Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([C@H:13]1[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]([C:16]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[O:11][CH2:12]1)[CH3:15]
Reactant: NCc1ccccc1
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.390 g, 1.504 mmol) in CH2Cl2 (10 mL) were added benzylamine (0.164 mL, 1.504 mmol), HOAt (0.205 g, 1.504 mmol) and EDC (0.346 g, 1.805 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was washed with H2O (3×) and the organics were then dried over Na2SO4 and concentrated to afford the title compound (0.551 g). LC-MS (ES) m/z=249 [M+H-Boc]+.
Reaction SMILES: [CH3:1][C:2]1([C:17]([OH:19])=O)[CH2:6][CH:5]2[CH:7]([CH3:16])[C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:12])[C:10]([CH3:11])=[C:4]2[O:3]1.S(Cl)([Cl:22])=O>C(Cl)Cl>[CH3:1][C:2]1([C:17]([Cl:22])=[O:19])[CH2:6][C:5]2[C:7]([CH3:16])=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1=C2OC(C)(C(=O)O)CC2C(C)C([N+](=O)[O-])=C1C
Solvent: ClCCl
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C(=O)Cl)C2

Procedure:
0.5 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid, 20 ml of methylene chloride and 0.27 g of thionyl chloride were added, followed by heating at reflux for 2 hours. After returning the temperature to room temperature, the solvent was distilled off to obtain 2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride. To 0.33 g of 2,3,4,9-tetrahydro-1H-beta-carboline, 0.23 g of triethylamine and 15 ml of DMF, a solution prepared by dissolving 2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride in DMF was added, followed by stirring overnight at room temperature. The mixture was poured into ice-water and a crystal was collected by filtration. The crystal was dissolved in chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 0.54 g of the objective product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)Cl>[Br:27][C:10]1[N:11]=[C:12]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[O:13][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(Sc2cnc(C3CCOCC3)o2)cc1
Solvent: ClCCl
Product: Clc1ccc(Sc2oc(C3CCOCC3)nc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (5.21 g, 17.61 mmol) in DCM (176 ml) was added NBS (3.45 g, 19.38 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica 330 g, 5 to 30% EtOAc in hexane), to give 4-bromo-5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (6.16 g). MS: M+H=376. H1NMR (400 MHz, CDCl3) δ: 7.28 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 4.01 (dt, J=11.7 Hz, 3.6 Hz, 2H), 3.50 (td, J=11.7 Hz, 2.7 Hz, 2H), 3.09-2.98 (m, 1H), 2.02-1.86 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:7][CH:8]=1)#N.[CH3:28][C:29](N=C(N(C)C)N(C)C)([CH3:31])[CH3:30].BrCC(C)C>C(#N)C.CO>[CH3:27][C:22]1[C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([S:10]([N:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:6]3[CH:5]=[CH:4][C:3]([CH3:1])=[CH:8][N:7]=3)(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C#N)cn2)cc1
Solvent: CC(C)CBr
Solvent: CO
Solvent: CC#N
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of N-(5-cyano-2-pyridinyl)-4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonamide (23 mg, 0.060 mmol) in acetonitrile (0.5 mL) at room temperature was added N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (0.024 mL, 0.120 mmol). The reaction mixture was stirred at 20° C. for 1 hour, then 1-bromo-2-methylpropane (0.013 mL, 0.120 mmol) was added. The reaction was heated by microwaves to 150° C. for 30 minutes. After cooling, the reaction mixture was diluted with methanol and passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge followed by a sulphonic acid (SCX) SPE cartridge, eluting with methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by mass directed autoprep (formic acid modifier), to provide the title compound (1.8 mg). LCMS (2 min, formic) Rt 1.25 min, m/z (ES+) 441 (M+H).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
24.3 g of magnesium turnings are suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride are added, and, when the reaction has started, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous toluene is added dropwise at 50°-60° C. Thereafter, the mixture is heated to 50°-60° C. for a further hour, and cooled to -5° C. to -10° C. with dry ice acetone, and a solution of 212.5 g of 2,3,4,5-tetrafluorobenzoyl chloride (1) in 80 ml of absolute toluene is slowly added dropwise at this temperature. The mixture is stirred for 1 hour at 0° to -5° C., and is allowed to reach room temperature overnight, and a mixture of 400 ml of ice water and 25 ml of concentrated sulphuric acid is allowed to run in whilst cooling with ice. The phases are separated, and extraction with toluene is repeated twice. The combined toluene solutions are washed with saturated NaCl solution and dried with Na2SO4, and the solvent is stripped off in vacuo. 335 g of diethyl 2,3,4,5-tetra-fluorobenzoylmalonate (3) are obtained as a crude product.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 67.1 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and ethanol (170.1 g) were mixed, and the resultant mixture was heated to 30° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (10 g) was added over six hours. Liquid chromatographic analysis revealed the reaction mixture contained 9.8 g of p-cyanobenzamide (yield 67%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:22]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[Si:26]([O:1][CH2:2][CH2:3][C:4]#[N:5])([C:22]([CH3:25])([CH3:24])[CH3:23])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#CCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypropanenitrile (1 g, 14.1 mmol), dimethylaminopyridine (0.34 g, 2.8 mmol), and triethylamine (2.9 ml, 21 mmol) in tetrahydrofuran (38 ml) was added tert-butyl(chloro)diphenylsilane (4.3 ml, 16.9 mmol). The mixture was stirred at room temperature overnight. The resulting white slurry was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via flash chromatography (silica, 0-17% ethyl acetate in hexane) to afford the title compound. 1H NMR (600 MHz, d6-DMSO): δ 7.65 (dd, 4H), 7.43 (dt, 2H), 7.40 (d, 4H), 3.82 (t, 2H), 2.52 (t, 2H), 1.10 (s, 9H).
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.Cl.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24]C=1>>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:24]2[CH2:25][CH2:26][CH2:27][C:22]2=[O:9])=[CH:15][CH:14]=1
Reactant: c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: Cc1ccc(C=C2CCCC2=O)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 24.0 g (0.20 mol) of 4-methylbenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield light yellow flaky crystal product with a yield of 94.5%.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH2:6]C(OCC)=O.[Cl:16][C:17]1[S:18][C:19]2[C:25]([N:26]=[C:27]=[O:28])=[C:24]([F:29])[CH:23]=[C:22]([Cl:30])[C:20]=2[N:21]=1.Cl.CN(C)C=[O:35]>O1CCCC1>[Cl:16][C:17]1[S:18][C:19]2[C:25]([N:26]3[C:6](=[O:35])[CH:5]=[C:4]([C:12]([F:13])([F:14])[F:15])[NH:3][C:27]3=[O:28])=[C:24]([F:29])[CH:23]=[C:22]([Cl:30])[C:20]=2[N:21]=1
Reactant: CCOC(=O)CC=C(N)C(F)(F)F
Reactant: CN(C)C=O
Reactant: O=C=Nc1c(F)cc(Cl)c2nc(Cl)sc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
1.6 g of sodium hydride (97% strength) in 200 ml of absolute dimethylformamide were initially taken. 11.0 g of ethyl 3-amino-4,4,4-trifluorobut-2-enecarboxylate were then added dropwise at from 0° to 5° C. Stirring was carried out for one hour at this temperature, after which the mixture was cooled to -30° C. and 16.2 g of 2,4-dichloro-6-fluoro-7-isocyanatobenzothiazole in 50 ml of absolute tetrahydrofuran were then added dropwise. The mixture was stirred for one hour at this temperature and then slowly warmed up to room temperature. Thereafter, ice water was added and the pH was brought to 3-4 with dilute hydrochloric acid, after which the product was extracted with ethyl acetate. The ester solution was dried and then evaporated down.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[CH3:13]NN(CC)NC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:23][CH:22]=1>O1CCCC1>[ClH:20].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([S:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:1]([NH:8][CH2:12][CH2:11][N:10]([CH3:9])[CH3:13])=[O:2])[CH2:29]2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(SC2CCCNC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(NC)NC
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCCC(Sc2ccc(Cl)cc2)C1
Product: Cl

Procedure:
A solution of 5.70 g (0.0352 mole) of 1,1'-carbonyldiimidazole and 2.91 g (0.033 mole) of N,N-dimethylaminoethylamine in 200 ml of tetrahydrofuran was stirred at room temperature for 1.5 hr. A solution of 7.02 g (0.031 mole) of 3-[(4-chlorophenyl)thio]piperidine in 50 ml of tetrahydrofuran was added and the solution was refluxed for 10 hr. The volume of the reaction solution was reduced to about 50 ml in vacuo. The solution was quenched in water and the aqueous mixture was extracted with methylene chloride. The methylene chloride phase was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil, the free base of the title compound. The free base was converted to the hydrochloride salt and recrystallized as in Example 14 to give 8.48 g (72.3%) of white crystals, m.p. 175°-176.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=O)[CH3:2].Cl.[CH3:13][O:14][NH2:15].[N:16]1C=CC=C[CH:17]=1>CCO>[CH3:13][O:14][N:15]=[C:1]([C:4]1[CH:5]=[C:6]([C:17]#[N:16])[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])[CH3:2]
Reactant: CC(=O)c1ccc(=O)[nH]c1C
Reactant: CON
Reactant: c1ccncc1
Agent: Cl
Solvent: CCO
Product: CON=C(C)c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A mixture of 5-acetyl-6-methyl-2(1H)pyridinone (1.76 g, 0.010 mol), methoxyamine hydrochloride (0.90 g, 0.107 mol) and pyridine (5.0 ml) were heated and stirred in EtOH (150 ml) at reflux. The initially heterogeneous mixture cleared as everything went into solution. At the end of 2 hours a solid precipitated. The reaction mixture was allowed to cool to room temperature and the solid was collected by filtration. Recrystallization (EtOH) gave 0.70 g (35%) m.pt. 275°-285° C.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:21])[CH2:7][C:8]1[NH:9][C:10](=[S:20])[CH:11]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:13]=1)C>C1COCC1>[N:14]1([C:12]2[N:13]=[C:8]([CH2:7][C:6]([O-:21])=[O:5])[NH:9][C:10](=[S:20])[CH:11]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1.[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)cc(=S)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.05 ml of 2N sodium hydroxide are added to a solution of 865 mg of (4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester in 15 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5, so as to give 0.8 g of sodium (4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate, the characteristics of which are the following:
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C(O)C1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: COC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 45.9 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.94 g, 6.6 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.1 g, 6.6 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.5 g, 46%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O[CH:2]1[C:6]2=[CH:7][CH:8]=[CH:9][C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH:5]2[CH:4](O)O1.[NH3:24].[CH3:25]O>>[N:13]1([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][CH2:15][C:10]2([C:5]3[C:6](=[CH:7][CH:8]=[CH:25][CH:4]=3)[CH2:2][NH:24][CH2:9]2)[CH2:11][CH2:12]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC2(C=CC=C3C(O)OC(O)C32)CC1
Reactant: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCc1ccccc12
Reaction time: 8 h

Procedure:
The intermediate of Step A (100 mg) was stirred in methanol (2 mL) saturated with ammonia for one day, and evaporated to remove ammonia. The residue was redissolved in methanol (3 mL) and sodium cyanoborohydride (50 mg, excess) was added. The mixture was stirred overnight. Evaporation and purification gave the amine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].[Al+3].[Cl-:17].[Cl-].[Cl-].S(=O)(=O)(O)O>[N+](C)([O-])=O>[Cl:17][CH2:13][CH2:12][C:11]([C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:8]=1)=[O:14]
Reactant: CCC(=O)Cl
Reactant: CCc1ccccc1CC
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: C[N+](=O)[O-]
Product: CCc1ccc(C(=O)CCCl)cc1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,2-Diethylbenzene (10.9 g, 74.6 mmol) and propionyl chloride (9.7 g, 74.6 mmol) are added dropwise to AlCl3 (22.3 g, 167.8 mmol) in nitromethane (75 mL) over 30 min. The reaction mixture is stirred at room temperature for 2 hours, after which 70 g of ice and 14 mL concentrated sulphuric acid are added. The aqueous phase is extracted with ether, and the combined organic phases extracted with 2N HCl and saturated aqueous NaCl. The organic phase is further treated with activated charcoal, magnesium sulphate, and filtered, and the solvent removed in vacuo.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C>ClCCl>[C:33]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C@@H:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:30][CH:31]=1)[N:7]1[CH2:8][C@@H:9]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][C@@H:6]1[CH3:32])(=[O:35])[CH3:34]
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC(C)=O)c2)C[C@H]1C
Yield: 70.3 %

Procedure:
A solution of (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.2 g, 2.8 mmol, Example 6), acetic anhydride (0.40 mL, 4.2 mmol), and triethylamine (0.80 mL, 5.6 mmol) in 30 mL of dichloromethane was stirred overnight under nitrogen. The solution was washed twice with 15 mL of 5% sodium bicarbonate, dried over sodium sulfate and the solvent removed. The product was purified by chromatography on silica gel with ethyl acetate (30-100%) in dichloromethane to give 0.94 g (71%) of (±)-4-((αR*)-3-acetoxy-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a white foam. NMR (200 MHz, DMSO-d6): δ 0.9 (d, J=6 Hz, 3H); 1.1 (d, J=6 Hz, 3H); 1.0-1.2 (br m, 6H); 1.75 (dd, J1 =7.5 Hz, J2 =12 Hz, 1H); 2.1 (dd, J1 =8.5 Hz, J2 =12.5 Hz, 1H); 2.2 (s, 3H); 2.4-2.6 (m, 3H); 2.7 (m, 1H); 2.8 (dd, J1 =7.5 Hz, J2 =15 Hz, 1H); 3.1 (dd, J1 =6 Hz, J2 =14 Hz, 1H); 3.1-3.4 (br m, 4H); 5.05 (d, J=15 Hz, 1H); 5.1 (s, 1H); 5.15 (d, 10 Hz, 1H), 5.8 (m, 1H) 7.0 (s, 1H); 7.0 (d, J=8 Hz, 1H); 7.15 (d, J=8 Hz, 1H); 7.25 and 7.4 (ABq, J=8 Hz; 4H); 7.4(t, J=8 Hz, 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration with ethanolic hydrogen chloride. After the solvent was removed, the salt was dissolved in a minimal amount of dichloromethane and precipitated with diethyl ether. Filtration gave 0.50 g of the hygroscopic salt. Calc for C29H39N3O3HCl H2O: C, 65.46; H, 7.97; N, 7.90; Cl, 6.66. Found: C, 65.43; H, 7.97; N, 8.00; Cl, 6.79.
Reaction SMILES: N1C=CC=CC=1C[N:8]1[C:12]([C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:9]1.O1CCOCC1.[Se](=O)=O>O>[C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:13]([C:12]3[NH:8][CH:9]=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]=3)=[O:26])=[CH:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cc(C(=O)c2ccc(-c3ccccc3)cc2)n(Cc2ccccn2)c1
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c[nH]c(C(=O)c2ccc(-c3ccccc3)cc2)c1
Yield: 75.2 %

Procedure:
Ethyl 1-(2-pyridylmethyl)-5-(4-phenylbenzoyl)pyrrole-3-carboxylate (5.3 g.) was combined with 150 ml. of dioxane, 5 ml. of water and 10 g. of selenium dioxide and refluxed for approximately 16 hours. Insoluble material was separated by filtration, the filtrate was diluted with 150 ml. of ether and 150 ml. of water, the mixture equilibrated, the ether phase separated, back-washed twice with 100 ml. portions of water, filtered and concentrated to yield ethyl 5-(4-phenylbenzoyl)pyrrole-3-carboxylate (3.1 g, solid; Rf 0.4 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1.C(N(CC)CC)C>CO>[OH:17][CH2:16][C@@H:14]1[C@H:13]([OH:18])[C@H:12]([OH:19])[C@H:11]([N:10]2[CH:9]=[N:8][C:4]3[C:3]2=[N:2][CH:1]=[N:6][C:5]=3[NH:20][CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[O:15]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCOC4)ncnc32)[C@@H](O)[C@H]1O
Temperature: 80 °C
Yield: 46 %

Procedure:
A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), 3-aminotetrahydrofuran (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C. for 40 hours. The mixture was cooled and concentrated under reduced pressure. The residue was chromatographed on a short column of silica gel, eluting with methylene chloride/methanol/propylamine (90/10/1). The fractions containing the product were combined and concentrated under reduced pressure. The residue was chromatographed on a chromatotron (2 mm plate, 92.5/7.5/1, methylene chloride/methanol/propylamine). The resulting white solid was recrystallized from methanol/ethyl acetate to give 0.27 gm of (4S,2R,3R,5R)-2-hydroxymethyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol as white crystals (mp 128° C.-130° C.).