Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH2:4]([O:11][CH2:12][CH:13]([OH:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.CS(C)=O>C(OCC)(=O)C.O>[CH2:4]([O:11][CH2:12][C:13]([CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:23])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(COCc1ccccc1)COCc1ccccc1
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a dichloromethane (200 ml) solution of 1,3 dibenzyloxy-2-propanol (52 g, 191 mmol), triethylamine (130 ml, 933 mmol), and dimethylsulfoxide (65 ml, 916 mmol), sulfur trioxide pyridine complex (131 g, 823 mmol) was added at 0° C. and stirred at 0° C. to room temperature for 2 hours. To the mixture, water and ethyl acetate were added. The organic layer was washed with 2N hydrochloric acid, water and an aqueous saline solution, dried over anhydrous sodium sulfate, and concentrated. As a result, the title compound (52.01 g, quantitative yield) was obtained as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:20]([CH3:22])[CH3:21].Cl>CN(C=O)C>[CH3:21][CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[CH3:22]
Reactant: CC(C)Br
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OC(C)C)cc1
Reaction time: 8 h

Procedure:
Methyl (4-hydroxyphenyl)acetate (1.0 g, 1.0 eq), Cs2CO3 (2.15 g, 1.1 eq) and 2-bromopropane (0.565 mL. 1.0 eq) were combined in 100 ml DMF at room temperature. The mixture was stirred overnight. The suspension was poured into 50 mL 1 N HCl and extracted with ethyl acetate. The organic phase was separated and washed with water followed by sodium bicarbonate. The organic phase was dried over sodium sulfate and the solvent was evaporated to give an oil. The resulting oil was chromatographed on silica gel using hexanes and ethyl acetate (95:5) to give methyl (4-(1-methylethoxy)phenyl)acetate.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:14]3[N:15]=[CH:16][CH:17]=[C:18]([OH:19])[C:13]=3[CH:12]=[N:11]2)=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].Cl>C(O)C>[Br:1][C:17]1[CH:16]=[N:15][C:14]2[N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:21][CH:20]=3)[N:11]=[CH:12][C:13]=2[C:18]=1[OH:19]
Reactant: BrBr
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(O)c(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Bromine (1.39 mL, 27.03 mmol) was added drop wise over 5 minutes to a solution of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (6.00 g, 23.50 mmol, prepared as described in WO 2007/103308) in absolute ethanol (60 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. 5% Sodium bicarbonate solution (100 mL) was then added, and the mixture was concentrated to give a slurry. The pH was next adjusted with 1N HCl to a pH of 4. The resulting solid was collected by filtration and dried. This solid was then suspended in ether (50 mL), stirred for 10 minutes, collected by filtration and dried to give 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (6.8 g, 87%). MS ESI (+) m/z 334 detected. 1H NMR (400 Hz, DMSO-d6) δ 12.68 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.47 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[H-].[Na+].[CH3:11][O:12][CH2:13]Cl>CN(C=O)C>[CH3:11][O:12][CH2:13][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=1
Reactant: COCCl
Reactant: Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To m-cresol (19.4 mL, 188 mmol) in DMF (1 L) was added NaH (60% disp. in oil, 9.04 g, 0.226 mmol) in several portions. The mixture was stirred at rt for 30 min, chloromethyl methyl ether (11.5 mL, 151 mmol) was added in one portion, and the reaction mixture was stirred at room temperature overnight, partitioned between 1N aq. NaOH and Et2O. The organic phase was washed with 1N aq. NaOH, dried over MgSO4, filtered and concentrated in vacuo, to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.18 (t, 1H), 6.86-6.77 (m, 3H), 5.18 (s, 2H), 3.43 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]([C:17](=[O:19])[CH3:18])[CH2:10][CH2:11][N:12]([C:14](=[O:16])[CH3:15])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=O>>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][N:9]1[C:17](=[O:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1C=C(C(=O)NC(C)(C)C)N(C(C)=O)CC1
Agent: O=O
Product: CC(=O)N1CCN(C(C)=O)[C@H](C(=O)NC(C)(C)C)C1
Reaction time: 20 h
Yield: 130.4 %

Procedure:
8.00 g (29.9 mmol) of 1,4-diacetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide, 10.0 mg (18 μmol) of 1-[1(R)-(di-tert-butylphosphino)-ethyl]-2(S)-(diphenylphosphino)ferrocene and 6.0 mg (16 μmol) of bis(bicyclo[2.2.1]hepta-2,5-diene)rhodium(I) tetrafluoroborate were placed in an autoclave, oxygen being excluded. After flushing with argon, 80 ml of oxygen-free methanol was added. Hydrogenation was carried out at an initial pressure of 50 bar and a temperature of 110° C. for 20 hours. Working-up of the reaction mixture analogously to Example 19 gave 10.50 g (75%) of the title product. GC analysis showed a conversion of 97 percent. After cleavage of the protecting groups with hydrochloric acid, the enantioselectivity of the hydrogenation was determined by GC analysis, giving an ee of 90.7 percent. The melting point of the title compound was: 139.9° to 150.6° C. Other data concerning the title compound was:
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>C(#N)C>[Si:24]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 12 g of 4-anilinophenol (64.7 mmol) in 200 mL of acetonitrile there are added at ambient temperature 6.7 g of imidazole (97.05 mmol) and 11.7 g of tert-butyl(chloro)dimethylsilane (77.64 mmol). The whole is stirred at 70° C. for 4 hours. Then the reaction mixture is poured onto water and extracted with ether. The organic phase is subsequently dried over magnesium sulphate and then filtered and evaporated to dryness. The crude product so obtained is then purified by chromatography over silica gel (petroleum ether/dichloromethane gradient). The title product is obtained in the form of a powder.
Reaction SMILES: [O-]P(OP([O-])([O-])=O)(=O)[O-].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP([O:28][P:29]([O:32][C@H:33]3[O:38][C@H:37]([CH2:39][OH:40])[C@@H:36]([OH:41])[C@H:35]([OH:42])[C@H:34]3[OH:43])([OH:31])=[O:30])(O)=O)[C@@H](O)[C@H]2O)C=1.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>>[CH2:39]([OH:40])[C@H:37]1[O:38][CH:33]([O:32][P:29]([OH:31])([OH:30])=[O:28])[C@H:34]([OH:43])[C@@H:35]([OH:42])[C@@H:36]1[OH:41]
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: O=P(O)(O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The multi-enzyme system (Scheme 15) started with 1-13C-Gal, [99 Atom Percent, purchased from Isotec Inc., Miamisburg, Ohio], GlcNAcβOallyl (Compound 40), [Lee et al., Carbohydr. Res., 37:193 (1974)] phosphoenolpyruvate (PEP), and catalytic amounts of Glc-1-P, ATP and UDP. UDP was converted into UTP with pyruvate kinase (PK; EC 2.7.1.40) and PEP, and UTP reacted with Glc-1-P catalyzed by UDPGP to produce UDP-Glc. The byproduct inorganic pyrophosphate (PPi) was decomposed by inorganic pyrophosphatase (PPase; EC 3.6.1.1). With Gal-1-P UT, UDP-Glc reacted with 13C-Gal-1-P, generated from 13C-Gal and ATP in the presence of GK, to give UDP-13C-Gal and Glc-1-P. The 13C-Gal of UDP-13C-Gal was transferred onto the acceptor (GlcNAcβOallyl) by GalT to give [Gal-1-13C]-containing LacNAcβOallyl (Compound 41). The produced UDP was again converted to UTP by a reaction of PK and PEP, which reacted with the released Glc-1-P to regenerate UDP-Glc. Using this multienzyme system, [Gal-1-13C]-LacNAcβOallyl was obtained in 54 percent yield. The same procedure was also used in the preparation of unlabelled LacNAc and analogs. Exemplary analogs 41a-c are illustrated in the scheme.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(F)cc1N

Procedure:
4,5-Difluoro-2-nitro-phenylamine is a known compound.8 It was reduced with tin (II) chloride dihydrate in ethanol to give the 4,5-difluoro-benzene-1,2-diamine. The diamine was reacted with hexaketocyclohexane octahydrate to give [(HATNA)F6]. The product was purified by train purification (sublimation). The compound is yellow needle like crystal. It is slightly soluble in chloroform. It is very soluble in chloroform/TFA (3:1) mixture.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:6])=[CH:7][C:8]=1[F:9]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(F)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
A mixture of 4,5-difluoro-2-nitroaniline (1.73 g, 10 mmol), palladium on activated charcoal (200 mg), and MeOH (50 mL) was stirred under hydrogen (1 atm) at rt for 12 h. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to afford 4,5-difluorobenzene-1,2-diamine (1.42 g, 97%) as a brown solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 6.50 (m, 2H), 2.75-3.48 (br s, 4H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CC#C.C(=O)=O.[CH2:12]([O:19][CH2:20][CH:21]([CH3:25])[CH2:22][CH:23]=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCCCCC.CCOCC.O1CCCC1>[CH2:12]([O:19][CH2:20][CH:21]([CH3:25])[CH2:22][CH:23]([OH:24])[C:1]#[C:2][CH3:3])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CC=O)COCc1ccccc1
Reactant: [Li]CCCC
Agent: C#CC
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC#CC(O)CC(C)COCc1ccccc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 72.8 ml. (0.146 mole) of 2 M n-butyllithium solution in hexane and 420 ml. of anhydrous tetrahydrofuran was stirred and cooled to -50° C. while 112 ml. of liquified methylacetylene was added dropwise from a dry ice cooled addition funnel. After the addition was complete, the reaction mixture was allowed to warm to reflux temperature (8° C.) (dry ice condenser) and stirred at this temperature for 1 hour. The white slurry was then cooled to 0° C. and stirred while a solution of 14 g. (0.0728 mole) of rac. 4-benzyloxy-3-methylbutanal in 125 ml. of anhydrous tetrahydrofuran was added dropwise. After stirring at 0° C. for 1 hour, the mixture was slowly warmed to 40° C. and stirred at this temperature for 1 hour whereupon the reaction mixture was treated with saturated aqueous ammonium chloride. The product was isolated by ether extraction and worked up as in Example 1. There was obtained 15.4 g. of crude material which was chromatographed on 400 g. of silica gel. Elution with 2:1 parts by volume and 1:1 parts by volume hexane: ether afforded rac. 1-benzyloxy-2-methylhept-5-yn-4-ol as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[S:18][CH:19]=[CH:20][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[S:18][CH:19]=[CH:20][C:11]2=3)=[O:9])=[CH:21][CH:22]=1
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccsc21
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCCC(=O)c3sccc32)cc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a mixture of 2.0 g of 4-(4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin-8-one in 40 ml of glacial acetic acid is added 20 ml of 6N-hydrochloric acid. The mixture is cooled and 3.53 g of iron powder added in portions. The mixture is allowed to warm to room temperature and is heated at 70°-80° C. for 1 hour and then cooled to 0° C. To mixture is basified with 10N NaOH(pH 14) and extracted with 200 ml of ethyl acetate. The aqueous layer is again extracted with 200 ml of ethyl acetate and the extracts combined. The combined extract is washed with 100 ml each of H2O and brine and dried (Na2SO4). The extract is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give a solid which is crystallized from ethyl acetate-hexane to give 1.24 g of crystals, m.p. 216°-218° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C.O.NN.[Cl-].[NH4+].[In]>O.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Yield: 57 %

Procedure:
tert-Butyl 2-(4-nitrophenyl)morpholine-4-carboxylate (I87) (100 mg, 0.324 mmol), activated charcoal (20 mg), iron(III) chloride hexahydrate (9 mg, 10 mol %), methanol (1 mL) and hydrazine hydrate (162 mg, 1.62 mmol @50%) were refluxed together for five hours. The mixture was filtered through cotton, and the cotton washed with DCM (5 mL). The filtrate was evaporated, and redissolved in 95% ethanol (3 mL) and ethyl acetate (2 mL). A solution of ammonium chloride (173 mg. 3.24 mmol) in water (1 mL) was added, followed by indium powder (153 mg, 1.30 mmol). The mixture was refluxed for four hours then filtered. The collected solids were washed with DCM (20 mL) and the combined filtrates then diluted with water (10 mL) and saturated sodium bicarbonate (10 mL). The aqueous phase was washed with DCM (2×25 mL), the combined DCM extracts dried (phase separation filter) and evaporated. The residue was dissolved in 95% ethanol (3 mL), and treated at reflux with further indium powder (153 mg, 1.30 mmol) and ammonium chloride (173 mg. 3.24 mmol) in water (1 mL). After three hours the mixture was diluted with water (10 mL) and filtered. The collected solids were washed sequentially with ethyl acetate (25 mL) and saturated sodium bicarbonate (10 mL). The filtrate aqueous phase was separated, and washed with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (50 mL), dried and evaporated. The residue was chromatographed (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I88) (51.4 mg, 57% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.19-7.12 (m, 2H), 6.71-6.63 (m, 2H), 4.33-4.25 (m, 1H), 4.03-3.85 (m, 3H), 3.73-3.60 (m, 3H), 3.02 (s, 1H), 2.84 (s, 1H). LCMS Method C: rt: 4.72 min; m/z 179.1 [M-Boc+2H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]([OH:20])[CH2:18][C:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[CH:4]([OH:39])[C:5]([C:7]1([CH3:38])[CH:12]([CH:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][CH:10]2[CH2:9][CH:8]1[OH:37])=[O:6].C[C@]12C34OOC5(CCC(C)(C)C[C@H]5[C@]3(C)CC[C@@H]1[C@@]1(C)C[C@@H](O)[C@H](O)C(C)(C)[C@@H]1CC2)C=C4.CC1[C@@H](O)C[C@]2(O)C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]
Reactant: CC(=O)OC12COC1CC(O)C1(C)C(=O)C(O)C3=C(C)C(O)CC(O)(C(OC(=O)c4ccccc4)C21)C3(C)C
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CC1(C)CCC23C=CC4(OO2)[C@@](C)(CC[C@@H]2[C@@]5(C)C[C@@H](O)[C@H](O)C(C)(C)[C@@H]5CC[C@]24C)[C@@H]3C1
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C

Procedure:
Alternatively, C-7 CBZ baccatin III can be synthesized directly from 1 0-deacetylbaccatin III as follows: ##STR9## Here, 10-DAB III is dissolved in THF to form a first solution which is cooled to a reduced temperature of less than -20° C., and preferably to -40° C., under a nitrogen atmosphere. At least two equivalents of n-butyl lithium (1.6 M in hexane) are then added dropwise to the first solution to form a second solution which is then stirred for approximately five minutes at the reduced temperature. Preferably, acetyl chloride (one equivalent) is added to the second solution to form a third solution which is stirred at the reduced temperature for approximately thirty minutes. Alternatively, acetic anhydride (one equivalent) may possibly be used in place of the acetyl chloride to acylate the 10-DAB III. In either case, benzyl chloroformate (one equivalent) is next added, and this fourth solution is stirred for an additional thirty minutes at the reduced temperature and then warmed to 0° C. over thirty minutes. The fourth solution is then quenched with cold saturated ammonium chloride at the reduced temperature to remove any excess n-butyl lithium, acetyl chloride and CBZ-Cl; this mixture is then warmed to room temperature. The solvent is removed under vacuum to yield an initial residue which is taken up in ethyl acetate and washed with water to remove unwanted salts. The organic layer is then washed with brine, dried and concentrated under vacuum to yield a final residue. The final residue is chromatographed (silica gel hexanes:ethyl acetate) to yield C-7 CBZ baccatin III. It is important to note that this method represents a direct synthesis of C-7 CBZ baccatin III from 10-DAB III, as the intermediate formed in this reaction is a C-7 lithium alkoxide of baccatin II, that is, the intermediate is not baccatin III itself.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc(Oc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 92.9 %

Procedure:
A solution of 4-phenoxyphenol (0.56 g, 3.0 mmol), 1-(2-chloroethyl)-pyrrolidine HCl (0.51 g, 3.0 mmol) and powdered K2CO3 (1.2 g, 8.7 mmol) in 30 mL DMF was stirred at 80°-90° C. for 15 hours. The solution was cooled, poured into Et2O and water and the ether layer washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 0.79 g of a brown oil. The crude product was flashed chromatographed on silica gel using a gradient of 2:1 hexane/EtOAc to 100% EtOAc to provide the title compound (0.65 g, 76.5%) as a light yellow oil:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].O.O.O.O.O.O.[Br-].[Mg+2].[Br-]>CO>[CH3:1][O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Br-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2 g of sodium 3-acetoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate were dissolved in 20 ml of 35% v/v aqueous methanol, and 25 g of magnesium bromide hexahydrate were added to the solution. The resulting mixture was heated and stirred at 70° C. for 2 hours, after which it was treated as described in Example 2, to give 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylic acid in the form of a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:18][O:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:7]=1.[Na+].[I-:20]>I>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:6]2[N:7]=[C:2]([I:20])[C:3]3[CH2:18][O:17][CH2:16][C:4]=3[N:5]=2)[CH:13]=1
Reactant: [I-]
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)COC2
Agent: I
Agent: [Na+]
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)COC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]-pyrimidine (78 mg, 0.275 mmol, 1 eq) in 57% HI(aq) (2 ml) at r.t. was added NaI (206 mg, 1.37 mmol, 5 eq). The reaction mixture was stirred at r.t. overnight and then was poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue of 2-(5-Chloro-2-fluorophenyl)-4-iodo-5,7-dihydro-furo[3,4-d]pyrimidine which was not further purified.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 99.6 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (1.719 g, 8.468 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.58 g, 8.468 mmol), triethylamine (3.54 mL, 25.4 mmol) in acetonitrile (6 mL) is heated at 86 C for 2 h. After it is evaporated, the residue is dissolved in methylene chloride, and washed with saturated sodium bicarbonate solution. The organic layer is evaporated to yield 2.6 g (99%) of the title compound as a pale-yellow solid. NMR (CDCl3) showed it is pure.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[OH-].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:20](=[O:22])[CH3:21])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C

Procedure:
To a solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (10 parts) in water (100 parts) containing sodium hydroxide (15 parts) was slowly added acetic anhydride (10 parts) with cooling to keep the temperature below 10°C. An oil separated which solidified on scratching. This was filtered off, washed with water, dried and recrystallised from 90% aqueous ethanol to give 2-acetoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate, melting point 84°-85°C.