Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:32][CH3:33])=[C:14]([C:16](=[N:30][OH:31])[CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1.ClCCl>[C:34]([O:31][N:30]=[C:16]([C:14]1[CH:15]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=[CH:12][C:13]=1[NH:32][CH3:33])[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])(=[O:36])[CH3:35]
Reactant: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NOC(C)=O
Yield: 85 %

Procedure:
A solution of methyl 4-[2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]-2-(hydroxyimino)ethyl]-3-methoxybenzoate (79.9 mg), 4-(dimethylamino)pyridine (22mg), and acetic anhydride (0.17 ml) in dichloromethane (11 ml) was stirred under a nitrogen atmosphere for 15 hours. The solution was diluted with dichloromethane, washed with 5% w/v sodium hydrogen sulfate, water, and brine, then dried (MgSO4), and evaporated to give methyl 4-[2-(acetoxyimino)-2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]ethyl]-3-methoxybenzoate (74.1 mg, 85%) as a pink solid; NMR (80 MHz, CDCl3): 1.2-1.8 [8H, (CH2)4 ], 2.1 (s, 3H, CH3CO), 3.0 (d, 3H, NCH3), 3.3 (dd, 2H, CH2NH), 3.9 (2s, 6H, 2×OCH3), 4.3(s, 2H, ArCH2), 5.8 (broad, 1H, NHCO), 6.7(d, 1H), 7.0 (d, 1H), 7.4-7.6 (m, 3H), 7.8 (d, 1H), 8.5 (broad, 1H, CH3NH).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1)=C.I([O-])(=O)(=O)=[O:15].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[O:13]=[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:15])[CH:12]=2)[CH2:7][CH2:8][NH:9]1
Reactant: C=Cc1ccc2c(c1)C(=O)NCC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 7-ethenyl-3,4-dihydro-1(2H)-isoquinolinone (232 mg, 1.341 mmol) in 1,4-dioxane (15 ml) and water (3 ml) at 0° C. was added sodium periodate (660 mg, 3.08 mmol) and osmium tetroxide (1.5 ml of a 4% aqueous solution). The reaction mixture was warmed to room temperature and stirred for 0.5 h before evaporation of the reaction mixture. The residue was dissolved in 1,4-dioxane (50 ml) and evaporated again. The mixture was then dissolved in dichloromethane (100 ml), dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% ethyl acetate/hexane, gave the product (133 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:50][C:51]1([CH3:57])[CH2:53][C@@H:52]1[C:54](O)=[O:55].CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][N:45]([C:54]([C@H:52]6[CH2:53][C:51]6([CH3:57])[CH3:50])=[O:55])[CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CC1(C)C[C@@H]1C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a mixture of the hydrochloride salt of ((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (60.0 mg, 0.0775 mmol) and (S)-(+)-2,2-dimethylcyclopropane carboxylic acid (10.6 mg, 0.093 mmol) in N,N-dimethylformamide (1.5 mL, 19 mmol) at RT was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yOuronium hexafluorophosphate (35.4 mg, 0.093 mmol) and N,N-diisopropylethylamine (54.0 uL, 0.310 mmol). The reaction mixture was stirred at RT overnight, and then concentrated. The residue was redissolved in 1:1 acetic acid:water (6 mL), filtered and purified by reverse phase preparative HPLC. Desired fractions were combined and freeze dried to give a white solid 34.1 mg). (m/z): [M+H]+ calcd for C43H52N8O5 761.42 found 761.7. 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.76 (s, 1H), 8.18-8.20 (m, 1H), 7.76-7.86 (m, 7H), 7.68-7.7 (m, 2H), 6.95-6.99 (m, 1H), 5.22-5.26 (t, 1H, J=16), 4.59-4.73 (m, 1H), 4.03-4.38 (m, 5H), 3.82-3.89 (m, 1H), 3.69-3.74 (m, 1H), 3.65 (s, 3H), 3.12-3.2 & 3.3-3.5 (m, total 2H), 2.53-2.6 (m, 1H), 2.0-2.3 (m, 4H), 1.75-1.78 & 1.82-1.85 (m, total 1H), 1.25 (s, 3H), 1.12 (s, 3H), 1.07-1.1 & 1.14-1.17 (m, total 1H), 0.96 (s, 3H), 0.88-0.96 & 1.21-1.27 (m, total 6H), 0.76-0.8 (m, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].CN([CH:15]=[N:16][C:17](=[O:19])[CH3:18])C.CCOCC>N1C=CC=CC=1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10]/[N:11]=[CH:15]/[NH:16][C:17](=[O:19])[CH3:18]
Reactant: NNc1cc(F)ccc1Br
Reactant: CC(=O)N=CN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)N/C=N/Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (1.21 g, 5 mmol) in pyridine (3 mL) was added a solution of N-((dimethylamino)methylene)acetamide (600 mg, 5.26 mmol) in pyridine (2 mL) and the mixture stirred at room temperature under nitrogen for 1 h. The precipitate formed was collected, washed with CH2Cl2 and then with ether to obtain 1.15 g (3.16 mmol, 63% yield) of the title compound which was contaminated with 1 mole of dimethylamine hydrochloride as a white crystalline powder: HPLC: 2.22 min (AP 84% at 220 nm); LC/MS m/z 274/276 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.00 (3H, s, 9-Me), 2.51 (6H, s, 2 N—CH3), 6.45 (1H, dt, J=8.5, 3 Hz, 5-CH), 6.89 (1H, dd, J=12, 3 Hz, 3-CH), 7.43 (1H, dd, J=8.5, 6 Hz, 6-CH), 8.68 (1H, d, J=9.5 Hz, 7-CH), 8.88 (2H, br.s, NH2+), 9.24 (1H, s, 7-NH), 10.54 (1H, d, J=9.5 Hz, 2-NH); No signals from the rotational isomer were observed; 13C NMR (CDCl3, 125.8 Hz) δppm 22.6 (9-CH3), 33.9 (2 NCH3), 99.6 (d, J=28 Hz, 3-CH), 99.7 (1-C), 105.0 (d, J=24 Hz, 5-CH), 133.5 (d, J=10.6 Hz, 6-CH), 137.1 (7-CH), 144.9 (d, J=11.6 Hz, 2-C), 162.4 (d, J=244 Hz, 4-CF), 168.5 (8-C═O). No signals from the rotational isomer were observed; Anal. calcd for C9H9BrFN3O.Me2NH.HCl.1/2H2O: C36.24, H4.99, N15.37, found C35.88, H4.87, N15.23. An analytical sample of the title compound without contamination of dimethylamine hydrochloride was obtained by column purification (SiO2, 10-15% EtOAc—CH2Cl2): TLC Rf 0.55 (20% EtOAc—CH2Cl2); HPLC: 2.17 min (AP 88% at 220 nm); LC/MS m/z 274/276 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.99 (3H, s, 9-Me), 6.45 (1H, dt, J=8.5, 3 Hz, 5-CH), 6.88 (1H, dd, J=12, 3 Hz, 3-CH), 7.43 (1H, dd, J=9, 6 Hz, 6-CH), 8.69 (1H, d, J=9.5 Hz, 7-CH), 9.23 (1H, s, 7-NH), 10.52 (1H, d, J=9.5 Hz, 2-NH); About 16% of rotational isomer was also observed as a set of minor peaks: 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.11 (3H, s, 9′-Me), 6.58 (1H, dt, J=8.5, 3 Hz, 5′-CH), 7.10 (1H, dd, J=11.6, 3 Hz, 3′-CH), 7.29 (1H, d, J=2.4 Hz, 7′-CH), 7.50 (1H, dd, J=8.7, 6 Hz, 6′-CH), 8.35 (1H, s, 2′-NH), 10.70 (1H, s, 7′-NH); 13C NMR (DMSO-d6, 125.8 Hz) δppm 22.6 (9-CH3), 99.7 (d, J=29 Hz, 3-CH), 99.8 (d, J=3 Hz, 1-C), 105.0 (d, J=24 Hz, 5-CH), 133.6 (d, J=10.6 Hz, 6-CH), 137.1 (7-CH), 144.9 (d, J=11.6 Hz, 2-C), 162.5 (d, J=241 Hz, 4-CF), 168.5 (8-C═O); 13C NMR (DMSO-d6, 125.8 Hz) δ ppm 22.9 (9′-CH3), 100.7 (d, J=3 Hz, 1′-C), 101.6 (d, J=29 Hz, 3′-CH), 106.8 (d, J=24 Hz, 5′-CH), 133.6 (d, J=9.6 Hz, 6′-CH), 162.4 (d, J=242 Hz, 4′-CF), 168.6 (8′-C═O); HRMS (ESI) calcd for C9H10BrFN3O (M+H) 273.9991, found 274.0004 (δ+4.6 ppm); Anal. calcd for C9H9BrFN3O: C39.43, H3.31, N29.15, found C39.67, H2.99, N29.09.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]1[CH3:10])(=O)C.[O:11]1CC[CH2:13][CH2:12]1>>[C:12]([C:8]1[NH:4][C:5]([CH3:10])=[N:6][C:7]=1[CH3:9])(=[O:11])[CH3:13]
Reactant: C1CCOC1
Reactant: CC(=O)n1cc(C)nc1C
Product: CC(=O)c1[nH]c(C)nc1C
Yield: 41 %

Procedure:
A solution of 6.9 g (0.05 M) of 1-acetyl-2,4-dimethylimidazole in 700 ml of dry tetrahydrofuran was photolyzed in a quartz flask with a short wave ultraviolet light source (254 nm) for 40 hours. The tetrahydrofuran solution was concentrated in vacuo to give an oil which was chromatographed on silica gel using 5% methanol in chloroform as eluent to give 2.8 g (41%) of 5-acetyl-2,4-dimethylimidazole as a white solid, mp 83°-87°. Recrystallization from isopropyl ether gave analytically pure material, mp 87°-88°. nmr (CDCl3) (δ): 2.53 (s, 6H); 2.40 (s, 3H). Anal. Calcd. for C7H10N2O: C, 60.85; H, 7.30; N, 20.27; found: C, 60.66; H, 7.26; N, 20.09.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCCl.CCOCC>[CH:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Temperature: 70 °C

Procedure:
To a stirred solution of tert-butyl (S)-3-cyclohexyl-1-hydroxypropan-2-ylcarbamate (0.23 g, 0.9 mmol) in 1,2-dichloroethane (5 mL), was added Dess-Martin periodinane (0.49 g, 1.34 mmol). The resulting mixture was heated in a CEM microwave synthesizer at 70° C. for 3 min, diluted with ether (100 mL), and washed with 1 N NaOH (2×10 mL). The ether layer was dried over Na2SO4, and the solvent was removed in vacuo to give (S)-tert-butyl 1-cyclohexyl-3-oxopropan-2-ylcarbamate as an oil. MS ESI+ve m/z 256 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 1.26 g (4.27 mmol) of the resulting compound (9) and 1.8 ml (24.8 mmol) of anhydrous triethylamine dissolved in 20 ml of tetrahydrofuran under argon atmosphere was added dropwise 5 ml of an tetrahydrofuran solution containing 0.38 ml (4.08 mmol) of acryloyl chloride. The whole was stirred at room temperature overnight, thereby a salt precipitated. After addition of water to the reaction mixture, the whole was extracted with diethyl ether. The extract was purified by silica gel column chromatography. The resulting pale yellow solid was recrystallized from methanol to obtain 1.01 g of 4-cyano-4'-(6-acryloxyhexyloxy)biphenyl (10) (yield: 67.7%).
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Brc1ccccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ccccn2)cc1
Yield: 90.9 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 2-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) were added. The mixture was degassed and purged withed nitrogen. The mixture was stirred under reflux for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=4 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.81 g of white solid of 4-(pyridin-2-yl)benzoic acid. Yield: 91%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][CH:6]=1)(=[O:4])=[O:3].[Br:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]=[O:19]>C1C=CC=CC=1>[Br:13][CH2:14][CH2:15][N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][N:7]=1)=[O:12]
Reactant: CS(=O)(=O)c1cnc(N=C=O)s1
Reactant: O=CCNCCBr
Solvent: c1ccccc1
Product: CS(=O)(=O)c1cnc(NC(=O)N(CC=O)CCBr)s1
Reaction time: 1 h

Procedure:
5-Methylsulfonylthiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-β-bromoethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-β-bromoethyl-3-(5-methylsulfonylthiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:14])[C:10]([CH3:13])([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]([CH3:11])([CH3:13])[O:12][C:15](=[O:16])[NH:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)C(N)c1ccc(F)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC1(C)OC(=O)NC1c1ccc(F)c(F)c1
Yield: 50 %

Procedure:
A mixture of 1-(3,4-difluorophenyl)-2-methyl-2-hydroxypropylamine (3.00 g, 14.9 mmol) and carbonyldiimidazole (2.418 g, 14.9 mmol) in dichloromethane (150 mL) was heated at reflux temperature for 36 h and the solvent evaporated. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) to give the product as a viscous oil which solidified on standing (1.80 g, 50% yield). The product was used in the next step without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1.C[C@H](N)C1C=CC=CC=1.CCCCCCC>COC(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@H:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Agent: C[C@H](N)c1ccccc1
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: O=C(O)C1=Cc2cc(Cl)ccc2O[C@@H]1C(F)(F)F
Reaction time: 24 h
Yield: 45.8 %

Procedure:
To a solution of 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 1, Step 2)(12.00 g, 43.07 mmol) and (S)(−)-α-methylbenzylamine (2.61 g, 21.54 mmol) in methyl-tert-butyl ether (30 mL) was slowly added n-heptane (200 mL) until the mixture became cloudy. The mixture was heated (steam bath) to boiling and set aside for 24 h during which time crystals formed. Filtration of the suspension yielded a crystalline product (5.5 g) which was recrystallized from methyl-tert-butyl ether (30 mL) and n-heptane (200 mL) yielding upon filtration a white solid (3.1 g). This solid was dissolved in EtOAc (100 mL) and washed with 1 N hydrochloric acid (50 mL) and brine (2×50 mL), dried over MgSO4 and concentrated in vacuo yielding a white solid. Recrystallization of this solid from methyl-t-butyl ether/n-heptane yielded the title compound as the highly enriched isomer, a white solid (2.7 g, 45%): mp 126.7-128.9 ° C. 1H NMR (CDCl3/300 MHz) 7.78 (s, 1H), 7.3-7.1 (m, 3H), 6.94 (d, 1H, J=8.7 Hz), 5.66 (q, 1H, J=6.9 Hz). Anal. Calc'd for C11H6O3F3Cl: C, 47.42; H, 2.17; N, 0.0. Found: C, 47.53; H, 2.14; N, 0.0. This compound was determined to have an optical purity of greater than 90% ee.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[Br:36][C:37]1[CH:38]=[N:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.BrC1C=NC(O)=NC=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[N:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1.[Br:36][C:37]1[CH:38]=[N:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cn1cc(Br)cnc1=O
Agent: Oc1ncc(Br)cn1
Product: C[C@@H](c1ccc(-c2cnc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-methylpyrimidin-2(1H)-one following a procedure analogous to that described in Example 1 Step 3. 5-bromo-1-methylpyrimidin-2(1H)-one was prepared from 5-bromopyrimidin-2-ol following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.068 min, m/z=462.1; 1H NMR (CD3OD) 0.95 (s, 3H), 1.28 (m, 3H), 1.54 (m, 3H), 2.15 (d, 2H), 2.20 (m, 1H), 2.47 (m, 2H), 3.04 (m, 1H), 3.63 (s, 2H), 5.56 (m, 1H), 7.06 (m, 2H), 7.29-7.37 (m, 7H), 8.40 (d, 1H), 8.81 (d, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1
Reactant: OCCc1ccncc1
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCc1ccncc1
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea (0.1 g, 0.24 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol), and triphenylphosphine (0.0944 g, 0.36 mmol) in 10 mL of dry THF was added diisopropylazo-dicarboxylate (0.0728 g, 0.36 mmol) at ambient temperature. The mixture was stirred for 2 hours. Next, additional triphenylphosphine (0.0944 g, 0.36 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol), and diisopropylazodicarboxylate were added and the reaction mixture further stirred at room temperature overnight. The solvent from the reaction mixture was evaporated and the crude residue was dissolved in 5.0 mL of DMSO and purified by RP-HPLC. The proper fractions were collected and concentrated to ¼ volume. The aqueous solution was neutralized with 1N NaOH and extracted with ethyl acetate (2×, 59 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea as a brown solid in 44% yield. LCMS m/z (%)=526 (M+H79Br, 100), 528 (M+H81Br, 67). 1H NMR (DMSO-d6) δ: 9.33 (bs, 1H), 9.24 (bs, 1H), 8.39 (dd, J=4.44 and 1.48 Hz, 2H), 7.63 (d, J=7.28 Hz, 1H), 7.59 (s, 1H), 7.56 (dd, J=8.94 and 2.71 Hz, 2H), 7.48 (m, 1H), 7.34 (d, J=2.67, 1H), 7.31 (d, J=2.67, 1H), 7.28 (dd, J=6.88 and 4.87 Hz, 2H), 7.14 (d, J=9.05 Hz, 1H), 7.09 (d, J=5.93 Hz, 1H), 4.01-4.2 (m, 2H), 3.48 (s, 3H), 2.96-2.91 (m, 2H).
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[F:5][C:6]1[CH:36]=[CH:35][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:26][CH2:27]3)=[CH:16][CH:17]=2)([OH:11])[CH2:2][CH3:3])=[CH:35][CH:36]=1
Reactant: CCBr
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCCCN2CCN(Cc3ccccc3)CC2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(c1ccc(F)cc1)c1ccc(OCCCN2CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a Grignard reactant prepared from 2.4 g. of magnesium turnings and 11 g. of ethyl bromide in 40 ml. of dry ether a solution of 10.8 g. of 4-fluoro-4'-[3-(4-benzyl-piperazin-1-yl)-propoxy]-benzophenone in 200 ml. of dry ether is added dropwise, at -30° C. The reaction mixture is stirred at 0° C. for additional 30 minutes, and is then refluxed for one hour. After cooling the reaction mixture is poured onto a solution of ammonium chloride in ice water. The ethereal phase is separated. The aqueous phase is extracted with ether. The ethereal phases are combined and washed to neutral with water. After drying over anhydrous magnesium sulfate, the solution is evaporated in vacuo. The residue is crystallized from isopropyl ether. 5.3 g. of the end product are obtained, melting at 119° to 121° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(Br)c(N)nc3=O)C[C@@H]2O)cc1
Reaction time: 22 h
Yield: 49.1 %

Procedure:
A solution of 3.06 g of 5-bromo-2'-deoxycytidine and 2.3 g of p-toluenesulfonyl chloride in 50 ml of pyridine was stirred at 4° C. for 24 hours. An additional 1.91 g of p-toluenesulfonyl chloride were added and stirring was continued at 4° C. for an additional 22 hours. 20 ml of methanol were added, the mixture was stirred at room temperature for 30 minutes and then evaporated. The crude product was subjected to flash chromatography on a column of silica gel using ethyl acetate/methanol (9:1) for the elution, there being obtained 2.26 g of 5-bromo-2'-deoxy-5'-O-p-toluenesulfonylcytidine in the form of a white solid of melting point 168° C. (decomposition).