F:25].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=1[F:25])=[O:5])[CH3:2]
Reactant: CSc1ccc(Br)c(F)c1
Reactant: CCOC(=O)c1[nH]c2ccncc2c1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(SC)cc1F
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A degassed solution of 3-amino-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (0.610 g, 3 mmol), 1-bromo-2-fluoro-4-methylsulfanyl-benzene (1.13 g, 5.1 mmol), Pd2dba3 (0.14 g, 0.15 mmol), Xantphos (0.17 g, 0.3 mmol) and cesium carbonate (1.94 g, 6.0 mmol) in toluene (20 ml) was subjected to microwave irradiation at 150° C. for 2 hours. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si-PPC, ethyl acetate: DCM, gradient 0:100 to 40:100) to afford the title compound as a yellow solid (0.25 g, 24%). LCMS (method B): RT=2.45 min, M+H+=346.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccc(Cl)cc1C(=O)OC
Yield: 61 %

Procedure:
To a solution of methyl 2-amino-5-chlorobenzoate (15 g) and triethylamine (12 ml) in methylene chloride (150 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (10 ml). The mixture was stirred at room temperature for further two hours. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and water, followed by drying. The solvent was distilled off to afford a pale yellow crystals (13.4 g, 61%), m.p. 48°-49° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[S:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[S:8][C:4]=2[CH:5]=[N+:6]([O-:27])[CH:7]=1
Reactant: Fc1cccc(Cl)c1-c1nc2c(Br)cncc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(Br)c2nc(-c3c(F)cccc3Cl)sc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 7-bromo-2-(2-chloro-6-fluoro-phenyl)thiazolo[5,4-c]pyridine (2.0 mmol, 690 mg) in DCM (20 mL) was added mCPBA (5. 2 mmol, 890 mg). The mixture was stirred at room temperature for 5 hours. A solution of 1 M Na2SO3 (10 mL) was then added. The mixture was then stirred at room temperature for 1 hour. A solution of sat. NaHCO3 was added. The layers were separated. The aqueous layer was extracted with DCM. Then the combined organics were dried (Na2SO4), filtered and concentrated to give the title compound as an off-white solid which was used in the next step without purification. LCMS (ESI) m/z 360.9 [M+H+].
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)=[N+]=[N-]>[Pt](=O)=O.C(OCC)(=O)C>[NH2:1][CH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
To a 250 mL round-bottomed flask was added 3-azidomethyl-7-chloro-1-phenyl-1H-quinolin-4-one (2.00 g, 6.44 mmol), ethyl acetate (120 mL) followed by platinum (IV) oxide (152 mg, 0.671 mmol). The reaction mixture was evacuated and back-filled with hydrogen gas using an atmospheric hydrogenation apparatus. The reaction mixture was stirred under hydrogen gas (1 atm.) at room temperature for 5 hr. TLC (40% ethyl acetate-hexanes) and LCMS indicated the absence of starting material. The reaction mixture was filtered through celite under N2 atmosphere, then the celite layer was washed with ethyl acetate. The combined filtrate and washings were concentrated to give 3-aminomethyl-7-chloro-1-phenyl-1H-quinolin-4-one (1.77 g, 96.6% crude yield) as a light beige/greyish solid. The material was used in the next step without further purification.