Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:10]#[N:11])[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(C#N)n1
Temperature: 110 °C

Procedure:
2-Chloro-4,6-dimethylpyrimidine (3.3 g, 0.023 mol) was combined with zinc cyanide (2.7 g, 0.023 mol, 1 eq.) and tetrakis(triphenylphosphine)palladium (0) (2.7 g, 0.0023 mol, 0.1 eq.) in DMF (20 ml), and the slurry was heated at 110° C. under nitrogen for 0.5 h. The mixture was cooled to room temperature, diluted with EtOAc (70 ml) and washed twice with 2N ammonium hydroxide (50 ml). The EtOAc solution was washed with brine (20 ml) and concentrated in vacuum to provide the crude mixture. The crude was then purified by column chromatography (30% EtOAc/hexane) to afford 4,6-dimethylpyrimidine-2-carbonitrile. Yield: 0.8 g (26%). 1H NMR (400 MHz, CDCl3): δ2.48 (s, 6H), 7.21 (s, 1H). LCMS: (ES+) m/z=133.6 (M)+
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[H-].[Na+].Br.Br[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CN(C=O)C.C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:22])=[C:12]([CH3:21])[N:13]2[CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Cl)cc2n1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The recovered crude material, along with an additional portion of the starting material, 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.075 g, 0.23 mmol), were dissolved in DMF:THF (1:1, 4 mL) and the reaction was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.95 mmol) was added and after five minutes 3-(bromomethyl)pyridine hydrobromide (0.57 mmol) was added and the ice bath was removed. After 10 minutes, LCMS of the reaction mixture indicated that the starting material was consumed and that the product was also hydrolyzed to from the methyl ester to the free acid in situ. Standard aqueous workup and purification by preparatory HPLC (10-100% ACN in H2O) afforded the title compound.
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:24])[C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][NH:6][C:7](=[O:24])[C@H:8]([N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[C@H:9]([O:11][CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)O)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]amino]-3(R)-hydroxybutanamide (3.04 g, 8.44 mmol) in dimethylformamide (150 mL) is added 3-picolyl chloride hydrochloride (1.45 g, 8.87 mmol) followed by potassium carbonate (11.65 g, 84.4 mmol). The reaction mixture is stirred at room temperature overnight, then heated to 45° C. for 5 hours. An additional mount of 3-picolyl chloride hydrochloride (692.0 mg, 4.23 mmol) is added at this point. The reaction mixture is stirred at 45° C. for 10 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product is purified by silica gel chromatography (ethyl acetate, then 5% methanol/methylene chloride) to give N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3(R)-(3-picolyloxy)butanamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[CH3:21][NH:22][CH3:23].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:21][N:22]([CH3:23])[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12](/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
A mixture of a solution of (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid obtained in Step 6 in THF (0.125 mol/L, 0.40 mL, 0.05 mmol), a solution of dimethylamine in THF (1 mol/L, 0.08 mL, 0.08 mmol), a solution of 1-hydroxybenzotriazole in THF (0.33 mol/L, 0.20 mL, 0.07 mmol) and polymer-bound 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 mol/g, 0.07 g, 0.07 mmol) was shaken at room temperature overnight. The reaction mixture was filtered, the solvent was evaporated by blowing air to the filtrate, and the residue was added with THF (0.6 mL), polyvinylpyridine (0.03 g, 0.29 mmol) and 4-chloroformyl polystyrene (3.5 mol/g, 0.03 g, 0.11 mmol), followed by shaking at room temperature overnight. The reaction mixture was filtered, and the solvent was evaporated by blowing air to the filtrate. The residue was added with ethanol (0.5 mL) and ion-exchange resin [Bio-Rad AG (registered trademark) 1 X-8 OH form, 0.15 g], followed by shaking for 10 minutes. The mixture was filtered, the resin was washed with ethanol, and the adsorbate was eluted with a 4 mol/L solution of hydrogen chloride in ethyl acetate. The solvent was evaporated by blowing air to the eluate, the residue was purified by thin-layer chromatography (chloroform/methanol=9/1) to obtain Compound 1 (0.4 mg, 3%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:18]2[CH2:19][O:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCCCCCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCCCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 4 g of 8-phenyloctyl alcohol, 3.18 ml of epibromohydrin, 0.85 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used, to give 2.42 g of the title compound having an Rf value of 0.51 (on silica gel thin layer chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>CS(C)=O.O>[CH:23]1([NH:28][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: NC1CCCC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (250 mg, 0.79 mmol) in DMSO (3 mL) was added cyclopentylamine (402.6 mg, 4.73 mmol), and the resulting solution was stirred overnight at 100° C. The resulting mixture was diluted with water (15 mL) and extracted with dichloromethane (3×10 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2%-5% ethyl acetate in petroleum ether) to afford methyl 3-(cyclopentylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (240 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[CH:22]=[O:23]>CC(O)=O>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[CH:22]([OH:23])[CH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cnc2ccccc2n1
Reactant: Cc1cnc2ccccc2n1
Solvent: CC(=O)O
Product: OC(Cc1cnc2ccccc2n1)c1cnc2ccccc2n1
Yield: 26.3 %

Procedure:
A solution of 2-methyl quinoxaline (0.11 g, 0.76 mmol) and quinoxaline-2-carbaldehyde (0.16 g, 0.63 mmol) in AcOH (2 mL) was stirred for 1 hour at 70° C. The reaction mixture was concentrated and purified with reverse phase column chromatography to afford 1,2-di(quinoxalin-2-yl)ethanol (0.05 g) as a yellow solid. MS (ESI) m/z 303.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[Br:19])=[O:11].F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>>[Br:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)=[O:11]
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-bromo-5-methylphenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470, 472 [M]+, [M+2]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.Br[CH2:13][CH:14]=[CH2:15].N(OC(C)(C)C)=O>CC#N>[CH2:15]([C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[F:1])[CH:14]=[CH2:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: C=CCBr
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: C=CCc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
2-Fluoro-4-nitroaniline (5 g, 32.0 mmol) was added to a solution of 3-bromoprop-1-ene (41.5 mL, 480 mmol) and tert-butyl nitrite (5.76 mL, 48.0 mmol) in 32 mL of degassed anhydrous CH3CN at 18-19° C. under nitrogen. At the end of the addition of the arylamine, another half-equivalent of tert-butyl nitrite (1.180 mL, 16.01 mmol) was added; the reaction was stirred at room temperature for 1 hr. The reaction was concentrated under reduced pressure to remove the volatile material. The residue was purified by silica gel flash chromatography, 100% Heptane-5% Ethyl Acetate/95% Heptane, to give 1-allyl-2-fluoro-4-nitrobenzene (2.98 g). 1H NMR (400 MHz, DMSO-d6) δ 3.51 (dd, J=6.4, 1.1 Hz, 2H), 5.05-5.16 (m, 2H), 5.96 (ddt, J=16.8, 10.2, 6.6, 6.6 Hz, 1H), 7.56-7.62 (m, 1H), 8.03-8.11 (m, 2H).
Reaction SMILES: CS(O[CH:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)(=O)=O.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:18][CH:17]([CH3:19])[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)[N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: CC(=O)Nc1ccc(C(OS(C)(=O)=O)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1
Yield: 25.1 %

Procedure:
A mixture of (±)-4-(acetylamino)-α-(1-methylethyl)benzenemethanol methane sulfonate (ester) (0.1541 mol), 1H-1,2,4-triazole (0.308 mol) and K2CO3 (0.308 mol) in CH3CN (500 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was taken up in water/CH2Cl2. The organic layer was dried, filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and evaporated, yielding 10 g (25%) of (±)-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-phenyl]acetamide (compound 153).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([NH:7][N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=1)[CH:9]([CH3:11])[CH3:10])=[O:6].[C:35]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH:9]([N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:16]=1)[NH:7][C:5](=[O:6])[C:4]1[CH:32]=[CH:33][CH:34]=[C:2]([O:1][CH3:35])[CH:3]=1)([CH3:11])[CH3:10]
Reactant: CC(C)N(NC(=O)c1cccc(O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Temperature: 85 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(3-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in anhydrous acetonitrile (10.0 ml), iodomethane (0.0673 ml, 1.08 mmol) was added drop-by-drop at 0° C. The reaction mixture was refluxed for 12 hr at 85° C. After concentration under reduced pressure, the solution was separated through the silica gel chromatography (30% EtOAc) so that ivoty solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(3-methoxybenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (43.5 mg, 42.2%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:21]([C@H:23]1[CH2:25][O:24]1)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([CH3:22])[C@@H:23]([OH:24])[CH2:25][N:2]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H]([C@H]1CO1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CNCCCc1ccc(F)cc1
Solvent: CCO
Product: C[C@H]([C@@H](O)CN(C)CCCc1ccc(F)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
The product of Step e (1.30 g, 7.80 mmol, 1 eq.), (1R)-N,N-dibenzyl-1-[(2S)-oxiran-2-yl]ethanamine (the synthesis of which is described in Example 100) (2.08 g, 7.80 mmol, 1 eq.) and ethanol (10 mL) were mixed at 25° C. under N2 then refluxed overnight. Worked up by stripping off the ethanol then purifying the residue over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc. Obtained 1.16 g of an amber oil. MS (ESI) detects (M+H)+=435.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O-])=O.Cl.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)cc1N1CCNCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N2CCCC2)cc1N1CCNCC1

Procedure:
A mixture of 1-nitro-2-piperazinyl-4-pyrrolidinylbenzene (4.57 g), ethanol (110 ml), hydrochloric acid (1.2 N, 6 ml) and palladium on carbon (10%, 1 g) is exposed to hydrogen 51 psi at 20°-25° in a Parr flask. After 16 h (49 psi total uptake) the mixture is filtered. Basic workup (chloroform, potassium carbonate) and column chromatography silica gel (50 g) eluting with chloroform/methanol (4/1) gives the title compound as an oil, IR (nujol) 3315, 2947, 2816, 1512, 1258, 1001 and 753 cm-1 ; NMR (CDCl3) 1.8-2.0, 2.9-3.2, 6.52 and 6.6-6.8 δ; MS (electron impact) 246, 204 and 189.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:3]=1.[C:20]([O:23][CH2:24][CH:25]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:27]I)(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:24][CH:25]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:27][N:6]1[C:5]2[C:9](=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:8]=[CH:7]1)(=[O:22])[CH3:21]
Reactant: Cc1ccc(CSc2nc(N)nc3nc[nH]c23)cc1
Reactant: CC(=O)OCC(CCI)COC(C)=O
Product: CC(=O)OCC(CCn1cnc2nc(N)nc(SCc3ccc(C)cc3)c21)COC(C)=O
Yield: 10 %

Procedure:
Using the previously described procedure 2-amino-6- [(4-methylphenyl)methylthio]purine (25 g) and 2-acetoxymethyl-4-iodobut-1-yl acetate (29 g) gave the title compound 33.3 g (79%) m.p. 102°-103°, and 4.2 g (9.9%) of 7-(4-acetoxy-3-acetoxymethylbut-1-yl)-2- amino-6-[(4-methylphenyl)methylthio]purine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)[CH2:6][OH:7]
Reactant: OB(O)c1cccs1
Reactant: OCCc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: OCC(c1ccccc1)c1cccs1

Procedure:
3-Bromophenethyl alcohol (4 ml, 29.8 mmol) was dissolved in 1,2-dimethoxyethane (225 mL) and mixed with tetrakistriphenylphosphine palladium[0] (2.6 g, 2.25 mmol) at room temperature. The reaction mixture was then added to a solution of 2-thienyl-boronic acid (12.6 g, 99 mmol) and 1N NaHCO3 (90 mL). The reaction mixture was heated to reflux under nitrogen atmosphere for 48 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was dried with MgSO4, filtered through a plug of silica and the solvent was evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (30% EtOAc/hexane) to yield the title compounds as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@:15]([C:17]#[CH:18])([OH:16])[C@H:14]([OH:19])[C@@H:13]([CH2:20][OH:21])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:22].O>>[NH2:22][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@:15]([C:17]#[CH:18])([OH:16])[C@H:14]([OH:19])[C@@H:13]([CH2:20][OH:21])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: N
Solvent: O
Product: C#C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Temperature: 100 °C

Procedure:
A mixture of (2R,3R,4R,5R)-2-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydrofuran-3,4-diol (198.0 mg, 0.64 mmol,) and NH3.H2O (30 mL) in a glass pressure tube is heated at 100° C. for 5 h. The reaction mixture is concentrated to dry and purified by flash chromatography (CH2Cl2:MeOH=80:20) to yield (2R,3R,4R,5R)-2-(4-Amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydrofuran-3,4-diol as pale yellow solid. 1H NMR (300 MHz, MeOD): δ 8.07 (1H, s), 7.48 (1H, d, J=3.9 Hz), 6.58 (1H, d, J=3.6 Hz), 6.29 (1H, s), 4.49 (1H, d, J=8.4 Hz), 4.08-3.96 (2H, m), 3.90-3.75 (1H, m), 2.52 (1H, s). 1H NMR (300 MHz, DMSO-d6): δ 8.05 (1H, s), 7.41 (1H, d, J=3.6 Hz), 6.97 (2H, s), 6.55 (1H, d, J=3.6 Hz), 6.23 (1H, s), 6.16 (1H, s), 5.61 (1H, d, J=7.5 Hz), 5.13 (1H, t, J=4.9 Hz), 4.33 (1H, t, J=7.8 Hz), 3.90-3.70 (2H, m), 3.78-3.68 (1H, m), 3.01 (1H, s). 13C NMR (75 MHz, DMSO-d6): δ 157.4, 151.6, 150.1, 121.6, 102.4, 99.6, 89.6, 82.1, 81.8, 76.5, 75.8, 74.0, 59.7. ESI-MS: calcd. for C13H14N4O4 (290.1). found: 291.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:14]([CH3:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.[OH-].[Na+].O>ClCCl.II>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:25][C:14]2([CH3:15])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=C(C)C)c1ccc(Cl)cc1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(Cl)cc2)OC1(C)C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
A solution of ethyl 2-(4-chlorophenyl)-3-methylbut-2-enoate (11.4 g, 0.048 mol), prepared in Example 1c, m-chloroperbenzoic acid (15.7 g, 0.050 mol) and iodine (0.1 g) in dichloromethane (400 ml) was stirred for 48 hours at 50°-55° c. During this period, the course of the reaction was monitored by analytical thin layer chromatography and three further portions (2.0 g) of m-chloroperbenzoic acid and two further portions (0.1 g) of iodine were added to the mixture. The precipitate which formed during this time was dissolved by the addition of 2N sodium hydroxide solution (40 ml) and iced water (200 ml). The organic phase was then separated and washed with dilute sodium hydroxide solution (100 ml) and then with water (3×200 ml). The solution was dried (sodium sulphate), evaporated in vacuo, and the crude product purified by flash silica column chromatography, eluting with 1,2-dichloroethane, to give the title compound (8.6 g, 71%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH4+:10].[OH-]>>[NH2:10][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1nc(N)cc(Cl)n1
Temperature: 90 °C
Yield: 81.5 %

Procedure:
Part A: A mixture of 4,6-dichloro-2-methylpyrimidine (1.63 g, 10.0 mmol) in NH4OH (35%, 8 mL, 200 mmol) was heated, in a Parr bomb, in an oven at 90° C. overnight. The vessel was cooled to room temperature, the mixture was filtered and the solids were washed with water (3×10 mL). Excess solvent was removed in vacuo to give 4-amino-6-chloro-2-methylpyrimidine (1.17 g, 81%) as an amorphous solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9].C(N(CC)CC)C>O1CCCC1>[CH3:1][S:2]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][Br:6])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Methanesulfonyl chloride (50 g, 436 mmol) was added to a solution of 2-bromo-1-(4-hydroxyphenyl)-ethan-1-one (85 g, 395 mmol) and triethylamine (48 g, 474 mmol) in tetrahydrofuran (1000 ml) at 0° C. and the mixture was stirred for 30 minutes at room temperature. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with diisopropyl ether to afford 4-(2-bromoacetyl)phenyl methanesulfonate (96 g, 83%) as white crystals.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C.[Cl:19][CH2:20][C:21](C1C=CC(CCC(O)=O)=CC=1)=[O:22]>>[Cl:19][CH2:20][C:21]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:3][CH:4]=1)=[O:22]
Reactant: O=C(O)CCc1ccc(C(=O)CCl)cc1
Reactant: COC(=O)CCCOc1ccccc1
Solvent: CC(=O)Cl
Product: COC(=O)CCCOc1ccc(C(=O)CCl)cc1

Procedure:
Methyl 4-phenoxybutyrate was reacted with acetyl chloride in a similar manner to that described above for 3-[4-(chloroacetyl)phenyl]propionic acid, except that the crude product was triturated with petrol to give methyl 4-[4-(chloroacetyl)phenoxy]butyrate as a crystalline solid which was pure by TLC analysis (on silica plates; eluant: 50% ether/50% petrol).