Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([Cl:13])[CH:6]=1)C=C.[CH2:14]([C:17]1C(O)=CC(Cl)=C(C=1)C#N)[CH:15]=C>>[CH2:17]([C:6]1[C:7]([Cl:13])=[C:8]([CH:11]=[CH:12][C:5]=1[OH:4])[C:9]#[N:10])[CH:14]=[CH2:15]
Reactant: C=CCOc1ccc(C#N)c(Cl)c1
Reactant: C=CCc1cc(C#N)c(Cl)cc1O
Product: C=CCc1c(O)ccc(C#N)c1Cl
Yield: 51 %

Procedure:
Following the process described in example 6 (point B), starting from 4-allyloxy-2-chlorobenzonitrile, a mixture of 5-allyl-2-chloro-4-hydroxybenzonitrile and 3-allyl-2-chloro-4-hydroxybenzonitrile was obtained. The two isomers were separated by chromatography through a silica gel column. Eluting with petroleum ether:ethyl ether, 8:2, the isomer 5-allyl-2-chloro-4-hydroxybenzonitrile (39% yield) was recovered and eluting with petroleum ether:ethyl ether, 6:4, the isomer 3-allyl-2-chloro-4-hydroxybenzonitrile was recovered (51% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][C:25]([CH3:40])([C:27]([O:29]CC2C=CC([N+]([O-])=O)=CC=2)=[O:28])[CH3:26])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15](=[O:17])[NH2:16])[N:13]([S:18]([O-:21])(=[O:20])=[O:19])[C:12]2=[O:22])=[O:9])[N:6]=1.[Na+].[H][H]>O.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][C:25]([CH3:40])([C:27]([OH:29])=[O:28])[CH3:26])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15](=[O:17])[NH2:16])[N:13]([S:18]([OH:21])(=[O:20])=[O:19])[C:12]2=[O:22])=[O:9])[N:6]=1
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(N)=O)c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1C(N)=O)c1csc(N)n1)C(=O)O
Reaction time: 0.08 h

Procedure:
In 10 ml of water is dissolved 200 mg of sodium cis-3-{2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) as obtained in Example 132C, followed by addition of 200 mg of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere at room temperature for one hour. The catalyst is filtered off, and under icecooling 27 mg of sodium hydrogen carbonate is added. The mixture is stirred for 5 minutes and washed with ethyl acetate. To the aqueous layer is added 30 ml of Dowex 50W (H-form) resin, and the mixture is stirred for 1.5 hours. The resin is filtered off and the filtrate is concentrated under reduced pressure to about a half volume thereof. The residue is chromatographed on an Amberlite XAD-II (40 g) column, eluting with water and then 15% ethanol. The fractions including the desired product are combined and lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn-isomer).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH3:14][N+:15]([CH3:17])=C.[I-].[C-]#N.[K+]>C(#N)C.C(OCC)(=O)C>[C:9]([CH2:8][C:7]1[C:6]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=[CH:2][C:17]=2[NH:15][CH:14]=1)#[N:1]
Reactant: C=[N+](C)C
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc2[nH]cc(CC#N)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl indole-4-carboxylate (1.1 g 6.2 mmol) and Eschenmoser's salt [N,N-dimethylmethyleneammonium iodide] (1.3 g, 7 mmol) in acetonitrile (15 ml) is refluxed for 3 hours. The reaction mixture is concentrated, redisolved in dichloromethane (400 ml) and washed with 1M sodium hydroxide (200 ml) and water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated. The resulting methyl 3-(dimethylaminomethyl)indole-4-carboxylate (1.2 g) is methylated with methyl iodide (0.7 ml) in a mixture of dichoromethane (25 ml) and ether (13 ml). The reaction mixture is concentrated, the product dissolved in DMSO (7 ml) and treated with potassium cyanide (700 mg, 10 mmol). After stirring at r.t. overnight the reaction mixture is diluted with ethyl acetate (200 ml) and washed with three portions of water (100 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 2:3 to give methyl 3-(cyanomethyl)indole-4-carboxylate as a dark oil. Hydrogenation in acetic acid over platinum oxide gives the desired intermediate as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][CH:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC1CCCN1
Solvent: CO
Solvent: CN(C)C=O
Product: CC1CCCN1c1nncc2cc(Br)ccc12
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (500 mg, 2.0 mmol) and 2-methylpyrrolidine (524 μl, 5.1 mmol) in DMF (3 mL) was heated at 120° C. in an oil bath for 8 h. The mixture was diluted with MeOH and concentrated over silica gel. The residue was purified using column chromatography (0-40% EtOAc in hexanes) to give the title compound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 292.0, 294.0 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].O>CN(C=O)C>[N+:7]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9.67 g (70 mmol) of potassium carbonate is added to a solution of 6.96 g (50 mmol) of 3-nitrophenol in 500 ml DMF, and then it is stirred for 10 minutes at room temperature. It is mixed with 14.1 g (50 mmol) of 2-(4-bromo-butyl)-isoindole-1,3-dione and stirred for 4 hours at 60° C. After cooling, it is mixed with water and extracted with ethyl acetate. The combined organic phases are dried (MgSO4), filtered and concentrated by evaporation. 17.2 g (50 mmol, corresponding to 100% of theory) of the product is obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:16][SiH:17]([Cl:19])[Cl:18]>>[CH2:8]([Si:17]([Cl:19])([Cl:18])[Cl:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 46.1 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.051 g (0.5 mmol) of triethylamine, 0.63 g (5.0 mmol) of benzyl chloride, and 3.41 g (25.2 mmol) of trichlorosilane were reacted at 150° C. for 18 hrs. The resulting mixture was distilled to give 0.52 g of benzyltrichlorosilane (yield; 47%).
Reaction SMILES: [CH2:1]([C:3]([NH:8][C:9]1[S:10][C:11]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=3)[C:12]=2[N:13]=1)([CH2:6][OH:7])[CH2:4][CH3:5])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1([CH2:4][CH3:5])[CH2:6][O:7][C:34](=[O:36])[N:8]1[C:9]1[S:10][C:11]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=3)[C:12]=2[N:13]=1)[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(CC)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CC)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
2-{[1-Ethyl-1-(hydroxymethyl)propyl]amino}-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (0.29 g, 0.89 mmol), prepared in the previous step, was dissolved in methylene chloride (10 mL) and diisopropylethyl amine (0.37 mL, 2.1 mmol) was added and the mixture was cooled to 0° C. Triphosgene (108 mg, 1.07 mmol) was added and the mixture was stirred for 2 h. The mixture was then diluted with methylene chloride and washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10%-15% ethyl acetate in hexane) afforded the title compound (230 mg, 73%) as a white solid. HRMS: calcd for C19H19N3O2S+H+, 354.12707; found (ESI-FT/MS, [M+H]1+), 354.127; Analytical HPLC: purity 98.1% at 210-370 nm, 10.7 min; 98.8% at 316 nm, 10.7 min; the Xterra® RP18 column, 3.5%, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][C:5]1=2.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][C:5]1=2)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Product: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
9-[2-(Hydroxy)ethyl]-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (I, J. Med. Chem., 38, 4161-3 (1995) is reacted with methanesulfonyl chloride by means known to those skilled in the art to give the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[S:20][C:19]([NH:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[N:18][C:17]=2[C:32]([NH2:34])=[O:33])=[O:14])=[CH:11][CH:10]=1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[OH:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[S:20][C:19]([NH:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[N:18][C:17]=2[C:32]([NH2:34])=[O:33])=[O:14])=[CH:35][CH:36]=1)=[O:7]
Reactant: CC(=O)OCC(=O)Nc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(NC(=O)CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.7 %

Procedure:
To a mixture of 5-[4-(2-acetoxyacetamido)benzamido]-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.10 g, 0.20 mmol) in MeOH (10 mL) was added K2CO3 (0.14 g, 0.99 mmol) and 1 drop of water at rt. The mixture was stirred for 16 hrs at rt. The insoluble material was filtered off, and the filtrate was concentrated in vacuo. The resulting solids were collected and washed with Et2O to give 0.008 g (5% yield) of the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:2]
Reactant: CCOC(=O)CCBr
Reactant: N#Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2c(C#N)cccc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-Cyanoindole (2.5 g) was dissolved in DMF (7.5 ml). Cs2CO3 (11.46 g) was added followed by ethyl 3-bromopropionate (3.38 ml). This mixture was heated to 80° C. for 40 minutes. A further portion of DMF (5 ml) was added and heating at 80° C. continued for 1 hour. The reaction mixture was evaporated then dissolved in H2O (200 ml) and extracted with EtOAc (200 ml). This was evaporated to give a yellow oil (3.5 g) which was purified on a 40+M Biotage cartridge, eluting with a 25-75% mixture of Et2O in hexane. This gave the title compound (3.44 g) as a pale yellow oil. δH (CDCl3, 400 MHz): 1.19 (3H, t), 2.82 (2H, t), 4.12 (2H, q), 4.50 (2H, t), 6.71 (1H, d), 7.23-7.28 (1H, m), 7.33 (1H, d), 7.47 (1H, d), 7.60 (1H, dd). MS (ES): C14H14N2O2 requires 242; found 243 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]C3CCCCO3)[C:9]=2[O:8][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[C:26]1([CH2:25][CH2:24][CH2:23][O:3][CH2:4][CH2:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]=3[O:8][CH:7]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCCc1ccccc1
Reactant: OCCc1coc2c(OC3CCCCO3)cccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc2c(CCOCCCc3ccccc3)coc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Sodium hydride (60%, 27 mg) was suspended in DMF (1 ml) and the obtained suspension was cooled to 0° C. To this solution, a solution of 3-(2-hydroxyethyl)-7-tetrahydropyranyloxybenzofuran (118 mg) in DMF (0.5 ml) was added dropwise and the obtained mixture was stirred at 0° C. for 10 minutes. To this solution, 1-bromo-3-phenyl-propane (0.27 ml) was added and the solution was stirred at 0° C. for 1 hour and then at room temperature for 45 hours. A catalytic amount of concentrated hydrochloric acid was added to the reaction solution and the solution was stirred for 2 hours. The reaction solution was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (15 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (106 mg, yield: 80%).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:33]=[CH:32][C:9]2[S:10][C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:35](=[NH:45])(OCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(#N)C1C=CC=CC=1.Cl>C(O)C.C(N(CC)CC)C>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:33]=[CH:32][C:9]2[S:10][C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C@H:27]4[CH2:31][CH2:30][N:29]([C:35](=[NH:45])[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:28]4)=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:4])[NH2:5]
Reactant: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2s1)c1ccc(O[C@H]2CCNC2)cc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: N#Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2s1)c1ccc(O[C@H]2CCN(C(=N)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
1.0 g of ethyl 3-(5-amidinobenzo[b]thien-2-yl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride was dissolved in 15 ml of ethanol. To this solution was added 773 mg of ethyl benzimidate hydrochloride which has been prepared by allowing benzonitrile to react with ethanol in the presence of hydrogen chloride. 631 mg of triethylamine was added to the thus prepared solution during stirring under ice cooling, and the mixture was warmed up to room temperature, and stirred for 18 hours. Thereafter, the solvent was distilled off to obtain ethyl 3-(5-amidinobenzo[b]thien-2-yl)-2-[4-[((3S)-1-benzimidoyl-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride. The thus obtained ester compound was dissolved in 60 ml of 3N hydrochloric acid and refluxed under heating for 30 minutes. After distilling off the solvent, the resulting residue was subjected to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Fractions of interest were pooled and concentrated, and the resulting residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 350 mg of the title compound was obtained in the form of a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 93.3 %

Procedure:
To a solution of 4-fluoro-2-nitrobenzoic acid (1 g, 5.4 mmol), N,O-dimethylhydroxylamine hydrochloride (0.58 g, 5.95 mmol) and N-methylmorpholine (0.65 mL, 5.91 mmol) in dichloromethane (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.14 g, 5.95 mmol). The mixture was stirred for 80 minutes at room temperature. The mixture was concentrated under reduced pressure and then diluted with EtOAc and water. The organic layer was washed with 3 N HCl, saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide (1.15 g, 95%).
Reaction SMILES: C1[C@H]([N:6]2[C:10]3[N:11]=[C:12]([Cl:16])[N:13]=[C:14](N)[C:9]=3[N:8]=[CH:7]2)O[C@H](CO)[C@H]1O.C(Cl)(=O)C.N([O-])=O.C([N+](CC)(CC)CC)C1C=CC=CC=1>>[Cl:16][C:12]1[N:11]=[C:10]2[C:9]([NH:8][CH:7]=[N:6]2)=[CH:14][N:13]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=N[O-]
Solvent: CC(=O)Cl
Product: Clc1ncc2[nH]cnc2n1

Procedure:
In preferred embodiments of the present invention, CldAdo is synthesized by employing acetyl chloride and benzyltriethylammonium nitrite (BTEA-NO2)-mediated diazotization/chloro-dediazoniation of 6-O-(2,4,6-triisopropylbenzenesulfonyl) (TiPBS) or 6-chloro derivatives that are readily obtained from dGuo. Non-aqueous diazotization/chloro-dediazoniation (acetyl chloride/benzyltriethylammonium nitrite) of 2, 2′b, or 5 gave the 2-chloropurine derivatives 3, 3′b, or 6, respectively. This new procedure for non-aqueous diazotization/chloro-dediazoniation27 (AcCl/BTEA-NO2/CH2Cl2/−5 to 0° C.) worked well for replacement of the 2-amino group of 2, 2′b, and 5 with chlorine to give 3a (89%), 3b (90%), 3′b (87%), 6a (95%), and 6b (91%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]1.CI>CN(C=O)C.O>[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:1])=[O:13])=[CH:8]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc[nH]c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
Potassium carbonate (0.65 g, 5.4 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (0.50 g, 4.5 mmol) in DMF (10 mL). Stirring for 2 h at room temperature, methyl iodide (0.34 mL, 0.77 g, 5.4 mmol) was added. The mixture was stirred overnight at room temperature, diluted with H2O (50 mL), and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl (10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (7:3) on silica gel to give 0.17 g (30%) of a white solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ 3.82 (s, 3 H), 6.56-6.72 (m, 1 H), 6.73-6.83 (m, 1 H), 7.36-7.50 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]=[N:17]O)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=NO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Reaction time: 16 h
Yield: 29.3 %

Procedure:
A solution of 3-[4-hydroxy-2-(hydroxyimino-methyl)-phenyl]-acrylic acid tert-butyl ester (0.50 g, 1.9 mmol) in ethanol (50 mL) was treated with 10% palladium on carbon (0.25 g). The resulting suspension was treated with hydrogen using a Parr shaker apparatus at ambient temperature and 50 psi for 16 h. The reaction mixture was filtered through Celite, rinsed with ethanol (20 mL), and concentrated. The residue was dissolved in ethyl acetate (50 mL) and washed with 10% K2CO3 solution (2×25 mL) and 1N NaOH (2×25 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was crystallized from isopropyl acetate to give the title compound (0.14 g, 40%), mp 154-157° C. 1H NMR (CD3OD): δ 1.37 (s, 9H), 2.44-2.50 (t, 2H), 2.80-2.85 (t, 2H), 3.75 (s, 2H), 4.83 (s, 3H), 6.57-6.63 (dd, 1H), 6.75-6.77 (d, 1H), 6.95-7.00 (d, 1H). MS (ES+) m/z 252.1 ([M+H]+). MS (ES−) m/z 250.2 ([M−H]−). Anal. Calculated for C14H21NO3: C: 66.9069; H: 8.4222; N: 5.5731. Found: C: 66.57; H: 8.29; N: 5.60.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29]C(=O)C2C=CC=CC=2)[C@@H:16]([O:17]C(=O)C2C=CC=CC=2)[C@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=O)[CH3:2].[F:38][C:39]([F:51])([F:50])[C:40]([NH:42][C:43]1[CH:44]=C(O)C=[CH:47][CH:48]=1)=[O:41].B(F)(F)F.ClCCl>O1CCCC1>[O:4]([C:1]1[CH:2]=[CH:47][CH:48]=[C:43]([NH:42][C:40](=[O:41])[C:39]([F:51])([F:38])[F:50])[CH:44]=1)[C@@H:5]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:16]([OH:17])[C@H:6]1[OH:7]
Reactant: O=C(Nc1cccc(O)c1)C(F)(F)F
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1cccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 168 h
Yield: 49.7 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (500 mg, 0.99 mmol), 3-trifluoroacetamidophenol (407 mg, 1.98 mmol) from Stage 1 and boron trifluoride diethyletherate (1.41 g, 9.93 mmol, 1.25 ml) in a mixture of dry dichloromethane (10 ml) and dry tetrahydrofuran (30 ml) was stirred at room temperature under argon for 7 days. Work-up as in Stage 1 of Example 1 and purification by flash chromatography on silica gel (2% acetone in toluene as eluant) gave the title compound as a colourless solid (166 mg, 21%).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH2:4][N:3]1[C:6]1[N:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].C(O)(=O)C.[Br:18]Br>[Pd].CCOCC>[BrH:18].[Br:18][C:11]1[CH:12]=[N:13][C:6]2[NH:3][CH2:4][CH2:5][C:2](=[O:1])[NH:9][CH2:8][C:7]=2[CH:10]=1
Reactant: N#Cc1cccnc1N1CCC1=O
Reactant: BrBr
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Br
Product: O=C1CCNc2ncc(Br)cc2CN1
Reaction time: 8 h

Procedure:
A round bottom flask was purged with argon and charged with 2-(2-oxoazetidin-1-yl)nicotinonitrile (600 mg, 3.46 mmol) and palladium (10%) on activated carbon (250 mg, 0.23 mmol) followed by acetic acid (15 mL). The flask was stirred under a hydrogen balloon overnight. A TLC analysis indicated that the starting material has been consumed. The mixture was filtered through a pad of celite and the filtrate was treated with bromine (0.27 mL, 5.19 mmol) dropwise over 20 minutes. The yellow-orange suspension was stirred for 3.5 hours at room temperature. The suspension was then treated with 150 mL Et2O and stirred rapidly then sonicated. The solvent was decanted and the solid was filtered and washed with 200 mL Et2O. The solid was collected and dried under reduced pressure. Yield: 600 mg (51.3%). 1H-NMR (400 MHz, DMSO-d6) δ 8.06 (d, 1H, J=2.4 Hz), 7.75 (d, 1H, J=2.4 Hz), 7.43 (t, 1H, J=7.6 Hz), 4.48 (d, 2H, J=7.6 Hz), 3.65 (t, 2H, J=8.0 Hz), 2.74 (t, 2H, J=8.0 Hz)