Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35](O)=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc12
Yield: 66.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(3,4-difluorophenyl)piperidine-1-carbonyl]-7-(2,5-dimethylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.20 mmol) obtained in step 4 and ethanesulfonamide (105 mg, 1.0 mmol), the title compound (79 mg, 66%) was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.[CH3:29][O-:30].[Na+]>CO.[Cu]I>[CH2:17]([CH:16]([C:15]1[N:10]2[N:9]=[C:8]([CH3:22])[C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[O:30][CH3:29])=[C:11]2[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Br)c(C)nn12
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3OC)c(C)nn12
Temperature: 25 °C
Yield: 13.8 %

Procedure:
Stir a mixture of 3-(4-bromo-2-morpholin-4-yl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (162 mg, 0.35 mmol), sodium methoxide (57 mg, 1.05 mmol) and copper(I) iodide (67 mg, 0.35 mmol) in methanol (3 mL) in a sealed 4-mL vial for 15 h at 120° C. Cool to room temperature, remove the solid by filtration, and concentrate the filtrate under vacuum. Purify the residue by flash chromatography, eluting with hexanes/THF (10/2). Recrystallize the material from methanol to give the title compound (20 mg). ES/MS m/z 416.0 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:15][C:14]2=[CH:38][CH:39]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[F:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([NH:27][C@H:16]2[CH2:15][C:14]3=[CH:13][CH:12]=[C:11]([CH:39]=[CH:38]3)[O:10][CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]([CH:3]=[O:2])[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:24])[CH3:25])[NH:18][C:17]2=[O:26])(=[O:29])=[O:30])=[CH:36][CH:35]=1
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H]1NC(=O)[C@@H](NS(=O)(=O)c2ccc(F)cc2)Cc2ccc(cc2)OCCCC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 53 (100 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.98 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 16 mg, 17%. Rf=0.35 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25](N(OC)C)=[O:26])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25](=[O:26])[CH3:31])[CH2:20]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To an ice-cooled solution of 3-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylbicyclo[3.1.0]hexane-6-carboxamide (37 g, 87 mmol) in anhydrous tetrahydrofuran (500 mL) was added dropwise methylmagnesium bromide (87 mL, 262 mmol, 3.0 M in diethyl ether). After 3 h, saturated aqueous ammonium chloride was added to the reaction mixture. The resulting aqueous solution was extracted with ethyl acetate (3×100 mL). The combined organics were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude 1-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)ethanone as a light brown solid (30.0 g, 91%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28]OS(C)(=O)=O)[CH2:24][CH2:23]2)=[O:20])[C:15]([CH3:18])=[N:16][CH:17]=1>C(#N)C.O>[Cl:11][C:12]1[CH:17]=[N:16][C:15]([CH3:18])=[C:14]([CH:13]=1)[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][N:4]2[C:3]([CH3:8])=[C:2]([Cl:1])[C:6]([CH3:7])=[N:5]2)[CH2:24][CH2:23]1)=[O:20]
Reactant: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: Cc1n[nH]c(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](Cn2nc(C)c(Cl)c2C)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-chloro-3,5-dimethyl-1H-pyrazole (step 5a)(37 mg, 0.283 mmol) in dry acetonitrile (4.5 mL) at room temp is added sodium hydride (14 mg of a 60% dispersion in mineral oil, 0.353 mmol). The mixture is stirred at room temp for 10 minutes before trans-methanesulfonic acid 4-[(5-chloro-2-methyl-pyridine-3-carbonyl)-amino]-cyclohexylmethyl ester (step 4) (85 mg, 0.236 mmol) is added in one portion. The mixture is heated at 120° C. for 30 minutes using microwave radiation. After cooling to RT, the reaction mixture is diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The EtOAc extracts are combined, washed with saturated brine (10 mL), dried (MgSO4), filtered and evaporated to give a colourless foam. Purification by chromatography on silica gel using a 12 g pre-packed column eluting with 0-100% EtOAc affords the title compound as a colourless solid. MS m/z 395.3/397.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 8.39 (1H, d), 7.78 (1H, d), 3.83 (2H, d), 3.67 (1H, m), 2.47 (3H, s), 2.20 (3H, s), 2.09 (3H, s), 1.89 (2H, m), 1.73 (1H, m), 1.57 (2H, m), 1.16 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:32])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH2:66]([N:73]1[C:77]2[CH:78]=[CH:79][C:80]([CH2:82]O)=[CH:81][C:76]=2[N:75]=[CH:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1(C)C=CC=CC=1>[CH2:66]([N:73]1[C:77]2[CH:78]=[CH:79][C:80]([CH2:82][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:6][CH:7]4[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:8]4=[O:32])=[CH:33][CH:34]=3)=[CH:81][C:76]=2[N:75]=[CH:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: OCc1ccc2c(c1)ncn2Cc1ccccc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: O=C1SC(Cc2ccc(OCc3ccc4c(c3)ncn4Cc3ccccc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A mixture of 822 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 454 mg of azodicarbonyldipiperidine, 6 ml of dehydrated toluene and 0.44 ml of tributylphosphine was stirred for 30 minutes at room temperature. At the end of this time, 349 mg of 1-benzyl-5-benzimidazolemethanol were added to the reaction mixture and then the mixture was stirred for 3 hours, after which it was allowed to stand for 10 days at room temperature. The solvent was then removed by distillation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane in ratios ranging from 3:1 to 1:0 by volume as the eluent, to give 0.32 g of the title compound, softening at 90°-91° C.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.COCN[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>O1CCCC1.CCCCCC>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: COc1ccccc1OC
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of veratrole (16.6 g, 0.120 mol) in tetrahydrofuran (130 mL) at −78° C. was added n-butyllithium (50.5 mL, of a 2.5 M solution in hexane, 0.126 mmol). The resulting mixture was allowed to warm to ambient temperature over 1 hour and then stirred at this temperature for 4 hours before recooling to −78° C. and treating the resulting slurry with a solution of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) (30.71 g, 0.1128 mol) in tetrahydrofuran (180 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight and then recooled to 0° C. and quenched by the addition of saturated aqueous ammonium chloride solution (110 mL). The aqueous layer was extracted with ether (110 mL) and the combined organic extracts were washed with brine (220 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (7).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: COc1ccccc1N
Reactant: COC(=S)c1cc(Br)c(C)s1
Product: COC(=S)c1cc(Nc2ccccc2OC)c(C)s1
Yield: 68.9 %

Procedure:
A stirred suspension of 103 mg (0.386 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 57 mg (0.46 mmol, 1.2 eq) of 2-methoxyaniline (Aldrich, Milwaukee, Wis.) was treated in a manner similar to Example 241, step (b) to give 78 mg the title compound (65%) as a yellow oil. 1H-NMR (CDCl3, 400 MHz) δ7.82 (s, 1H), 7.12-6.52 (m, 4H), 6.52 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.40 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C14H15NO3S2, 310.1 (M+H), found 310.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
1-Chloro-4-fluoro-2-methyl-5-nitrobenzene (D22) (1.5 mmol, 284 mg) in dimethylformamide (5 mL) was treated under argon at room temperature with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 194 mg, 1 eq) then stirred at 75° C. overnight. The mixture was concentrated under reduced pressure, treated with 10% Na2CO3 aqueous solution and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a clean orange solid (1.46 mmol, 539 mg, 97% yield). M−H=368.16.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[N:14][C:15]([NH:16][C@@H:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18]O)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl>C(Cl)Cl>[C:1]1([N:7]2[C:11]3[N:12]=[CH:13][N:14]4[CH2:18][C@H:17]([CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:16]=[C:15]4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H](Cc1ccccc1)Nc1ncnc2c1cnn2-c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C1=Nc2c(cnn2-c2ccccc2)C2=N[C@@H](Cc3ccccc3)CN12

Procedure:
Next, 300 mg of the above product (S)-β-[(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol was dissolved in 15 ml CH2Cl2 followed by addition of 0.44 ml SOCl2. The reaction was heated to reflux for 3.5 hours. The solvent was then removed under a stream of nitrogen. The white solid was recrystallized from about 30% isopropyl alcohol/hexane followed by a second recrystallization from about 5%MeOH/butanone to yield 45 mg of (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-3H-imidazo[1,2-c]pyrazolo[4,3-e]-pyrimidine after drying under vacuum at 39° C. for 5 days (m.p. 255° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH2:15](Br)/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18]>CN(C=O)C>[CH3:18]/[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:16]\[CH2:15][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/COc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (114 mg, 0.7 mmol) and 4 mL of anhydrous DMF were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask and the solution was kept stirring at 0° C. for 30 minutes. Geranyl bromide (329 μL, 1.66 mmol) in 1 mL of anhydrous DMF was cooled to 0° C. and added dropwise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen at room temperature for 14 hours. The desired product was isolated by column chromatography using a solvent system of 100% Hexanes, 20:1 Hexanes:Ethyl acetate, 15:1 Hexanes:Ethyl acetate, 10:1 Hexanes:Ethyl acetate, 7:3 Hexanes:Ethyl acetate, and 2:1 Hexanes:Ethyl acetate. The purified product was characterized by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). 1H-NMR (300 MHz, CDCl3): ∂ 1.61-1.84 (9H), 2.13 (m, 4H), 4.57 (d, 2H, J=6 Hz), 5.1 (m, 1H), 5.48 (t, 1H), 6.43 (d, 1H, J=9 Hz), 6.93-7.67 (4H); 13C-NMR (75 MHz, CDCl3): ∂ 18.0, 18.2, 26.25, 26.38, 39.06, 65.20, 111.08, 117.01, 117.83, 118.89, 119.14, 119.70, 123.88, 131.94, 141.44, 143.27, 148.41, 155.33, 161.06. HRMS (CI) Calcd. for C19H23O3: 299.16473. found: 299.16377.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][S:24]([O:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:4]2([CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH:10]=1)(=[O:26])=[O:25]
Reactant: CC1(c2cccc(CO)c2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cccc(COS(C)(=O)=O)c2)OCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-methanol (1.68 g, 8.65 mmol) in dry CH2Cl2 (20 mL) was treated at 0° C. with Et3N (1.60 mL, 11.38 mmol) followed by DMAP (109 mg, 0.88 mmol) and Ms-Cl (0.80 mL, 10.13 mmol). After stirring at 0° C. for 0.5 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 0:1) to give pure (3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl)methyl methanesulfonate as a white solid. Part of this material (300 mg, 1.10 mmol) was dissolved in dry DMF (5 mL) and treated with NaN3 (220 mg, 3.35 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 3-(azidomethyl)-(2-methyl-[1,3]dioxolan-2-yl)benzene as a yellow oil. LC-MS-conditions 02: tR=0.99 min.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:22]2[CH2:23][CH2:24][CH:19]([C@@H:17]([NH:16][C:12]3[N:11]=[C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])[CH:15]=[CH:14][N:13]=3)[CH3:18])[CH2:20][CH2:21]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCNCC2)n1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)n1
Yield: 1.3 %

Procedure:
A solution of (S)-4-isopropyl-3-(2-((S)-1-(piperidin-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (225 mg, 0.675 mmol), 4-fluorobenzene-1-sulfonyl chloride (146 mg, 0.750 mmol) and DIPEA (1 ml) in CH2Cl2 was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with water. Aqueous layer was extracted with CH2Cl2. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (S)-3-(2-((S)-1-(1-(4-fluorophenylsulfonyl)piperidin-4-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (4.5 mg, 0.009 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]([S:5][C@H:6]1[N:9]([C:10]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[O:31])=[P:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:43])[C@@H:7]1[C@H:44]([O:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=1)=[O:48])[CH3:45])=[O:4].N1C=CC=CC=1.[C:66](OC(=O)C)(=[O:68])[CH3:67]>C(Cl)Cl>[C:66]([O:1][CH2:2][C:3]([S:5][C@H:6]1[N:9]([C:10]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[O:31])=[P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:8](=[O:43])[C@@H:7]1[C@H:44]([O:46][C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([N+:57]([O-:59])=[O:58])=[CH:55][CH:56]=1)=[O:48])[CH3:45])=[O:4])(=[O:68])[CH3:67]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)CO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)S[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A stirred solution of 4(R)-hydroxyacetylthio-3(S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl]-1-(1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-azetidin-2-one (418 mg, 0.5 mmole) in CH2Cl2 (5 ml) was sequentially treated with pyridine (162 mg) and acetic anhydride (90 mg) and then stirred at room temperature for six hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH2:17])[C:6]([O:8]CC)=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:37][C:38](O)=[O:39])[CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])=[O:28].CCN(CC)CC.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][C:38](=[O:39])[CH2:37][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[O:28])=[C:20]([O:19][CH3:18])[CH:21]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(OCCN)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)NCCOc2ccc(C(=O)O)cc2OC)ccc1NC(=O)Nc1ccccc1C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-aminoethoxy)benzoate (250 mg, 1.04 mmol) and pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (500 mg, 1.04 mmol) was added Et3N (210 μl, 3.01 mmol), and the resulting mixture was stirred for 2 days. 0.25 N NaOH (20 ml) and THF (20 mL) was added to the mixture and the resulting mixture was heated under reflux overnight. After cooling, the mixture was evaporated and the residue was acidified by the addition of 1 N HCl. The mixture was extracted with CHCl3, and the extract was washed with brine, dried over Na2SO4, and evaporated. The obtained crude solid was recrystallized from CHCl3 to give 110 mg (20% for 2 steps) 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]aminoethoxy]benzoic acid 255 as a white crystalline powder. mp 180-181° C.; IR (KBr) 1687 cm−1; 1H-NMR (DMSO-d6) d 2.24 (s, 3 H), 3.37 (s, 2 H), 3.38 (s, 2 H), 3.41-3.50 (m, 2 H), 3.81 (s, 3 H), 3.83 (s, 3 H), 4.06-4.08 (m, 2 H), 6.76-8.55 (series of m, total 12 H); MS (FAB) m/z 508 (M++1); Anal. Calcd. for C27H29N3O7.1/2H2O: C, 62.78; H, 5.85; N, 8.13. Found: C, 62.46; H, 5.69; N, 8.03.