Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[C@H:37]12[CH2:43][C@H:40]([NH:41][CH2:42]1)[CH2:39][N:38]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>ClCCl>[C:34]([C:18]1[S:17][C:16]([N:15]2[C:9]3[CH:8]=[C:7]([CH2:6][N:41]4[CH2:42][C@@H:37]5[CH2:43][C@H:40]4[CH2:39][N:38]5[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:12]=[CH:11][C:10]=3[N:13]=[CH:14]2)=[CH:20][C:19]=1[O:21][C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:32])([F:33])[F:31])[CH3:23])(=[O:36])[NH2:35]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate are dissolved in 2.5 ml dichloromethane. Under N2 atmosphere tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (198 mg) is added. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain tert-butyl (1S,4S)-5-{[1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:10][CH2:9][C@H:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:7]1=[O:19].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O1CCCC1>[CH3:16][C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C@H:8]1[CH2:9][CH2:10][N:6]([CH2:5][C:4]#[C:3][CH2:2][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:7]1=[O:19])([CH3:18])[CH3:17]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCBr)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCn2ccnc2)C1=O
Yield: 83.1 %

Procedure:
A solution of 2.0 g of (S)-1-(4-bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2pyrrolidinone, 1.3 g of imidazole and 50 ml of tetrahydrofuran is stirred at room temperature for 72 hours. The solution is concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 2% methyl alcohol/methylene chloride) to give 1.6 g of the desired product as a colorless oil. [α]D26 =-30° (methylene chloride).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC(Br)(Br)Br.CC[O:27]CC>C1(C)C=CC=C(C)C=1>[C:14]1([P:7](=[O:27])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCC
Agent: BrC(Br)(Br)Br
Solvent: Cc1cccc(C)c1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
2.15 gms. of triphenylphosphine and 2.85 gms. of tetrabromomethane were added to a solution of 1.65 gms. of 19-hydroxy cholesterylacetate [prepared according to the method of J. Am. Chem. Soc. 86(1964), 1528] in 70 mls. of dry ether and 10 mls. of dry m-xylene. A white precipitate of triphenylphosphine oxide was formed. Then the mixture was refluxed for 20 hours, the progress of the reaction being examined with the aid of thin-layer chromatography (toluene/ethyl acetate 3:1; silica gel H). After completion of the reaction 100 mls. of n-hexane and 0.5 mls. of methanol were added and approx. 15 minutes later the mixture was filtered and the filtrate evaporated. The residue was taken up in 10 mls. of ether and thereafter 15 mls. of n-hexane were added. Then this hexane/ether mixture was brought on to a column filled with 40 gms. of deactivated Al2O3 and subsequently was eluated with an ether/n-hexane mixture (2:3). The composition of the column fractions was examined with the aid of thin-layer chromatography. The fractions, in which 19-bromocholesterylacetate was present, (Rf = 0.7) were collected and evaporated at a film evaporator. Upon crystallization of the residue from ether/methanol, 1.45 gms. of the product were obtained, having a melting point of 91°-92° C. The structure was confirmed by means of NMR- and mass-spectrometry.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[O]N(S(=O)([O-])=O)S(=O)([O-])=[O:22].[K+].[K+].OP([O-])([O-])=O.C(OCC)C>CN(C)C=O.O>[CH3:8][C:7]1[C:2](=[O:1])[C:3]([CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH3:10])[C:5](=[O:22])[C:6]=1[CH3:9]
Reactant: Cc1cc(C)c(C(O)CCCCCO)c(O)c1C
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1=C(C)C(=O)C(C(O)CCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (formula III-3 wherein R=H3C, X=H, Y=OH, n=4 in the free form) (0.32 part) in dimethyl formamide (20 volume parts) was added all at once a mixture of Fremy's salt (0.5 part) and potasium biphosphate (0.5 part) in water (50 volume parts). The mixture was stirred for 3 hours at room temperature. The reaction product was taken up with diethyl ether. The diethyl ether layer was washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to chromatography on silica gel and eluted with ethyl acetate-diethyl ether (4:1) to give 2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1,4-benzoquinone (formula IV-3 wherein R=H3C, n=4, in the free form) (0.26 part) as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:16])=[N:12]2)=[CH:7][CH:6]=1)=O.[NH3:17]>>[OH:15][C:14]1[C:5]([C:3]([NH2:17])=[O:2])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:16])[CH:10]=[CH:9]2
Reactant: N
Reactant: COC(=O)c1ccc2ccc(C)nc2c1O
Product: Cc1ccc2ccc(C(N)=O)c(O)c2n1

Procedure:
8-Hydroxy-2-methyl-7-quinolinecarboxylic acid methyl ester is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][N:16]([CH3:18])[CH3:17])[CH2:9]2)[N:5]=[C:4]([NH:19][CH3:20])[N:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[F:32])#[N:22]>O1CCOCC1.C([O-])(O)=O.[Na+].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>[CH3:17][N:16]([CH2:15][C@H:10]1[O:11][CH2:12][C@@H:13]([CH3:14])[N:8]([C:6]2[N:5]=[C:4]([NH:19][CH3:20])[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[C:24]([F:32])[CH:25]=3)[CH:7]=2)[CH2:9]1)[CH3:18]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](CN(C)C)OC[C@H]2C)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](CN(C)C)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A mixture of 4-chloro-6-{(2R,5R)-2-[(dimethylamino)methyl]-5-methyl-4-morpholinyl}-N-methyl-2-pyrimidinamine (60 mg, 0.20 mmol), (4-cyano-3-fluorophenyl)boronic acid (73 mg, 0.44 mmol), and Pd(PPh3)4 (12 mg, 0.010 mmol) in 1,4-dioxane (2 mL) and saturated aqueous NaHCO3 (1 mL) was degassed with nitrogen for 10 minutes. The vial was then capped and stirred at 100° C. for 15 hours. The mixture was cooled, diluted with saturated aqueous NaHCO3 (5 mL) and water (5 mL), and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (10 g SiO2, CH2Cl2 to 95/5/0.5 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (58 mg, about 85% purity) as a yellow oil. LC-MS (ES) m/z=385 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:9]1[O:19][C:18]2[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][C:11]=2[O:10]1.[OH-:20].[Na+]>CN(C=O)C>[CH2:9]1[O:19][C:18]2[CH:17]=[CH:16][C:13]([CH2:14][N:1]3[CH2:6][CH2:5][N:4]([CH2:14][C:13]4[CH:16]=[CH:17][C:18]5[O:20][CH2:9][O:10][C:11]=5[CH:12]=4)[CH2:3][CH2:2]3)=[CH:12][C:11]=2[O:10]1
Reactant: C1CNCCN1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: [OH-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc2c(cc1CN1CCN(Cc3ccc4c(c3)OCO4)CC1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine (207 mg) in dry DMF (5 ml) under nitrogen was added sodium hydride (80% w/w in oil, 250 mg), followed by 3,4-methylenedioxybenzylchloride (0.90 g) and the mixture stirred at room temperature overnight. Aqueous NaOH (50 ml, 1M) was added slowly, then saturated NaCl solution (50 ml) and the product extracted with dichloromethane (2×100 ml). The organic layer was washed with water (2×100 ml), dried and evaporated in vacuo to give a white solid. Column chromatography eluting with increasing proportions of ether in dichloromethane gave pure DC-0009B (0.68 g, 80%) as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10](Cl)=[O:11].C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][N:2]1[CH2:13][CH:9]([C:8]([F:15])([F:14])[F:7])[C:10](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CNC(=O)NC
Reactant: C=C(C(=O)Cl)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A solution of 1,3-dimethylurea (168 mg; 1.9 mmoles) in DMF (2 ml) was cooled to 0° C., and α-trifluoromethylacryloyl chloride (317 mg; 2.0 mmoles) and triethylamine (0.31 ml; 2.2 mmoles) were added dropwise. The mixture was stirred at 0° C. for 2 hours, and then water (20 ml) was added. The mixture was extracted with methylene chloride (20 ml×1, 10 ml×2). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel (chloroform) to give 197 mg (yield: 49%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.C(N(C(C)C)C(C)C)C.[C:48]([Si:50]([CH3:53])([CH3:52])[CH3:51])#[CH:49]>CN(C=O)C.[Cu]I>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:49]#[C:48][Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:10][CH:9]=2)[C:5]([C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:26][CH2:27]4)[CH:20]=[N:19][CH:18]=2)=[N:6]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C#C[Si](C)(C)C)cc34)n2)C1
Temperature: 160 °C
Yield: 99.9 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (579 mg, 0.991 mmol), copper(I) iodide (37.7 mg, 0.198 mmol), PdCl2(Amphos) (70.1 mg, 0.099 mmol), N-ethyl-N-isopropylpropan-2-amine (530 μL, 2.97 mmol), and ethynyltrimethylsilane (208 μL, 1.486 mmol) in DMF (9906 μL) was heated in the microwave for 15 min at 160° C. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 20% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (596 mg, 0.990 mmol, 100% yield) as a yellow foam. MS (ESI, pos. ion) m/z: 602.3 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=[CH:2]1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1F>>[ClH:12].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:11][CH:10]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]2[S:1][CH:2]=[CH:3][C:4]1=2
Reactant: OC1CCNCc2sccc21
Reactant: Fc1cccc(Cl)c1Cl
Product: Cl
Product: Clc1cccc(OC2CCNCc3sccc32)c1Cl

Procedure:
The same method as in Example 3 was conducted using 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 35) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:8]([C:7]2[C:6]([CH3:5])=[C:14]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:20][CH:19]=1
Reactant: COc1ccccc1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2C)cc1
Yield: 68.8 %

Procedure:
To a suspension of 95.6 g (0.716 mole) of aluminum chloride in 500 ml of methylene dichloride was added, rapidly and with stirring, a solution of 110.1 g (0.551 mole) of 2-methyl-3-nitrobenzoyl chloride in 400 ml of methylene dichloride. The mixture was then transferred to an addition funnel, added with stirring to a solution of 59.8 g (0.551 mole) of anisole over a thirty minute period, and the reaction mixture then heated under reflux for two hours. The mixture was decomposed by the careful addition, with stirring, of 1 liter of water and then filtered. The organic layer was separated from the aqueous layer, dried and taken to dryness, and the residue recrystallized from ethyl acetate to give 102.9 g of 3-(4-methoxybenzoyl)-2-methylnitrobenzene, m.p. 110°-113° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:38]([O:45][CH2:46][C@@H:47]1[CH2:52][N:51]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=2)[C@@H:50]([CH3:61])[CH2:49][NH:48]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH2:38]([O:45][CH2:46][C@@H:47]1[CH2:52][N:51]([CH2:53][C:54]2[CH:55]=[CH:56][C:57]([F:60])=[CH:58][CH:59]=2)[C@@H:50]([CH3:61])[CH2:49][N:48]1[C:14](=[O:16])/[CH:13]=[CH:12]/[C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Reactant: C[C@H]1CN[C@H](COCc2ccccc2)CN1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 46.7 %

Procedure:
(E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid (168 mg, 0.7 mmol), EDCI (269 mg, 1.4 mmol); HOBT (190 mg, 1.4 mmol) and 230 mg (0.7 mmol) (2S,5S)-5-Benzyloxymethyl-1-(4-fluorobenzyl)-2-methyl-piperazine (prepared as outlined in example 47) were dissolved in 10 ml THF and stirred for 28 hours at room temperature. This mixture was then extracted 3 times with water and once with saturated sodium chloride solution. The title compound was purified by chromatography (SiO2, ethyl acetate/MeOH/NH3conc. 90/10/1) and was isolated as a pale solid (180 mg, 47%)
Reaction SMILES: [OH:1][C@H:2]([CH2:36][O:37][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O)[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@H:31]([CH3:35])[O:30][C:15]1[CH:16]=[C:17]([CH:18]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:1][C@@H:2]([CH2:36][O:37][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:39]([CH3:41])[CH3:40])[CH:42]([CH3:44])[CH3:43])[C@@H:3]([CH3:4])[N:5]=3)=[CH:12][CH:11]=2)[CH:14]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[N:22][CH:21]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
N-[(1R,2S)-2-Hydroxy-1-methyl-3-[(triisopropylsilyl)oxy]propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.69 g, 2.45 mmol) synthesized in Example (89f) was dissolved in tetrahydrofuran (25 mL), and anhydrous methanesulfonic acid (0.88 g, 4.90 mmol) and triethylamine (1.37 mL, 9.80 mmol) were added, followed by stirring at 50° C. for 5 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (40 mL) was added, and the solution was separated with ethyl acetate (60 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (1.23 g, yield 75%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=[O:15])[O:12][CH:11]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH:16]([CH:11]1[C:10]2[CH:19]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][S:30][C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:7]=[CH:8][C:9]=2[NH:14][C:13](=[O:15])[O:12]1)([CH3:18])[CH3:17]
Reactant: CC(C)C1OC(=O)Nc2ccc(OCCCCl)cc21
Reactant: COc1ccc(S)cc1OC
Product: COc1ccc(SCCCOc2ccc3c(c2)C(C(C)C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 1 from 6-(3-chloropropoxy)-4-isopropyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[C@H:10]([O:31]2)[C@H:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)OCc1ccccc1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2O[C@@H]2[C@H]1C(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (6.14 g, 20.2 mmol) were added 3-chloroperbenzoic acid (6.99 g, 40.5 mmol) and 4,4′ thiobis(6-tert-butyl-m cresol) (0.726 g, 2.02 mmol). The mixture was refluxed under nitrogen atmosphere overnight then an additional batch of 3-chloroperbenzoic acid (6.99 g, 40.5 mmol) and 4,4′ thiobis(6-tert-butyl-m cresol) (0.726 g, 2.02 mmol) was added. Refluxing was continued for 24 h. The reaction mixture was diluted with CH2Cl2, washed with sodium metabisulphite aqueous (5%), saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The diastereomeric epoxides in a ratio of 65/35 (determined by NMR on the crude mixture) were separated by flash column chromatography (c-hexane to c-hexane/EtOAc 4:1) to give (1R,2S,5S)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester: TLC, Rf (c-hexane/EtOAc 4:1)=0.20; MS (LC/MS): 220 [MH−Boc]+, 342 [M+Na]+; tR (HPLC conditions f): 2.14 min and (1S,2S,5R)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester: TLC, Rf (c-hexane/EtOAc 4:1)=0.15; MS (LC/MS): 220 [MH−Boc]+, 342 [M+Na]+; tR (HPLC conditions f): 2.03 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4](=O)[C:5]2=O.COP([CH2:18][C:19](=O)[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=O)OC.O.[NH2:27][NH2:28]>>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]1[CH:18]=[C:5]2[C:4]([CH:3]3[C:2]([CH3:11])([CH3:1])[CH:6]2[CH2:7][CH2:8]3)=[N:28][N:27]=1
Reactant: CC1(C)C2CCC1C(=O)C2=O
Reactant: NN
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Solvent: O
Product: CC(C)(C)Cc1cc2c(nn1)C1CCC2C1(C)C

Procedure:
light yellow solid. MS (ESI): 245.2 (MH+). Prepared from 7,7-dimethyl-bicyclo[2.2.1]heptane-2,3-dione, (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]([C@@H:8]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([OH:30])[C@@H:19]([CH2:31][OH:32])[O:18][C@H:9]1[O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N+:6]=[N-:7].O.CCOC(C)=O>N1C(C)=CC(C)=CC=1C>[C:1]([O:32][CH2:31][C@H:19]1[O:18][C@@H:9]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12])[C@H:8]([N:5]=[N+:6]=[N-:7])[C@@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:20]1[OH:30])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1N=[N+]=[N-]
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H](OCc2ccccc2)[C@@H]1O
Temperature: -40 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Acetyl chloride (4.5 mL, 63.3 mmol) was added dropwise to a solution of tert-butyldimethylsilyl 2-azido-3-O-benzyl-2-deoxy-β-D-glucopyranoside (25 g, 61 mmol) in 2,4,6-collidine (110 mL) under nitrogen at −40° C. After stirring at −40° C. overnight, water was added. The mixture was poured into EtOAc and extracted with 1 N HCl, brine and saturated NaHCO3. The organic phase was dried over Na2SO4, filtered and the solvents were removed in vacuo to afford 6 (26.5 g, 58.7 mmol, 96%) as a colorless solid. [α]24D: −27.1 (c 1.00, CH2Cl2); IR (thin film) 3482, 2110, 1743, 1255 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.43-7.30 (m, 5H), 4.96 (d, J=11.4 Hz, 1H), 4.73 (d, J=11.4 Hz, 1H), 4.55 (d, J=7.6 Hz, 1H), 4.34-4.27 (m, 2H), 3.50-3.38 (m, 2H), 3.33 (dd, J=7.6, 9.9 Hz, 1H), 3.21 (dd, J=8.3, 9.9 Hz, 1H), 2.59-2.46 (br s, 1H), 2.09 (s, 3H), 0.96 (s, 9H), 0.18 (s, 6H); 13C-NMR (75 MHz, CDCl3) δ 171.5, 138.1, 128.8, 128.31, 128.28, 97.4, 82.2, 75.3, 73.8, 70.3, 68.3, 63.5, 25.8, 21.1, 18.3, −4.1, −5.0; FAB MS (C21H33N3O6Si) m/z (M+) calcd 451.2138, obsd 451.2135.