Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:48]1[N:53]=[C:52]([C:54]2[CH:55]=[N:56][CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:51]2[N:61]([CH2:73][C:74]3[CH:79]=[CH:78][C:77]([C:80]([F:83])([F:82])[F:81])=[CH:76][CH:75]=3)[C:62]([N:64]3[CH2:69][CH2:68][O:67][C@@H:66]4[CH2:70][CH2:71][CH2:72][C@@H:65]34)=[N:63][C:50]=2[CH:49]=1.[CH3:84][N:85](C)C(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:60][C:58]1[CH:59]=[C:54]([C:52]2[C:51]3[N:61]([CH2:73][C:74]4[CH:75]=[CH:76][C:77]([C:80]([F:83])([F:81])[F:82])=[CH:78][CH:79]=4)[C:62]([N:64]4[CH2:69][CH2:68][O:67][C@@H:66]5[CH2:70][CH2:71][CH2:72][C@@H:65]45)=[N:63][C:50]=3[CH:49]=[C:48]([C:84]#[N:85])[N:53]=2)[CH:55]=[N:56][CH:57]=1
Reactant: CC(=O)N(C)C
Reactant: FC(F)(F)c1ccc(Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: N#Cc1cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(Cc3ccc(C(F)(F)F)cc3)c2c(-c2cncc(Cl)c2)n1
Temperature: 80 °C

Procedure:
Palladium(II) acetate (70 mg, 0.312 mmol) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (195 mg, 0.313 mmol) were placed in a dry flask. N,N-dimethylacetamide (18.7 mL) was added and the mixture was degassed for three minutes with nitrogen. Sulfuric acid (0.015 mL) was added, and the mixture was degassed for an additional three minutes with nitrogen. The flask was sealed and heated to 80° C. for 30 minutes. The mixture was cooled to room temperature and added to a separate nitrogen purged flask containing 6-chloro-4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine (racemic; 0.5 g, 0.9 mmol), zinc cyanide (46 mg, 0.45 mmol), and zinc (6 mg, 0.09 mmol). The flask was purged with nitrogen for five minutes, sealed, and heated to 100° C. for 2 hrs. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (racemic). MS APCI calc'd. for C27H22ClF3N6O [M+H]+ 539. found 539.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].[OH-].[Na+]>CS(C)=O>[OH:19][CH2:18][C:17]1[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=1)[O:14][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.2 %

Procedure:
20.0 g (93.5 mmoles) of 2-chloromethylquinoline hydrochloride, 11.6g (93.5 mmoles) of 3-hydroxybenzylalcohol and 7.48g (186.42 mmoles) of powdered sodium hydroxide are combined in 56 ml of dimethylsulfoxide. After stirring room temperature for 24 hours the mixture is poured into ice-water and the resulting solid is collected and dried to give 25.6g of 2-(3-hydroxymethylphenoxy)methylquinoline.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:8]=1)(=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:43](Br)([F:45])[F:44]>ClCCl>[C:21]([C:5]1[C:4]([C:1]([CH3:2])=[C:43]([F:45])[F:44])=[CH:8][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:10]=2[Cl:20])[N:6]=1)#[N:22]
Reactant: CC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Reactant: FC(F)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=C(F)F)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 90 °C
Reaction time: 12 h

Procedure:
4-Acetyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.5 g), triphenylphosphine (1.884 g), dibromodifluoromethane (0.33 ml) and dichloromethane (50 ml) were placed in a stainless steel bomb and heated and stirred at 90° C. for 12 hours. The reaction mixtiure was evaporated and the residue was purified by column chromatography on silica gel eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 66-68° C.
Reaction SMILES: [C:1]([Br:4])(=[O:3])[CH3:2].[Br-].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:40])[CH2:14][N+:15]23[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]2)[C@@H:17]([O:23][C:24](=[O:39])[C@@H:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]3)=[CH:9][CH:8]=1.C(Cl)Cl.CO.CC#N.O>C(Cl)Cl>[Br-:4].[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:40])[CH2:14][N+:15]23[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]2)[C@@H:17]([O:23][C:24](=[O:39])[C@@H:25]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:16]3)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc(O)cc1
Reactant: CC(=O)Br
Agent: [Br-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Acetyl bromide (10 μl, 0.14 mmol) was added to a solution of (R)-1-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (diastereomer 1 of I71) (70 mg, 0.13 mmol) in TEA (19.5 μl, 0.14 mmol) and DCM (3 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude product was purified first by trituration with Et2O, then by flash-chromatography (DCM/MeOH=95/5) and finally by preparative HPLC (eluents: CH3CN/H2O) to obtain (R)-1-(2-(4-acetoxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (24 mg, 31.9% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([OH:24])=[CH:22][C:21]([CH:25]([CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:26])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:37][CH2:36]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:34].[CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([O:24][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:38]4[CH2:37][CH2:36][O:35][CH2:40][CH2:39]4)=[CH:22][C:21]([CH:25]([CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:26])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1

Procedure:
2-Benzyl-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-morpholinobutyric acid hydrochloride and dicyclohexyl-carbodiimide are combined in equimolar amounts in methylene chloride and reacted as in Example 1 to give the desired product.
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[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:6]=2[N:7]=1.[CH3:20][N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)CC)(C)C>CN(C=O)C>[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[O:10][C:9]([C:11]([NH:21][CH3:20])=[O:13])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1

Procedure:
A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (1.0 eq), HATU (1.5 eq), hydrochloride salt of methylamine (1.5 eq), diisopropylethylamine (3.0 eq) in DMF was stirred for 30 minutes. Reaction mixture was quenched with saturated aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to give 2-chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide. MS (Q1) 297 (M)+
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:20](O)=[O:21])=[CH:14][C:15]=2[O:17][CH2:18][CH3:19])[N:10]([CH:23]2[CH2:25][CH2:24]2)[CH:9]=1)=[O:7])(C)(C)C.Cl.[NH:27]1[CH:31]=[C:30]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][C:35]3=[O:47])[CH:29]=[N:28]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH:23]1([N:10]2[C:11]3[C:16](=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[C:13]([C:20]([N:40]4[CH2:41][CH2:42][C:37]5([CH2:36][C:35](=[O:47])[C:34]6[C:44](=[CH:45][CH:46]=[C:32]([C:30]7[CH:31]=[N:27][NH:28][CH:29]=7)[CH:33]=6)[O:43]5)[CH2:38][CH2:39]4)=[O:21])[CH:12]=3)[C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)[CH2:24][CH2:25]1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3cn[nH]c3)cc21
Reactant: CCOc1cc(C(=O)O)cc2c1c(C(=O)OC(C)(C)C)cn2C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cn[nH]c4)ccc2O3)cc2c1c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.21 mL) was added to a solution of 3-(tert-butoxycarbonyl)-1-cyclopropyl-4-ethoxy-1H-indole-6-carboxylic acid (177 mg), 6-(1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (156 mg), WSC hydrochloride (106 mg) and HOBT (85 mg) in DMF (4 mL) and the mixture was stirred at 90° C. for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate, then washed with water, 1N hydrochloric acid solution, aqueous saturated sodium bicarbonate and saturated saline in this order, and dried over sodium sulfate. The solution was filtered, concentrated, and purified through silica gel column chromatography (chloroform/methanol) to give the methyl ester of the title compound as a colorless amorphous substance. TFA (3 ml) was added to the solution of this ester in chloroform (10 ml) at room temperature and stirred for 3 h. The solvent was evaporated and the residue was crystallized from a mixed solvent of methanol and ether to give title compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.03 (2H, s), 7.94 (1H, s), 7.87 (1H, d, J=2.4 Hz), 7.83 (1H, dd, J=8.5, 2.4 Hz), 7.33 (1H, d, J=1.0 Hz), 7.10 (1H, d, J=8.5 Hz), 6.79 (1H, d, J=1.0 Hz), 4.31-4.19 (1H, br m), 4.21 (2H, q, J=7.0 Hz), 3.85-3.21 (4H, br m), 2.89 (2H, s), 2.11-1.70 (4H, br m), 1.39 (3H, t, J=7.0 Hz), 1.10-1.00 (4H, m); MS [M+H]+=555.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[CH2:22]([OH:25])[CH2:23][OH:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:24][CH2:23][CH2:22][OH:25])[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (1 g, 2.45 mmol), ethane-1,2-diol (15 mL) and cesium carbonate (3 g, 9.18 mmol) was stirred overnight at room temperature and then diluted with 200 mL of water. The resulting solution was extracted with 2×200 mL of dichloromethane. The combined organic layers were washed with 3×200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 300 mg (34%) of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol as a yellow solid. 1H NMR (300 MHz, DMSO) delta 8.39 (d, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.51 (s, 2H), 7.09 (d, J=5.4 Hz, 1H), 4.78 (t, J=5.2 Hz, 2H), 4.08 (t, J=4.2 Hz, 2H); LC-MS: m/z=+350 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]#[N:8].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17](F)[C:16]=1[F:25].Cl>C1COCC1>[F:25][C:16]1[C:15]([F:14])=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[C:17]=1[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]#[N:8]
Reactant: COc1cc(O)cc(C#N)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
NaH (2.05 g, 51.2 mmol) was added portionwise to a 0° C. solution of 3-hydroxy-5-(methyloxy)benzonitrile (7.63 g, 51.2 mmol) (prepared following the procedure in Magano et al. J. Org. Chem. 2006, 71, 7103) in THF (205 ml). When addition was complete, the thick suspension was stirred at this temperature for another 30 mins, and trifluoronitrobenzene (9.51 g, 53.7 mmol) was then added. The reaction mixture was stirred at RT for 3 h, dilute HCl was added and the solution was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-30% EtOAc/hexanes) to afford the title compound (14.44 g, 92%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.96 (ddd, J=9.36, 4.97, 2.24 Hz, 1H) 7.28-7.35 (m, 1H) 6.95 (d, J=0.73 Hz, 1H) 6.78 (t, J=2.15 Hz, 1H) 6.73 (s, 1H) 3.85 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=O.[F:13][C:14]([F:31])([F:30])[CH2:15]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>[F:13][C:14]([F:31])([F:30])[CH:15]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C=CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
4A Molecular sieves (7 g; activated powder) was suspended in 8.8 ml of 1.0M TBAF in THF and stirred overnight at room temperature under nitrogen. To the solution was added methyl 4-formylbenzoate (160 mg; 0.97 mmol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (415 mg; 1.46 mmol) in 10 ml of anhydrous THF. After stirring overnight, the solvents were evaporated to dryness. The residue was dissolved in EtOAc and washed with water and brine. The organic dried over Na2SO4, filtered and evaporated. The residue was dissolved in 10 ml of THF and 10 ml of 1N NaOH and refluxed for 30 minutes. The mixture was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (125 mg; 60%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:11]([O:10][C@H:9]1[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3[NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:7][C@@H:8]1[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:13])[CH3:12]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(6-chloro-2-iodopurin-9-yl)oxolan-3-yl acetate (1.15 g, 2.13 mmol) in N,N-dimethylformamide (20 ml) was added cyclopentylamine (0.42 ml, 4.26 mmol) and diisopropylethylamine (10 ml), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue chromatographed on a silica gel column, eluting with a mixture of 40% ethanol/60% hexane, to provide (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxymethyl)-5-[6-(cyclopentylamino)-2-iodopurin-9-yl]oxolan-3-yl acetate (0.9 g), a compound of formula (4).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([O:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:18]([NH2:31])[N:17]=1)[CH2:11][CH2:12][CH2:13][CH3:14].O>C(Cl)(Cl)Cl>[Br:1][C:21]1[N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:23]2[C:19]([N:20]=1)=[C:18]([NH2:31])[N:17]=[C:16]([O:15][C@@H:10]([CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[N:24]=2
Reactant: CCCC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reaction time: 3 h

Procedure:
N-Bromosuccinimide (1.504 g, 8.45 mmol) was added portionwise to a stirred solution of 2-{[(1S)-1-methylpentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.453 g, 7.68 mmol) in chloroform (40 ml) under at atmosphere of nitrogen cooled in an ice-bath. After 3 hours LCMS indicated the reaction to be 80% complete and more N-bromosuccinimide (0.68 g) was added and stirring continued for a further 2 hours. Water (40 ml) was added and the phases separated using a hydrophobic frit. The organic phase was evaporated and the residue dissolved in dichloromethane and purified on an aminopropyl (NH2) cartridge (100 g) using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to the title compound as a white foam (2.38 g).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](OC)=[CH:10][CH:9]=1.OC(COC(C)C)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl>C(OCC)C>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COC(C)C)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(Cc1ccccc1)NCC(O)COc1ccccc1

Procedure:
Using the method of Example 5, supra, 1,2-epoxy-3-phenoxypropane (600 mg, 4 mmol) and 1,1-dimethyl-2-phenylethylamine (596 mg, 4 mmol) yielded the title compound: GC/EI-MS, m/z (rel. int.) 284 (M+1, 1), 208 (100), 162 (1), 133 (7), 91 (27), 77 (15), 70 (22). The free base in diethyl ether was treated with excess 1M HCl (diethyl ether). The resulting solid was recrystallized from hot acetonitrile to afford 596 mg of the hydrochloride product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:15]([NH2:17])=O>>[CH2:12]([C:4]1[S:3][C:2]2[N:1]=[CH:15][N:17]=[C:7]([OH:8])[C:6]=2[CH:5]=1)[CH2:13][CH3:14]
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Reactant: NC=O
Product: CCCc1cc2c(O)ncnc2s1

Procedure:
The product of example 3a was reacted with excess formamide at reflux for 3 hours. The reaction mixture was quenched with water and the resulting precipitate was collected by filtration and washed with water and dried under vacuum to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:21](Cl)(=[O:23])[CH3:22].O>ClC(Cl)C>[C:21]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([CH3:16])[C:7]=2[C:2]=1[OH:1])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.6 %

Procedure:
To a solution of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (220 mg, 1 mmol) in dichloroethane (10 ml) was added aluminum chloride (665 mg, 5 mmol). To the resulting brown solution was added acetyl chloride (0.178 ml, 2.5 mmol). The mixture was stirred for 5 hours at room temperature. Ice and water (20 ml) was added. The mixture was extracted with ethyl acetate. The extracts were dried and concentrated to a white solid which was then treated with 1 ml of 10% K2CO3 aqueous solution in 10 ml methanol for 2 hours. The resulting mixture was poured into 0.1N HCl (25 ml) and filtered. The solid obtained was recrystallized from ethyl acetate/toluene to give the title compound (130 mg, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C1COCC1>[CH3:13][C:10]1([CH3:14])[CH2:11][CH2:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)[CH:3]=2)[CH2:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)CCN(c2cccc(Br)c2)C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
1-(3-Bromophenyl)-3,3-dimethyl-pyrrolidine (6.7 g, 26.4 mmol) was suspended in 132 ml of THF and cooled to −78° C. in a dry ice acetone bath. tert-Butyl lithium (1.7 M solution in pentane, 46.6 ml, 79.2 mmol) was added dropwise and the reaction was stirred at −78° C. for 15 min. 2-Isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.8 ml, 52.8 mmol) was added and the reaction was stirred at −78° C. for 2 h. The reaction was quenched with saturated aqueous ammonium chloride and warmed to room temperature. Water was added and the layers were separated. The aqueous layer was back extracted twice with ethyl acetate. The combined organic layers were dried, filtered and concentrated. The crude product was chromatographed using a gradient of 0% to 10% ethyl acetate in hexanes to give 6.0 g (75%) of 3,3-dimethyl-1-[3 (4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[OH:24][CH:23]([C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])=[O:4]
Reactant: C#CC(=O)OCCOCCOC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCCOC(=O)C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 0.17 h

Procedure:
A solution of 10 g (58 mmol) of 2-(2-methoxyethoxy)ethyl propiolate in 80 ml of tetrahydrofuran was treated at -78° under argon with 36 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 11.4 g (58 mmol) of 3,4,5-trimethoxy-benzaldehyde in 60 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes, then brought to room temperature and treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained 2-(2-methoxyethoxy)ethyl 4-hydroxy-4-(3,4,5-trimethoxyphenyl)-2-butynoate as a red oil.