Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]1[C:26]2[C:27](=[O:52])[N:28]3[CH2:43][C@H:42]([O:44][Si](C(C)(C)C)(C)C)[CH2:41][C@H:29]3[C:30](=[O:40])[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=2[CH:24]=[CH:23][C:22]=1[O:53][CH3:54]>C1COCC1.C(Cl)Cl>[CH3:19][O:20][C:21]1[C:26]2[C:27](=[O:52])[N:28]3[CH2:43][C@H:42]([OH:44])[CH2:41][C@H:29]3[C:30](=[O:40])[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:37])[CH3:38])[C:25]=2[CH:24]=[CH:23][C:22]=1[O:53][CH3:54]
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
A solution of 1 N TBAF in THF (19.58 mL, 19.58 mmol) was added to a stirred solution of 172 (7.0 g, 13.05 mmol) in THF (50 mL). The reaction mixture was allowed to stir at room temperature for 2 hours and diluted with DCM (200 mL), washed with water (2×200 mL), brine (2×200 mL) and dried over anhydrous MgSO4. Filtration and removal of excess solvent afforded the crude product, which was purified by flash column chromatography using 50:50 petroleum ether:EtOAc as eluent. Evaporation in vacuo of the pure fractions afforded the product (173) (5.9 g). 1HNMR (270 MHz, CDCl3) δ 7.30 (s, 1H, ArH), 7.24 (s, 1H, ArH), 5.52 (d, 1H, J=9.9 Hz, SEM amino acetal CH2), 4.68-4.64 (m, 2H, SEM amino acetal CH, +2), 4.30 (dd, 1H, J=5.86, 8.24 Hz), 3.91 (s, 3H, OMe), 3.90 (s, 3H, OMe), 3.87-3.51 (m, 4H, SEM 1′ CH2+3), 2.95 (dt, 1H, J=5.31, 13.56 Hz, 1), 2.17-2.08 (m, 1H, 1), 1.02-0.93 (m, 2H, SEM 2′ CH2), 0.03 (s, 9H, 3×SiCH3); 1C NMR (67.8 MHz, CDCl3) δ 169.7, 165.9, 151.9, 147.1, 134.0, 121.1, 111.2, 105.5, 78.2, 69.1, 67.1, 56.5, 56.1, 53.9, 34.9, 18.4, −1.3.
Reaction SMILES: CC1(C)CC(O)CC(C)(C)N1[O:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=3)([CH2:16][CH2:17]1)[O:14][CH2:13]2.CC(O)=O.O>C1COCC1.[Zn]>[O:26]([C:22]1[CH:21]=[C:20]([C:15]23[CH2:18][CH2:19][C:12]([OH:11])([CH2:17][CH2:16]2)[CH2:13][O:14]3)[CH:25]=[CH:24][CH:23]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.4 %

Procedure:
A mixture of 96B [2,2,6,6-tetramethyl-1-((1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)oxy)piperidin-4-ol] (140 mg, 0.310 mmol), activated zinc dust (203 mg, 3.10 mmol), and HOAc (3.55 mL, 62.0 mmol) in THF (1 mL)/water (0.5 mL) was stirred at rt for 3 days, then was filtered. The filtrate was dissolved in EtOAc (5 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed [SiO2; continuous gradient of EtOAc/hexane (0% to 50% over 10 min)] to give the title compound (62 mg, 0.209 mmol, 68% yield) as a clear oil. [M+Na]+=319.1; 1H NMR (CDCl3) δ: 7.38-7.27 (m, 3H), 7.20-7.09 (m, 3H), 7.06-6.99 (m, 2H), 6.92-6.86 (m, 1H), 3.88 (t, J=1.6 Hz, 2H), 2.24-2.12 (m, 4H), 2.01-1.84 (m, 4H), 1.70 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]=[C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10]2)[CH:2]=1.ON1C(=O)C2C=CC=CC=2N=N1.Cl.[CH3:38][O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH2:42].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH3:38][O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH:42][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)C1=C(Oc2ccccc2)CC(=COc2cccnc2)C=C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a solution in DMF (3 mL) of 4-(3-pyridyloxymethylene)-2-phenoxybenzoic acid (321 mg), prepared as in Example 157F, was added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (345 mg, 1.5 mmol) followed by methionine methyl ester hydrochloride (300 mg, 1.5 mmol), ethyl dimethylaminopropyl carbodiimide hydrochloride (288 mg, 1.5 mmol), and triethylamine (280 mg). The reaction mixture was stirred for 15 hours at ambient temperature. The reaction mixture was diluted with water and extracted with toluene. The toluene solution was washed with, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (75% ethyl acetate-hexanes) gave [4-(3-pyridyloxymethyl)-2-phenoxybenzoyl]methionine methyl ester (425 mg, 98%).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=[CH2:2].Cl.C(OCC)C.[OH-].[Na+]>ClCCl>[CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)=[CH2:2]
Reactant: C=Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: C=Cc1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(4-ethenyl-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 4, Step A) (471 mg, 1.6 mmol) in dichloromethane (5 mL) was added a solution of hydrogen chloride in diethyl ether (2.0 M, 7 mL, 14 mmol). The reaction mixture was stirred under nitrogen at room temperature for 4 h, and then 1 N aqueous sodium hydroxide solution was added until pH of the reaction mixture increased to about 10. The resulting mixture was extracted with dichloromethane (2×). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 302 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:65]1([CH2:71][C:72]([NH2:74])=[O:73])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@H:9]2[C:28]([N:68]2[CH2:69][CH2:70][N:65]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:66][CH2:67]2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCN(CC(N)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (5 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA (0.145 mL, 0.83 mmol) and 2-piperazin-1-yl-acetamide (Chembridge, 45 mg, 0.21 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 87 mg.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.[N:13]#[C:14][C:15]#[N:16].N1C=CC=CC=1>CN(C)C=O>[C:14]([C:15]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:16]=1)#[N:13]
Reactant: Cc1ccc(C(=O)CN)cc1
Reactant: N#CC#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(-c2c[nH]c(C#N)n2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
2.0 g (11 mmol) of 2-amino-4'-methylacetophenone hydrochloride was measured out in a 100-ml round bottom flask. To the material was then added 40 ml (40 mmol) of a 1 mol/l N,N-dimethylformamide solution of cyanogen at a temperature of 0° C. To the mixture was then added 1.7 g (22 mmol) of pyridine. The mixture was then heated at a temperature of 60° C. with stirring for 18 hours. The reaction mixture was then allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography to obtain 1.55 g (yield: 77 %) of 2-cyano-4- (p-tolyl)imidazole.
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>C1(C)C=CC=CC=1>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1CCCCC1
Reactant: Clc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(c2nccs2)CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of cyclohexanecarbonitrile (0.913 g, 8.36 mmol) in toluene (25 ml) at 0° C. was added sodium bis(trimethylsilyl)amide (1M solution in THF, 10.0 ml, 10.0 mmol) and the resulting mixture was stirred for 1 hr at 0° C. 2-Chlorothiazole (1 g, 8.36 mmol) was then added dropwise as a solution in toluene (0.5 mL) over a period of 5 minutes and the resulting mixture was allowed to warm up from 0° C. to room temperature over 16 hrs. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (60 mL, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 2% to 12% EtOAc in Hexanes) to afford 1-(1,3-thiazol-2-yl)cyclohexanecarbonitrile (686 mg, 3.57 mmol, 42.7% yield) as a pale yellow oil which solidified upon standing. MS ESI: [M+H]+ m/z 193.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[NH:42][C:41]2[C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][C:48](=[NH:51])[NH:49]O)[C:38](=[O:52])[N:37]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]=2[N:35]=1>CS(C)=O>[Cl:33][C:34]1[NH:42][C:41]2[C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][C:48]3[N:49]=[C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][N:51]=3)[C:38](=[O:52])[N:37]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]=2[N:35]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCn1c(=O)n(CCCCC(=N)NO)c(=O)c2[nH]c(Cl)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: CCCCCn1c(=O)n(CCCCc2noc(-c3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 40 °C
Reaction time: 5 h
Yield: 25.1 %

Procedure:
Benzoic acid (18 mg, 0.15 mmol) was treated with a solution of 1H-1,2,3-benzotriazol-1-ol hydrate (25 mg, 0.19 mmol) in DMSO (0.3 ml). To this was added a solution/suspension of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) in DMSO (0.3 ml) followed by a solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (55 mg, 0.15 mmol) in DMSO (0.3 ml). The mixture was heated at 40° C. for 1 h, then at 80° C. for 5 h and then cooled. The mixture was subjected to purification by MDAP. Product-containing fractions were blown to dryness by a stream of nitrogen to yield the title compound as a white solid (17.2 mg, 25%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6][Si](C)(C)C.[O:14]1[CH2:18][CH2:17][C:16](=O)[CH2:15]1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>[N+](C)([O-])=O>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6][CH:16]1[CH2:17][CH2:18][O:14][CH2:15]1
Reactant: O=C1CCOC1
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: COC(=O)C(C)(C)COC1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
2,2-Dimethyl-3-trimethylsilanyloxy-propionic acid methyl ester (478 mg, 2.34 mmol) was added to a solution of dihydro-furan-3-one (168 mg, 1.95 mmol) and FeCl3 (16 mg, 0.097 mmol) in nitromethane (6.0 mL) at 0° C. Triethylsilane (0.374 mL, 2.33 mmol) was added and the reaction was warmed to room temperature and stirred for 2 h. Sat. NaHCO3 was added and the reaction was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to give a pale liquid. Purification by flash column chromatography on silica gel using 30% ethyl acetate in hexanes provided dimethyl-3-(tetrahydro-furan-3-yloxy)-propionic acid methyl ester (353 mg, 75%) as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]2[NH:30][N:31]=[CH:32][C:25]=12.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([N:13]3[CH2:14][CH2:15][N:16]([C:24]4[N:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)[CH2:17][CH2:18]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:20])[F:21]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: Fc1ccc(-c2cnc(N3CCNCC3)[nH]2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(-c2cnc(N3CCN(c4ncnc5[nH]ncc45)CC3)[nH]2)cc1C(F)(F)F
Yield: 79.7 %

Procedure:
Combine 1-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazine (195 mg, 1.00 equiv; 0.620 mmoles); 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 equiv; 0.620 mmoles; 96 mg); isopropyl alcohol (3 mL); diisopropylethylamine (1 mL) and heat in a microwave reactor at 80° C. for 60 min. Evaporate the reaction mixture and purify on silica gel with 5% MeOH/DCM. Combine the fractions to give 213.2 mg (0.494 mmol, 80%) of 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine. Dissolve the free base in DCM/MeOH and add 1.0 eq 1M HCl in ether. Concentrate the mixture to give 237.2 mg 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine hydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:42](=[O:43])[C:41]2[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=2[CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CCc1ccc(N)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCc1ccc(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 4-ethylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(4-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (87%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, DMSO-d6) δ10.50 (s, 1H), 7.68-7.55 (m, 3H), 7.49-7.35 (m, 2H), 7.23-7.10 (m, 5H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.39 (s, 1H), 5.15-4.99 (m, 2H), 4.83 (d, J=8.9 Hz, 1H), 4.68 (d, J=8.9 Hz, 1H), 4.46 (t, J=8.7 Hz, 2H), 2.99-2.85 (m, 2H), 2.54 (q, J=7.5 Hz, 2H), 1.14 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 167.4, 161.6, 161.2, 142.8, 139.7, 137.2, 136.7, 134.4, 132.7, 130.8, 129.1, 129.3, 127.8, 127.1, 124.1, 123.6, 120.9, 120.4, 120.3, 119.6, 109.7, 92.9, 80.4, 72.6, 57.4, 41.5, 28.8, 28.1, 16.3; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [N:1]([C@:4]1([CH2:19][OH:20])[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][C@@H:5]1[OH:18])=[N+:2]=[N-:3].P(Cl)(Cl)([O:23][P:24](Cl)(Cl)=[O:25])=O.C(=O)(O)[O-:31].[Na+:34].C>C(OCC)(=O)C>[Na+:34].[Na+:34].[P:24]([O:20][CH2:19][C@@:4]1([N:1]=[N+:2]=[N-:3])[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][C@@H:5]1[OH:18])([O-:23])([O-:31])=[O:25]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@](CO)(N=[N+]=[N-])O2)c(=O)[nH]c1=O
Reactant: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cn([C@H]2C[C@H](O)[C@](COP(=O)([O-])[O-])(N=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of 4'-azidothymidine (0.20 g, 0.71 mM) in ethyl acetate (12 mL) cooled to 0° C. was added pyrophosphoryl chloride (0.5 mL, 3.7 mM). After stirring for 4 hours at 0° C., the solution was neutralized (pH 6 to 7) by the addition of saturated aqueous sodium bicarbonate. The organic phase was discarded, and the aqueous phase was stirred for 20 minutes with activated, 14-60 mesh, charcoal. The charcoal mixture was filtered and the charcoal rinsed with water (200 mL). All filtrates and rinsings were discarded. The charcoal was next washed with 50% aqueous ethanol containing 5% ammonium hydroxide (250 mL). These washings were concentrated in vacuo to about 5 mL and applied onto a 3×23 cm column of DEAE Sephadex (carbonate form). The column was eluted with a linear gradient consisting of 1 L of water and 1 L of 0.5M triethylammonium bicarbonate (pH 7). Pure product was collected and the solvent removed by evaporation. The residue was co-evaporated repeatedly with water, then dissolved in methanol (0.5 mL). The addition of 0.45M sodium perchlorate in acetone (2 mL) to this solution caused the title compound to precipitate out. Filtering off the solid and drying under vacuum left 55 mg of 4'-azidothymidine 5'-monophosphate disodium salt (mp 185° C., decomposition).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([P:18]([O:21]C)[O:19][CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOC(C)=O>[CH3:20][O:19][P:18]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:21]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: COP(OC)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(P(=O)(OC)c2ccccc2)cc1
Temperature: 160 °C

Procedure:
From a related procedure (Helv. Chim. Acta, 2004, 87, 825) a mixture of methyl 4-bromobenzoate (676 mg, 3.14 mmol), anhydrous NiBr2 (34.3 mg, 0.157 mmol), and PhP(OMe)2 (0.500 mL, 3.14 mmol) was added to a pressure vessel and heated to 160° C. (oil bath temperature) for 2 h. The reaction was cooled, diluted with EtOAc and washed with water (3×), brine, dried (MgSO4) and concentrated to afford ˜800 mg of a clear, colorless oil that solidified upon standing. The product was purified by MPLC (15-50% EtOAc in CH2Cl2) to afford the requisite product: MS: cal'd 291 (MH+), exp 291 (MH+).
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[C:19]([Mg]Br)[CH:18]=1.C1COCC1>>[OH:15][C@H:4]([C:19]1[CH:18]=[C:17]([CH3:25])[CH:22]=[CH:21][CH:20]=1)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Cc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1cccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)c1

Procedure:
The subtitle compound was prepared in two steps analogous to the methods described in Example 19 (step 19c+19d). Starting from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (2.323 g, 10 mmol), and m-tolylmagnesium bromide 1.0M solution in THF (12.00 mL, 12.00 mmol). Yield 2.33 g (88%)
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[CH:20][C:19]=1[F:30].CC(=O)OCC>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[CH:20][C:19]=1[F:30]
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Reactant: C=C(c1ccc(F)c(Cl)c1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4ccc(F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.7 %

Procedure:
To a solution of (Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (239 mg, 1.0 mmol) and 2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (240 mg, 1.07 mmol) in DMF (5 mL) at rt was added TEA (108 mg, 1.07 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to give the final title compound 5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (140 mg; yield 30.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.80-7.70 (m, 4H), 7.64-7.60 (m, 2H), 4.43 (d, J=18.4 Hz, 1H), 4.27 (d, J=18.4 Hz, 1H), 1.48 (s,6H) ppm; HPLC purity: 96.0% at 220 nm and 96.4% at 254 nm; MS: m/z=428.1 (M+, ESI+).