Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH3:13])[CH2:3][C:4]([O:6][CH2:7]CCC)=[O:5].[OH:14][CH:15]([CH2:27][CH2:28][CH3:29])[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[OH:1][C@H:2]([CH2:11][CH2:12][CH3:13])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[OH:14][C@@H:15]([CH2:27][CH2:28][CH3:29])[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: CCCC(O)CC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)CC(O)CCC
Product: CCC[C@@H](O)CC(=O)OC
Product: CCC[C@H](O)CC(=O)OCc1ccccc1
Reaction time: 9 h
Yield: 36 %
Yield: 40 %

Procedure:
The same procedure was repeated except that racemic butyl 3-hydroxyhexanoate was changed into the racemic benzyl 3-hydroxyhexanoate 1.0 g (4.5 mmol) obtained in Reference example 3 and stirring time was changed into nine hours. The resulting mixture was reacted with stirring. After the reaction was stopped, the conversion of 52% was determined. The steps from filtration of the lipase to chromatograph with a silica gel column were conducted as shown in Example 1 to obtain (R)-methyl 3-hydroxyhexanoate 0.24 g (1.6 mmol, 36%) and (S)-benzyl 3-hydroxyhexanoate 0.40 g (1.8 mmol, 40%). Optical purity of these compounds was determined by HPLC. The optical purity of the (R)-compound was 88% ee and that of the (S)-compound was 96% ee.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40]Br)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][S:19][CH2:20][CH2:21][OH:22])=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1ccccc1-c1ccccc1CBr
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1-c1ccccc1CSCCO

Procedure:
2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester (13.2 g, 41.35 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (3.88 g, 49.62 mmol, 1.2 eq.) and potassium carbonate (17.14 g, 124.05 mmol, 3 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][NH:7][C:6]=2[CH:17]=1.[H-].[Na+].[Cl:20][C:21]1[CH:22]=[CH:23][C:24](F)=[N:25][CH:26]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=3)[C:6]=2[CH:17]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NC[C@H]2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of (R)-8-bromo-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (1.0 g, 3.4 mmol) in DMF (5 mL) was added NaH (280 mg, 6.8 mmol) at 0° C. After 0.5 h, 5-chloro-2-fluoropyridine (540 mg, 4.08 mmol) was added. The mixture was stirred at room temperature overnight. After quenching with H2O (30 mL), the reaction mixture was extracted with ethyl acetate (10 mL*3). The organic layer was washed with brine and dried over sodium sulfate. Concentrated in vacuo gave (R)-8-bromo-6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (1.0 g, crude) for the next step directly. LRMS (M+H+)+: calcd 403.02. found 404.01.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.[CH3:18][Si:19]([CH3:22])([CH3:21])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.CN(C)C=O>[F:1][CH:2]([F:12])[C:3]([O:11][Si:19]([CH3:22])([CH3:21])[CH3:18])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C#CCC(O)(CCCC)C(F)F
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C(F)F
Temperature: 0 °C

Procedure:
A solution of 11.5 g. of 4-difluoromethyl-4-hydroxy-1-octyne and 11.32 g. of imidazole in 45 ml. of dimethylformamide is cooled in an ice bath under nitrogen. A 10.3 ml. portion of trimethylchlorosilane is added using a syringe over a 15 minute period. The mixture is stirred in the ice bath for one hour and then overnight at room temperature. The solution is diluted with hexane and then poured into saturated aqueous sodium bicarbonate solution. The hexane solution is separated, washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and the solvents are evaporated to dryness giving the desired product as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:30])[CH2:17][CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH2:10]1.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH:16]([OH:30])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])[CH2:14][CH2:13]1
Reactant: Cc1cccc(N2CCN(CC(O)CCN3C(=O)c4ccccc4C3=O)CC2)c1C
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(N2CCN(CC(O)CCN)CC2)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.5 %

Procedure:
To a mixture of 2-(4-(4-(2,3-dimethylphenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-dione obtained in step 4 (0.26 g, 0.65 mmol) in ethanol (1.5 ml), was added hydrazine monohydrate (0.063 ml, 2.02 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 17 hours. After the reaction complete, the reaction mixture thus obtained was sonicated and filtered. The filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The organic phase thus separated was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.1 g). The compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[CH2:34]([O:36][C:37](=[O:43])/[CH:38]=[CH:39]/C(O)=O)[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>CO.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])/[CH:39]=[CH:38]/[C:37]([O:36][CH2:34][CH3:35])=[O:43])[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/C(=O)N1CC[C@H](NC(=O)c2nc(Cl)c(CC)[nH]2)[C@H](OC)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (133 mg, 0.34 mmol) was dissolved in methanol (2 mL). A 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at 70° C. for 30 minutes. Following concentration under reduced pressure, the residue was dissolved in DMA (5 mL). Fumaric acid monoethyl ester (54.42 mg, 0.38 mmol), WSC hydrochloride (197.41 mg, 1.03 mmol) and DMAP (41.94 mg, 0.34 mmol) were added, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=40/1, 20/1, 10/1) to obtain 147.3 mg of the title compound as a solid (100%).
Reaction SMILES: [NH2:1][C@H:2](C(O)=O)C[SeH].N#CBr.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1.C>CC#N.O.CO>[NH2:1][C:2]1[NH:20][C:14]2[CH:13]=[C:12]([Cl:11])[C:17]([Cl:18])=[CH:16][C:15]=2[N:19]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: N[C@@H](C[SeH])C(=O)O
Agent: N#CBr
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 24 h

Procedure:
A modified procedure of the procedure described by Leonard, N. J., et al., J. Am. Chem. Sec. 69:2459 (1947), was followed. Cyanogen bromide (136.6 g, 1.3M, 260 mL of a 5M solution in CH3CN from) was added to a solution of MeOH (250 mL) in H2O (1500 mL). 4,5-Dichloro-1,2-phenylenediamine (available commercially from Aldrich Chemical Company) (222.4 g, 1.26M) was then added in five portions, as the initial reaction is exothermic. The reaction mixture was stirred without heating for 80 hr. then treated with activated charcoal (5 g). The 80 hr time period was for convenience alone, since the reaction is probably complete within 24 hr. After stirring for two hrs, the reaction mixture was filtered through Celite. The filter cake was washed with MeOH (250 mL) and H2O (750 mL) and the filter cake was discarded. The filtrate was diluted with H2O (1.5 L), adjusted to pH 10 with conc. NH4OH (1750 mL) and then allowed to stand overnight at 5° C. The precipitate (yellow leaflets) was collected by filtration, washed with H2O and then dried under reduced pressure at 50° C. for 60 hr. Crude yield: 265 g. This product was purified by recrystallization from CH3CN to yield: 205.6 g (80.7%) of 4. MP: 264°-266° C. TLC: Rf =0.22 (CHCl3 --MeOH), 10:1; SiO2). See Horner, J. K. et al., J. Med. Chem. 11:946-949 (1968), lit. MP: 260°-262° C. As an alternative, the crude material is dissolved in absolute ethanol, treated with activated charcoal, and the solution diluted with an equal volume of H2O and stored at 5° C. for 18-24 hr.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@@:11]([NH:34]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:18]=2)[C:10]1=[O:42]>C(Cl)Cl>[NH2:34][C@@:11]1([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:42]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(N)CCN(C)C2=O)n1
Reaction time: 8 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (5 mL, 67.31 mmol) was added to a solution of tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (3.83 g, 7.84 mmol) (which may be prepared as described in Description 7) in DCM (50 mL) at 20° C. and the reaction was stirred overnight. The reaction was concentrated and a further portion of trifluoroacetic acid (2 ml) added. Stirring was continued for 3 hrs then solid K2CO3 was added (care: gas evolved) and the mixture was diluted with water. The phases were separated and the organic layer was dried (Na2SO4). The solvent was evaporated to give (3S)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (D8) (2.71 g, 6.9775 mmol, 89% yield) as a yellow oil;
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([O:20]CC)=[O:19])[CH:12]1[CH2:11][CH2:10]2)(C)C.[OH-].[Na+]>CO.O>[C:6]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([OH:20])=[O:19])[CH:12]1[CH2:11][CH2:10]2)#[CH:5]
Reactant: CCOC(=O)C1C2CCc3cc(C#C[Si](C)(C)C)ccc3C21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1ccc2c(c1)CCC1C(C(=O)O)C21
Temperature: 65 °C
Yield: 88.3 %

Procedure:
Ethyl 5-[(trimethylsilyl)ethynyl]-1a,2,3,7b-tetrahydro-1-H-cyclopropa[a]naphthalene-1-carboxylate (0.2 g, 0.64 mmol) was dissolved in 4 ml of methanol and the solution of sodium hydroxide (0.05 g, 1.2 mmol) in 2 ml of water was added to the reaction mixture and stirred at heating at 65° C. for 6 h. The extraction of basic reaction mixture into hexane showed that no starting material present. The reaction mixture was acidified with excess of 3M HCl solution (pH=1), and extracted into ethylacetate (3×15 ml). The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated by rotary evaporation to give 0.12 g of mixture of cis/trans acids (85:15) as white solid. Yield 88%. 7
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][O:14][C:15]1[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][C:18]([CH2:25][CH3:26])=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:17]=[C:18]([CH2:25][CH3:26])[CH:19]=[C:20]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:15]=2[O:14][CH2:13][O:12][CH3:11])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: CCc1cc(B(O)O)c(OCOC)c(C(C)(C)C)c1
Reactant: O=Cc1cc(Br)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1cc(-c2ccc(O)c(C=O)c2)c(OCOC)c(C(C)(C)C)c1
Yield: 76.9 %

Procedure:
To a mixture of 91 mg (0.078 mmol, 5%) of Pd(PPh3)4 and 252 mg (1.26 mmol) of 5-bromo salicylaldehyde in 10 mL of dry toluene was added 685 mmol (2.5 mmol, 2 equivalents) of 2-methoxymethoxy-3-tert-butyl-5-ethyl phenylboronic acid diluted in 5 mL of ethanol followed by 1.3 mL of a 2N aqueous solution of Na2CO3. The mixture was stirred at reflux for 3 hours and after cooling extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified over silica gel (eluent: ethyl acetate/hexane: 10/90) to give 333 mg (0.969 mmol, yield: 77%) of 2-hydroxy-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzaldehyde a pale brownb oil. 1H NMR (CDCl3), δ: 11.04 (s, 1H), 9.95 (s, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.06 (d, J=8.9 Hz, 1H), 6.98 (d, J=1.9 Hz, 1H), 4.52 (s, 2H), 3.29 (s, 3H), 2.64 (dd, J=15.2, 7.6 Hz, 2H), 1.47 (s, 9H), 1.26 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=O)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[S:12]([NH2:16])([NH2:15])(=[O:14])=[O:13].[BH4-].[Na+]>C(O)C.O>[S:9]1[CH:8]=[C:7]([CH2:10][NH:15][S:12]([NH2:16])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)NCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thianaphthene-3-carboxaldehyde (1.62 g, 10.0 mmol) was dissolved in anhydrous ethanol (50 mL). Sulfamide (4.0 g, 42 mmol) was added and the mixture was heated to reflux for 16 hours. The mixture was cooled to room temperature. Sodium borohydride (0.416 g, 11.0 mmol) was added and the mixture was stirred at room temperature for three hours. The reaction was diluted with water (50 mL) and extracted with chloroform (3×75 mL). The extracts were concentrated and chromatographed (5% methanol in DCM) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C(O)CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]4[NH:48][N:47]=[N:46][N:25]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCC#N)c23)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: OCCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCc4nnn[nH]4)c23)cc1
Reaction time: 1 h

Procedure:
Stir 1.00 g (2.1 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}hexanenitrile, 0.79 g (3.2 mmol) di-n-butyltin oxide and 3.68 g (32 mmol) trimethylsilylazide in 44 ml toluene overnight at 80° C. Then add 1 ml ethylene glycol, stir for 1 h under reflux and then concentrate by evaporation. Take up the residue in ethyl acetate, wash with dilute hydrochloric acid and with sodium chloride solution, dry, and concentrate by evaporation. Purify the raw product by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). Crystallize the combined product fractions from diethyl ether. 372 mg (38% of theor.) of the title compound is obtained as beige crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C@H:6]1[CH2:10][N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8](=[O:21])[NH:7]1)[CH3:5].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:21]=[C:8]1[N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[CH2:10][C@H:6]([CH:4]([CH3:3])[CH3:5])[N:7]1[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.53 g) was added to a solution of (4S)-4-(propan-2-yl)-1-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-2-one (5.6 g) in DMF (20 mL), and the mixture was stirred at room temperature for 10 min. Thereafter, tert-butyl bromoacetate (2.0 mL) was added portionwise thereto, and the mixture was stirred at room temperature for 2 hr. Water and saturated aqueous sodium hydrogen carbonate solution were added thereto, and the mixture was extracted with chloroform. The organic layer was separated out by phase-separation cartridge (Biotage, Isolute Phase Separator) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford tert-butyl {(5S)-2-oxo-5-(propan-2-yl)-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}acetate (802 mg).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C@@H:4]([OH:16])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8].N[C@@H](CCCC)[C@H](O)CNS(C1C=CC=CN=1)(=O)=O.[C:40](=O)([O:60]C1C=CC([N+]([O-])=O)=CC=1)[O:41][C@H:42]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH:59]=[CH:58][N:57]=[CH:56]2)=[CH:51][CH:50]=1)[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:16][C@H:4]([C@@H:3]([NH:2][C:40](=[O:60])[O:41][C@H:42]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH:59]=[CH:58][N:57]=[CH:56]2)=[CH:51][CH:50]=1)[C:43]([CH3:45])([CH3:46])[CH3:44])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8]
Reactant: CCCC[C@H](N)[C@@H](O)CNS(=O)(=O)c1ccccn1
Reactant: CC(C)(C)[C@@H](COc1ccc(-n2ccnc2)cc1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CCCC[C@H](N)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](NC(=O)O[C@H](COc1ccc(-n2ccnc2)cc1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
To 154 mg (0.31 mmol) of N-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride & N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide in 3 mL of dimethylformamide, 132 mg (0.31 mmol) of (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl 4-nitrophenyl carbonate was added, followed by 0.25 mL (1.43 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred for 18 h at room temperature. It was concentrated, a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an methanol:chloroform solution (1:9) to yield 101.3 mg (57%) of (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate and (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. ES-LCMS m/z 574 (M+H) Rt=2.7 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)[C:5]([NH:16][CH:17]=O)=[C:4]([Cl:19])[N:3]=1.C(OC(OCC)OCC)C.Cl>CO.[OH-].[Na+]>[ClH:19].[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:16]=[CH:17][N:8]2[C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)=[C:4]([Cl:19])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(OCC)OCC
Solvent: CO
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reaction time: 4 h
Yield: 184.4 %

Procedure:
A mixture of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (Example 7, 1.00 g, 3.50 mmol) and triethylorthoformate (Aldrich, Sure Seal, 18 mL) was stirred while concentrated hydrochloric acid (37%, 1.25 mL) was added in one portion. The resulting clear, colorless solution was stirred under nitrogen. A white precipitate began to form after 15 minutes. After 4 hours, TLC of a drop of the reaction mixture dissolved in methanol and neutralized with sodium hydroxide (silica gel plates developed in 10% methanol-chloroform, visualized in UV light) showed almost complete conversion of VIa to a higher-Rf material. The precipitate was filtered, washed with t-butyl methyl ether (15 mL) and dried at 0.2 mm Hg/25° C. for 18 hours to give the title compound as a white powder (975 mg, 92%), m.p.>300° C. dec.; mass spectrum (CI/CH4): 266(M+1); 1H-NMR (DMSO-d6)δ: 8.18 (s, 1, purine CH), 7.2-6.7 (br s, NH2, OH overlapped by water), 6.20 and 5.90 (both m, 1 each, CH═CH), 5.48 (m, 1, NCH), 3.47 (d, J=5.7 Hz, 2, CH2O), 2.90 (m, 1, CH), 2.75-2.55 and 1.75-1.60 (both m, 1 each, CH2).