Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>CC#N.O.[OH-].[Na+]>[CH:14]1[C:2]2[C:1](=[C:14]3[C:5](=[CH:4][CH:3]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:16])[C:13]3=[O:15])[CH:3]=[CH:2][CH:1]=1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C1C(=O)c2c(ccc3ccccc23)-c2ccccc21

Procedure:
In a typical preparation, 50 mg of Rh(III) starting material was dissolved in 32 mL of MeCN/water, 3:1,0.1 M in NaOH. To this mixture was added 1 equiv or more of, for example, 9,10-phenanthrenequinone to produce non-hindered control DNA photocleaving compounds, or 5,6-chrysenequinone (chrysi) or benzophenanzineduimine (phzi) to produce hindered intercalating compounds. During constant stirring, the reaction was allowed to progress for approximately 18 h at room temperature. After neutralization with dilute hydrochloric acid and addition of 500 mL of water, the reaction mixture was loaded onto a Sephadex SP-C25 ion exchange column equilibrated in 0.05 M MgCl2. The product was purified by elution with a gradient of 0.05-0.5 M MgCl2, and the orange product bands were collected. The fractions were concentrated on a Waters Sep-Pak 5 g C18 cartridge and washed with copious amounts of water. The metal complex was eluted from the cartridge with a minimum volume of 0.1% TFA in MeCN/water, 1:1, and lyophilized to dryness.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:8]NC(=O)C(C)C)[CH:5]=[CH:6][CH:7]=1.[OH2:16].Cl.[OH-].[Na+]>C1C2C(=CC=CC=2)CCC1.CCOC(C)=O.CO>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]2[C:5]([C:3]([CH3:15])([CH3:4])[C:2](=[O:16])[NH:8]2)=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NNC(=O)C(C)C
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccc2c(c1)CCCC2
Product: Cc1c(Br)ccc2c1NC(=O)C2(C)C
Temperature: 200 °C
Reaction time: 17 h

Procedure:
A mixture of N′-(3-bromo-2-methylphenyl)isobutyrohydrazide (1.14 g, 4.23 mmol) and CaH (0.356 g, 8.46 mmol) in 1,2,3,4-tetrahydronaphthalene (10 mL) was heated to 200° C., and stirred at 200° C. for 17 h. The mixture was cooled to 0° C. and to the mixture was added water (1.63 mL) and MeOH (1.63 mL) slowly. At 0° C. the PH of the mixture was adjusted to PH1 by adding conc. HCl. The mixture then was heated to reflux for 1 h. The reaction mixture was cooled to rt, and NaOH (3N) was added to the mixture, adjusting to pH 5. The resultant mixture was diluted with EtOAc, washed with water and brine, dried and concentrated. Purification of the residue by flash chromatography over silica gel, using 30% EtOAc in hexane, gave 6-bromo-3,3,7-trimethylindolin-2-one. 1H-NMR (DMSO-d6) δ 10.58 (1H, s), 7.21 (1H, d, J=8.0 Hz), 7.07 (1H, d, J=8.0 Hz), 2.27 (3H, s), 1.24 (6H, s). Mass Spectrum (ESI) m/e=254.0 (M+1).
Reaction SMILES: [C:1]1([S:7]([CH2:9][Cl:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[C:13]=1[CH3:20].[F:21][C:22]([F:35])([F:34])[S:23]([O:26]S(C(F)(F)F)(=O)=O)(=[O:25])=[O:24]>C(OCC)C>[O-:26][S:23]([C:22]([F:35])([F:34])[F:21])(=[O:25])=[O:24].[Cl:10][CH2:9][S+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:16]=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]([CH3:20])[C:12]=1[CH3:11]
Reactant: Cc1ccc(C)c(C)c1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(CCl)c1ccccc1
Solvent: CCOCC
Product: Cc1cc([S+](CCl)c2ccccc2)c(C)c(C)c1C
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Chloromethyl phenyl sulfoxide (12 g, 68.71 mmol) of example 21 was dissolved in dry diethyl ether (100 mL) under an argon atmosphere. 1,2,3,4-Tetramethylbenzene (10.3 mL, 1 eq) was added to the previous solution and then the mixture was cooled to a temperature between 5° C. and 0° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (11.5 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred until the reaction was complete. The precipitate triflate salt formed was isolated by filtration and washed with diethyl ether at 0° C. (50 mL). 16.18 g (57.4%) of the desired product was obtained as a white solid. mp: 125-127° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2F)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccccc1F

Procedure:
From 2-amino-4-(2-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([N:18]([CH3:20])[CH3:19])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.O1CCC[CH2:22]1.[Cl-].[NH4+]>CCOCC.C1C=CC=CC=1.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2([N:18]([CH3:20])[CH3:19])[CH2:12][CH2:13][C:14]([CH3:22])([OH:17])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CN(C)C1(c2ccc(Cl)cc2)CCC(C)(O)CC1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 10 ml. of 3 M methyl magnesium bromide in Et2O is added a solution of 1.25 g. (0.005 mole) of 4-(p-chlorophenyl)-4-(dimethylamino)cyclohexanone in 25 ml. of tetrahydrofuran. The mixture is stirred under nitrogen in the cold for one-half hour and then at room temperature for forty-eight hours. Following ice bath cooling there is added 20 ml. of saturated aqueous ammonium chloride, 10 ml. of water, 10 ml. diethyl ether and 25 ml. benzene. The organic layer is washed with 10 ml. water and 10 ml. brine and taken to dryness. The residue is chromatographed on a 1"×48" high pressure liquid chromatography column (elution with 3% MeOH in chloroform). Starting ketone is first eluted followed by a second material. Those fractions containing the second material are combined, concentrated to dryness and crystallized from CH3CN:H2O to yield 0.20 g. of the tertiary alcohol, melting point 119°-120°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH:15][C:16]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[O:17])[C:3]=12.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>CCCCO>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]([NH:15][C:14]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=2[N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)[NH:12][CH:13]=1)=[O:17]
Reactant: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1cnccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(C(F)(F)F)cnc3[nH]cc(NC(=O)c4cnccn4)c23)C1
Temperature: 155 °C
Yield: 35.3 %

Procedure:
N-(4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide (0.230 g, 0.673 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.404 g, 2.02 mmol) were placed in n-BuOH (3 mL) and heated to 155° C. for 18 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-75% CH3CN/water gradient; 25 CV) to give (R)-tert-butyl 1-(3-(pyrazine-2-carboxamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.120 g, 35% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([C:31]([O:33][CH3:34])=[O:32])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(C(=O)OC)c2C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
Alternatively, to a solution of 8-bromo-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (220 mg, 0.71 mMol) in tetrahydrofuran (5 mL) at -78° C. was added a solution of n-butyl lithium in hexane (1.6 M, 1 mL, 1.6 mMol), and the solution was stirred for two hours at -78° C. The solution was then cannulated into a solution of methyl chloroformate (0.5 mL, 6.5 mMol) in tetrahydrofuran (10 mL) at -78° C., and the reaction mixture was allowed to warm gradually to room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and was then extracted with diethyl ether. The combined extracts were dried over sodium sulfate and evaporated in vacuo to give a greenish-yellow oil. Purification by flash chromatography (3:1 hexane:tetrahydrofuran+tr. NH4OH) gave the title compound as a colorless glass (130 mg, 63%). The hydrochloride salt was formed and recrystallized (acetone/diethyl ether) to give colorless crystals (m.p.=132° C.).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1.C([BH-](CC)CC)C.[Li+].O>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(CO)ccc1Cl
Reaction time: 0.5 h

Procedure:
To a suspension of 4-chloro-3-(methylsulfonyl)benzoic acid methyl ester (2.4 g) in tetrahydrofuran (50 mL) was added lithium triethylborohydride (1 M in tetrahydrofuran, 24 mL) at 0-5° C. under nitrogen. The mixture was stirred for 30 min and then more of lithium triethylborohydride (1M in tetrahydrofuran, 5 mL) was added and the mixture was further stirred for 60 min. Water (2 mL) was added and the tetrahydrofuran was evaporated under vacuum. Toluene (100 mL) and water (30 mL) were added and then hydrogen peroxide (30% in water, 20 mL) was added at 10-20° C. After 30 min the organic phase was separated and washed with potassium bicarbonate solution (1 M) and then dried with sodium sulphate and evaporated to dryness (yield 1.2 g). 1H-NMR (400 MHz, DMSO-d6) d=3.36 (s, 3H), 4.59 (d, J=5.7 Hz, 2H), 5.52 (t, J=5.7 Hz, 1 H), 7.66 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]([Mg]Br)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:15]1[N:16]=[C:17]([O:31][CH2:32][CH2:33][CH3:34])[C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)[O:21][C:19]=2[N:20]=1)(=O)=O.[Cl-].[Li+].C(OCC)(=O)C>O1CCCC1>[C:1]1([C:7]([C:15]2[N:16]=[C:17]([O:31][CH2:32][CH2:33][CH3:34])[C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)[O:21][C:19]=3[N:20]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C([Mg]Br)c1ccccc1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1nc(OCCC)c2nc(-c3cccc(C)c3)oc2n1
Reaction time: 1 h

Procedure:
298 mg of 1-phenyl-vinylmagnesium bromide were added to a solution of 500 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine (example 5, step (f)) and 61 mg of lithium chloride in 20 ml of tetrahydrofuran. The reaction mixture was stirred for 1 h. Then 100 ml of ethyl acetate were added. The solution was extracted with 1 N hydrochloric acid, dried over sodium sulfate, filtered and evaporated in vacuo to give the crude title compound.
Reaction SMILES: CCO[C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)=[O:5].Cl.[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl>[C:17]1([C:16]2[N:24]=[C:4]([OH:5])[CH:6]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:23]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1

Procedure:
Ethyl benzoyl acetate (60 g, 312 mmol), benzamidine hydrochloride (65 g, 375 mmol) and potassium carbonate (172 g, 1250 mmol) were dissolved in 1,4-dioxane (1.2 liter) the reaction mixture was refluxed for 12 hours under nitrogen atmosphere. Reaction mixture was diluted with water, neutralized with cold 2N HCl, solid was filtered, washed with water and dried to yield the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>C(OCC)C.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:18]=[O:19])=[N:7][C:6]=2[CH:10]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1nc2cc(F)ccc2s1
Temperature: -50 °C

Procedure:
To a stirred solution of 36 g of 5-fluorobenzothiazole in 100 ml of diethyl ether cooled to -70° C. was added dropwise over a 5 minute period 9.4 ml of a 2.5M solution of n-butyl lithium in hexane. The reaction mixture was allowed to warm to -50° C. for one hour and was then cooled to -78° C. Dry dimethylformamide (2.8 ml) was added dropwise and the reaction mixture allowed to warm to room temperature over a period of two hours. The reaction was diluted with 300 ml of diethyl ether and washed with 1N hydrochloric acid (1×40 ml), water (1×40 ml), a saturated sodium bicarbonate solution (1×40 ml) and dried over magnesium sulfate. The solvent was removed and the residual product flash chromatographed on silica (50% ethyl acetate--hexane; v:v) to give 24.7 g of the titled product, m.p. 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[C:19]([CH:28]=[CH:29][CH:30]=3)[CH2:20][N:21]3[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH:33][S:34]([OH:37])(=[O:36])=[O:35]>C1COCC1>[S:34]([O-:37])([OH:36])(=[O:35])=[O:33].[C:25]([CH:23]1[CH2:24][NH+:21]([CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[C:17]([C:15]3[S:16][C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][N:14]=3)[C:18]=2[CH2:31][CH3:32])[CH2:22]1)([OH:27])=[O:26]
Reactant: O=S(=O)(O)O
Reactant: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Solvent: C1CCOC1
Product: CCc1c(C[NH+]2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Product: O=S(=O)([O-])O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-(5-(3-chloro-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-ethylbenzyl)azetidine-3-carboxylic acid (100 mg, 0.212 mmol) in THF (2 mL) was added H2SO4 (0.286 mL, 4%, aq. solution). The mixture became clear and stirred for 30 min at rt. The solution was concentrated under the reduced pressure and dried in vacuum to give 3-carboxy-1-(3-(5-(3-chloro-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-ethylbenzyl)azetidin-1-ium hydrogensulfate (123 mg) as pale yellow crystalline solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[C@@H:25]([OH:33])[C@H:24]3[OH:34])=[C:16]([NH:35]C(CC)CC)[N:15]=2)[CH2:10]1.FC(F)(F)C(O)=O.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(N[CH2:71][C:72]2[C:81]3[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=3)[CH:75]=[CH:74][CH:73]=2)N=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[C@@H:25]([OH:33])[C@H:24]3[OH:34])=[C:16]([NH:35][CH2:71][C:72]3[C:81]4[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=4)[CH:75]=[CH:74][CH:73]=3)[N:15]=2)[CH2:10]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide trifluoroacetate by replacing N-{(1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide with N-((1S,2R,3S,4R)-4-{2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate.
Reaction SMILES: C[Si]([O:5][P:6]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])[O:7][Si](C)(C)C)(C)C.[O-]CCC.[Zr+4:26].[O-]CCC.[O-]CCC.[O-]CCC>>[Zr:26].[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][P:6](=[O:5])([O-:12])[O-:7])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCCCP(=O)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: [Zr+4]
Agent: CCC[O-]
Product: CCOC(=O)CCCCP(=O)([O-])[O-]
Product: [Zr]

Procedure:
To a reaction flask under an inert atmosphere was added 3.13 g of bis-trimethylsilyl-4-carboethoxybutylphosphonate. To the flask was slowly added 1.44 g of zirconium propoxide. After the first few drops were added, a gelatinous product was formed. Agitation was continued during the remainder of the addition.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:25]2[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:23][CH2:24]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(NC1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1

Procedure:
p-Nitrophenylethyl bromide (1.15 g.) was refluxed for 20 hours in isopropylalcohol (75 ml.) with 4-benzamidopiperidine (1.032 g.) and anhydrous potassium carbonate (1.037 g.). The mixture was filtered hot, refrigeratedand product was filtered off (547 mg.), washed with cold isopropyl alcohol and ether. The filtrate was evaporated to yield more product (1.4 g.). Recrystallisation from a mixture of benzene and petroleum ether (b.p. 40°-60° C) gave the title compound, m.p. 209°-216° C. (Found: C, 68.2; H, 6.7; N, 11.8. C20H23N3O3 requires C, 68.0; H, 6.6; N, 11.9%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:11][C:12]1[NH:31][C:15]2=[CH:16][C:17]3[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:21]=3[CH:22]=[C:14]2[N:13]=1.ClC1C=C(C(OO)=[O:40])C=CC=1>C(Cl)Cl>[C:1]1([S:7]([CH2:11][C:12]2[NH:31][C:15]3=[CH:16][C:17]4[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:21]=4[CH:22]=[C:14]3[N:13]=2)=[O:40])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CCl)nc3cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CS(=O)c4ccccc4)nc3cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of thiophenol (70 μl) in CH2Cl2 (4 ml) is added NaH (43 mg; 1.08 mmol) and the resulting suspension is stirred for 5 min at RT. Then freshly prepared 2-chloromethyl-7,7-dimethyl-5-pentyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (265 mg) dissolved in CH2Cl2 (5 ml) is added and the mixture is stirred at 40° C. for 20 h. After cooling to 0° C. 3-chloro-benzenecarboperoxoic acid (186 mg; 0.83 mmol) is added and stirring is continued for another 3 h. After completion of the reaction the mixture is concentrated in vacuo and purified by NP-HPLC eluting with CH2Cl2/MeOH to give the desired compound (5.8 mg).
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14].[Fe:21](Cl)Cl>C(O)C>[C:12]1([CH3:11])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[N:5]=[C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[N:14][C:13]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[CH3:11])[NH:10]1.[Fe+2:21]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Cl[Fe]Cl
Reactant: N#Cc1ccccc1C#N
Solvent: CCO
Product: Cc1cc(C)c(N=C2NC(=Nc3c(C)cc(C)cc3C)c3ccccc32)c(C)c1
Product: [Fe+2]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL round-bottom flask equipped with a nitrogen inlet and an internal fritted-glass filter is charged with phthalonitrile (2.56 g, 20.0 mmol) and ethanol (50 mL). 2,4,6-Trimethylaniline (5.68 g, 42.0 mmol, 2.1 eq.) and iron(II) chloride (2.54 g, 20.0 mmol) are added to the flask, and the mixture is stirred at room temperature under nitrogen for 1 h.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:26]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:26])[C:3](=[O:2])[N:13]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)N[C@H](C)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n([C@H](C)c2ccccc2)c1C
Temperature: 25 °C
Yield: 51.8 %

Procedure:
MeOH (170 mL) was added to a flask containing (R)-4-[1-(1-phenyl-ethylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (5.56 g, 18.3 mmol). NaOMe solution (4.2 mL, 18.3 mmol, 4.375 M in MeOH) and N-bromosuccinimide (3.92 g, 22 mmol) were added, and the resulting mixture was refluxed for 7 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-25% EtOAc/hexanes) to give 3.32 g of the title compound as an off-white solid. MS: (+) m/z 372.20, 374.16 (M+Na, 79/81Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[C:18]1[C@@:19]2([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:22]([CH:23]=1)[CH2:21][CH2:20]2.S(Cl)([Cl:30])=O>C(Cl)Cl.CN(C=O)C>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Cl:30])=[CH:12][C:11]=2[C:18]2[C@@:19]3([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:22]([CH:23]=2)[CH2:21][CH2:20]3)[C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a stirred solution of 66.15F (0.035 g, 0.10 mmol) in DCM (2.00 mL) and DMF (0.01 mL) at 0° C. was added thionyl chloride (0.01 g, 0.10 mmol). The reaction was then stirred at room temperature for 2 hours and was then concentrated in vacuo. The resulting product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.15G as a colorless oil (0.035 g, 95% yield).