Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:33][CH2:32]1.O>C1COCC1>[CH2:40]([O:39][C:37]([N:34]1[CH2:35][CH2:36][C:31](=[CH:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[CH2:32][CH2:33]1)=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(=CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
To a suspension of phosphonium bromide 78NLS66 (4.69 g, 10.1 mmol) in THF (100 mL) n-butyllithium (1.6 M in hexane, 6.3 mL, 10.1 mmol) was added at 0° C., giving a deep red solution. After stirring for 1 h at rt, a solution of benzyl 4-oxo-1-piperidinecarboxylate (2.24 g, 9.6 mmol) in THF (10 mL) was added dropwise over 30 min. The mixture was stirred at rt for 20 h, then water was added and the mixture extracted three times with diethylether. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 0-10% ethyl acetate in n-heptane, afforded the title compound (0.56 g, 17%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: O=C(O)c1c[nH]c2ccc(Cl)cc12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1c[nH]c2ccc(Cl)cc12

Procedure:
To a suspension of 5.23 g (26.74 mmol) 5-chloro-1H-indole-3-carboxylic acid in 140 ml dry ethanol were added 10 ml concentrated sulfuric acid, and the mixture was heated with reflux for 16 h. It was concentrated under reduced pressure, and the residue was tretaed with ethanol/hexane to give the crystalline title ester, which was filtered and dried in vacuo.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[CH3:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[CH3:4]
Reactant: CC(C/C=C/c1ccc2c(c1)OCO2)N(C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1ccc2c(c1)OCO2
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 117.4 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3,4-methylenedioxyphenyl)-4-penten-2-amine (1.08 g, 3.38 mmol) in anisole (11 mL) was treated drop-wise over 45 min with trifluoroacetic acid (16.28 g, 142.8 mmol). The resulting solution was stirred for 1.5 h at 0-5° C. The solution was then concentrated by rotary evaporation followed by further drying under high vacuum. The resulting red oil was cooled (0-5° C.), basified with 10% NaOH solution (15 mL), treated with saturated NaCI solution (10 mL) and extracted with CHCl3 (6×20 mL). The combined CHCl3 extracts were washed with saturated NaCl solution (25 mL), dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum to produce a brown oil (0.87 g). The crude product was purified by column chromatography on silica gel (50 g), eluting with CH3OH—Et3N (98:2, v/v). Selected fractions containing the product (Rf 0.37) were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation and dried under high vacuum to give 380.3 mg (51.3%) of a light-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[C:15](=[O:17])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:15](=[O:17])[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(CCNC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CC(=O)N(CCNC(=O)OCc1ccccc1)c1ccc(N)cc1

Procedure:
450 mg (1.26 mmol) of 4-[N-(2-benzyloxycarbonylamino-ethyl)-N-acetyl-amino)-nitrobenzene (prepared analogously to Example I) are dissolved in 20 ml of methanol and after the addition of 100 mg of Lindlar catalyst hydrogenated for 2 hours with hydrogen. The catalyst is filtered off, the solution is evaporated down.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][NH2:16])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH2:17](OC(OCC)OCC)C>>[CH3:1][O:2][C:3]1[C:4]2[N:5]([CH:17]=[N:16][N:15]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc2nc(NN)c(OC)nc2c1
Product: COc1ccc2c(c1)nc(OC)c1nncn12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 1.5 g. (0.068 mole) of 3,6-dimethoxy-2-hydrazinoquinoxaline and 20 ml. of triethylorthoformate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration and washed with ethanol to ultimately afford 1.8 g. of pure 4,7-dimethoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 238°-240° C. (decomp.). Mass Spectrum: m/e, 230 (P); m/e, 231 (P+1); m/e, 232 (P+2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24]>C(Cl)Cl>[CH2:26]([O:25][C:23]([N:11]1[CH2:10][CH:9]2[CH2:14][CH:13]([N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12]1)=[O:24])[CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2CNCC1C2
Reactant: CCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)N1CC2CC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2) (50 mg, 0.25 mmol) in 5 mL of methylene chloride was added triethylamine (67 μL, 0.5 mmol) and the solution was cooled to 0° C. Propyl chloroformate (31 μL, 27.5 mmol) was added and the solution was stirred for 1 h. The solvent was removed in vacuo and the residue was washed with 50 mM sodium acetate in methylene chloride solution. The solution was stirred 10 min and passed through a phase separator. The solvent was removed in vacuo to give crude 3-(propoxycarbonyl)-6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1.[OH-].[Ca+2:28].[OH-]>>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24].[Ca+2:28].[CH2:1]([O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: [Ca+2]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCC(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
696.4 g of a commercially available technical stearyl alcohol were introduced into a reaction vessel and heated to 80° C. 256.6 g succinic anhydride were then added; the reaction mixture was heated to 130° C. The reaction was mildly exothermic; the temperature rose to 140° C. The reaction mixture was then stirred for 30 minutes at 130 to 140° C.; the acid value of the reaction mixture was 151 to 152. 94.3 g plus 2.8 g (3% excess) calcium hydroxide Were then introduced in portions over a period of 30 minutes at temperatures of 145° to 150° C. The reaction mixture was kept at that temperature for 4 hours, a light vacuum being applied at the beginning of the reaction. The vacuum was increased to 500 hPa after 30 minutes, to 32 hPa after 1 h and 39 hPa after 2 h and was left at that value until the end of the 4-hour reaction time.
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:14][O:15][CH3:16])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].C(N(CC)CC)C.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](Cl)=[O:31])[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]1>ClCCl>[F:1][CH2:2][CH:3]([N:14]([O:15][CH3:16])[C:30]([C:28]1[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26][N:25]([CH3:24])[CH:29]=1)=[O:31])[CH2:4][C:5]1[C:6]([Cl:13])=[CH:7][C:8]([Cl:12])=[CH:9][C:10]=1[Cl:11]
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: CONC(CF)Cc1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)(F)F)C(CF)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a stirred solution of N-[1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-O-methyl-hydroxylamine (0.20 g; 0.70 mmol), prepared as described in example P6f2 and triethylamine (0.12 ml; 0.84 mmol) in dichloromethane (1.6 ml) under nitrogen at 4° C. was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.15 g; 0.70 mmol). The reaction mixture was stirred at 24° C. for 3 h under nitrogen. Triethylamine (0.19 ml; 1.4 mmol) was added again to the mixture followed by 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (74 mg; 0.35 mmol). The mixture was stirred at 24° C. for 18 h. The mixture was washed with 1M sodium hydroxide (20 ml), 1M hydrochloric acid (20 ml) and brine (20 ml). Organics were dried over sodium sulfate. The solvent was removed in vacuo. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 50:50) to afford 0.17 g (51% of theory) of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-methoxy-amide as a yellow solid (melting point: 131-133° C.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]([OH:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]([O:13][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
To a solution of 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol (500 mg) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.28 mL) and then methanesulphonyl chloride (0.14 mL) and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into dichloromethane (2×20 mL). The combined organic layers were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40]([O:42]C)=[O:41])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.CO.O.[OH-].[Li+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40]([OH:42])=[O:41])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: COC(=O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 0 °C
Yield: 66.5 %

Procedure:
To a suspension of methyl (4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-yl)acetate of Example 32 (0.585 g, 1.03 mmol) in 2:1 v/v methanol:water (12 mL) was added lithium hydroxide monohydrate (87 mg, 2.07 mmol) and the mixture heated to reflux for 90 minutes. The cooled reaction mixture was concentrated in vacuo to remove methanol and then diluted with water (10 mL). The aqueous phase was washed with ethyl acetate (2×10 mL) then slowly added to a mixture of 1 M aqueous hydrochloric acid (2.2 mL) in water (20 mL) and the resulting suspension cooled to 0° C. for 1 hour. Filtration afforded the title compound (0.381 g, 66%) as a tan solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Reaction time: 1 h

Procedure:
(ab) 23 ml of thiomorpholine are slowly added dropwise at about 80° to 17.17 g of p-fluoronitrobenzene in such a manner that the internal temperature does not rise above 110°. The mixture is then stirred at 120° for an additional 1 hour, whereupon it is extracted three times with 1 l of dichloromethane each time and the organic phases are washed three times with 500 ml of water each time, dried over sodium sulfate and evaporated. By recrystallization of the crude product from dichloromethane/ether, there is obtained 4-(p-nitrophenyl)-tetrahydro-4-H-1,4-thiazine of melting point 142°-144°.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[CH:21][CH:20]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:25](/[CH:24]=[CH:23]/[C:22]3[CH:28]=[CH:29][C:19]([O:18][CH2:17][O:16][CH3:15])=[CH:20][CH:21]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COCOc1ccc(C=CC(=O)O)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)cc3)nc2n(CC)c1=O
Yield: 64.2 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 4.00 g (20.2 mmol) of 5,6-diamino-1,3-diethyluracil and 4.62 g (22.2 mmol) of 4-methoxymethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 4.80 g (yield 64%) of Compound 144 as pale yellow needles.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:14][CH2:15][CH2:16]Br.O>CS(C)=O>[CH2:14]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:15][CH3:16]
Reactant: CCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Methyl 4-hydroxybenzoate (15.4 g: 101.2 mmol) was dissolved in 150 ml of dimethylsulfoxide (DMSO), and an aqueous solution of potassium hydroxide (KOH/H2O: 7 g/15 ml) was added to the mixture. The resultant mixture was stirred until dissolving homogeneously. Next, 12.5 g (101.6 mmol) of n-propyl bromide was added thereto, and the reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into 1 L of an iced water and the resultant precipitate was collected by filtration. The obtained precipitate was dissolved in 300 ml of ethanol, and an aqueous solution of sodium hydroxide (NaOH/H2O: 5 g/100 ml) was added thereto. Thus obtained mixture was refluxed by heating for 1 hour, and water (the amount of the water: about 300 ml) was added thereto with removing ethanol (EtOH). After cooling to a room temperature, the transparent solution was acidified by adding a concentrated hydrochloric acid. The resultant white precipitate was filtered and recrystallized from toluene to give 17.5 g (97.2 mmol) of 4-n-propyloxybenzoic acid.
Reaction SMILES: Cl[S:2]([C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])=[O:3].[NH2:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+].C(=O)(O)[O-]>ClCCl.O>[CH3:21][Si:20]([CH3:22])([NH:19][S:2]([C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])=[O:3])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)N[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.3 %

Procedure:
A suspension of ethyl 2-(chlorosulfonyl)-3-nitrobenzoate (14.7 g), amino-t-butyldimethylsilane (15.4 g), and sodium bicarbonate (3.5 g) in dichloromethane (300 mL) was stirred at room temperature in a stoppered flask for 4 days. Water (90 mL) and saturated aqueous bicarbonate (45 mL) were added, and the mixture was stirred. The dichloromethane phase was dried over magnesium sulfate, filtered, concentrated, and chromatographed on silica gel eluted with 20% ethyl acetate in hexanes to give 12.9 g of the title compound as a white solid, m.p. 101-102° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]=[CH:5][N:6]=1.C([Li])CCC.[O:20]=[C:21]1[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>O1CCCC1>[CH3:14][Si:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][O:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH2:1][C:21]1([OH:20])[CH2:24][NH:23][CH2:22]1
Reactant: Cc1nccn1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1CC1(O)CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A solution of 2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.5 g, 2.3 mmol) (prepared using procedures similar to those described in Clader et. al. J. of Med. Chem. 1995, 38(10), 1600-7) in tetrahydrofuran (5 mL) was cooled to −78° C., and n-butyllithium was added (2.5 M in hexanes, 0.990 mL, 2.5 mmol). After 2 hours, 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (0.60 g, 3.5 mmol), prepared using procedures similar to those described in Example 3, in 2.0 mL tetrahydrofuran was added and the solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.37 g (41%) of 3-{[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]methyl}azetidin-3-ol: 1H NMR (400 MHz, CDCl3): 6.96-6.92 (m, 1H), 5.23 (s, 2H), 3.98 (d, 2H), 3.79 (d, 2H), 3.52-3.47 (m, 2H), 3.13 (s, 2H), 1.43 (s, 9H), 0.94-0.88 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18].[NH3:25]>>[CH2:20]([O:19][P:17]([CH2:16][O:15][CH2:14][CH2:13][CH2:12][O:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:25])([O:22][CH2:23][CH3:24])=[O:18])[CH3:21]
Reactant: N
Reactant: CCOP(=O)(COCCCOn1cnc2c(Cl)ncnc21)OCC
Product: CCOP(=O)(COCCCOn1cnc2c(N)ncnc21)OCC
Temperature: 110 °C
Yield: 38 %

Procedure:
6-Chloro-9-[3-(diethoxyphosphorylmethoxy)propoxy]purine (0.75 g, 1.98 mmol) was dissolved in ethanolic ammonia (20 ml) and heated at 110° C. in an autoclave for 7.5 h then cooled for 13 h. The reaction was then evaporated to dryness under reduced pressure and chromatographed in chloroform/methanol (30:1) to give 9-[3-(diethoxyphosphorylmethoxy)propoxy]adenine (270 mg, 38%) as a white solid; νmax (KBr) 3378, 3335, 3186, 1660, 1598, 1230, 1019 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz, (CH3CH2O)2), 1.94(2H, m, CH2CH2CH2), 3.74(2H, t, J6 Hz, CH2OCH2P), 3.83(2H, d, J8.3 Hz, CH2P), 4.04(4H, m, (CH3CH2O)2), 4.42(2H, t, NOCH2), 7.37(2H, br.s, D2O exchangeable, NH2), 8.14 and 8.42(2H, 2s, H-2 and H-8); Found: C, 43.63; H, 6.15; N, 19.78%; M+ 359.1350; C13H22N5O5P requires: C, 43.45; H, 6.17; N, 19.49%; M+ 359.1359.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (Aldrich, 6.0 g, 26.2 mmol), N,O-dimethylhydroxylamine hydrochloride (3.06 g, 31.4 mmol), DMAP (3.20 g, 26.2 mmol), and triethyl amine (4.74 mL, 34 mmol) in DCM (200 mL) was stirred at room temperature overnight. The mixture was washed with saturated aqueous KHSO4 and brine. The organic layer was dried (MgSO4) and the solvent was removed. The crude material was directly used in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[OH:14][CH2:15][C:16](O)=O.C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]1[C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:12]=2[N:13]=[C:16]1[CH2:15][OH:14]
Reactant: CNc1ccc2cccnc2c1N
Reactant: O=C(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(CO)nc2c3ncccc3ccc21
Temperature: 115 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A mixture of N7-methylquinoline-7,8-diamine (1.0 g, 5.8 mmol) and 2-hydroxy acetic acid (2.2 g, 29 mmol) was stirred at 115° C. for 2 h. Then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc. The organic layer was concentrated to give a residue which was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 30:1) to give (3-methyl-3H-imidazo-[4,5-h]quinolin-2-yl)methanol as a yellow solid (1.0 g, yield 83%). ESI MS: m/z 214 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[O:17][N:16]=[C:15]([C:18]([OH:22])([C:20]#[CH:21])[CH3:19])[CH:14]=2)(=O)=O)=CC=1.[F-:23].[K+]>C(#N)C>[F:23][CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]([OH:22])([C:20]#[CH:21])[CH3:19])[CH:14]=1
Reactant: [F-]
Reactant: C#CC(C)(O)c1cc(COS(=O)(=O)c2ccc(C)cc2)on1
Agent: [K+]
Solvent: CC#N
Product: C#CC(C)(O)c1cc(CF)on1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [3-(2-hydroxybut-3-yn-2-yl)isoxazol-5-yl]methyl 4-methylbenzenesulfonate (259 mg, 0.81 mmol) in dry acetonitrile (10 mL) was introduced potassium fluoride (94 mg, 1.61 mmol) and Kryptopfix® 222 (606 mg, 1.61 mmol). After 5 hr rapid stirring at RT, the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (40 mL) and water (2×40 mL). The organic extract was washed with brine (30 mL), dried (Na2SO4), filtered and the filtrate adsorbed onto silica gel in vacuo. Purification by silica gel flash column chromatography (heptane/EtOAc gradient of increasing polarity) furnished the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 1.91 (3H, s), 2.69 (1H, s), 2.86 (1H, s), 5.42 (1H, d, J=47.3 Hz), 6.55 (1H, d, J=2.8 Hz); 19F NMR-decoupled (235 MHz, CDCl3) delta −218.8 (s); LC-MS: m/z=+169.9 (M+H)+.