Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[F:56][C:57]1[CH:58]=[C:59]([CH2:65]O)[S:60][C:61]=1[CH2:62][CH2:63][CH3:64]>C1COCC1>[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:65][C:59]3[S:60][C:61]([CH2:62][CH2:63][CH3:64])=[C:57]([F:56])[CH:58]=3)=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCc1sc(CO)cc1F
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCc3cc(F)c(CCC)s3)cc2)nc1

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 4-fluoro-5-propyl-thiophen-2-yl-methanol (prepared by LiAlH4 reduction of methyl 4-fluoro-5-propyl-thiophene-2-carboxylate). After 24 h at room temperature the mixture is evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1([F:27])[CH2:17][CH2:16][C@@H:15]([NH:18][CH2:19][C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)[CH2:14]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:18]([CH2:19][C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)[C@@H:15]2[CH2:16][CH2:17][C:13]([F:12])([F:27])[CH2:14]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C1(CN[C@@H]2CCC(F)(F)C2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
2,4-Dichloro-5-nitropyrimidine (2.16 g, 11.15 mmol) was added to a mixture of (R)-methyl 1-((3,3-difluorocyclopentylamino)methyl)cyclopropanecarboxylate (2.6 g, 11.15 mmol) and sodium bicarbonate (3.75 g, 44.64 mmol) in dichloromethane (15 mL) and petroleum ether (60 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and dried over magnesium sulfate. The solids were filtered off, rinsing with more dichloromethane. The mother liquors were adsorbed on silica gel and concentrated in vacuo. The residue was purified by flash column chromatography to afford the desired product as a yellow solid (3.974 g, 91% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:12][NH2:13]>ClCCl.C(O)C>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:13][CH3:12])[C:8]1=2
Reactant: BrCc1cccc2ccsc12
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNCc1cccc2ccsc12
Reaction time: 8 h

Procedure:
7-Bromomethylbenzo[b]thiophene is dissolved in dichloromethane, added to 40 ml of a 33% solution of methylamine in ethanol and allowed to stand overnight. The resulting mixture is concentrated and the residue taken up in dichloromethane and extracted with 2N HCl. The aqueous phase is made strongly basic with NaOH and shaken with dichloromethane. The organic phase is dried with potassium carbonate, concentrated by evaporation and the residue vacuum distilled to produce the title product as an oil. B.p.=103°/1.3 mbar.
Reaction SMILES: Br.[N:2]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.S(Cl)(Cl)=O.Cl.[CH3:19][NH:20][O:21][CH3:22].N1C=CC=CC=1>Cl.O>[N:2]12[CH2:8][C:5]([C:9]([N:20]([O:21][CH3:22])[CH3:19])=[O:11])([CH2:4][CH2:3]1)[CH2:6][CH2:7]2
Reactant: CNOC
Reactant: CCOC(=O)C12CCN(CC1)C2
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CON(C)C(=O)C12CCN(CC1)C2
Temperature: -30 °C
Yield: 84.6 %

Procedure:
Ethyl 1-azabicyclo[2.2.1]hept-4-yl carboxylate hydrobromide salt (D13) (34 g, 0.136 mole) in concentrated hydrochloric acid (200 ml) and water (50 ml) was heated under reflux for 17 h. The solution was concentrated in vacuo to afford a white solid. Thionyl chloride (250 ml) was added and the solution heated under reflux for 3 h when a homogenous solution was obtained. The excess thionyl chloride was then removed in vacuo and the residue azeotroped with dry toluene to remove the last traces of thionyl chloride. The residue was dissolved in dry acetonitrile (250 ml) and treated with N,O-dimethyl hydroxylamine hydrochloride (16 g, 0.165 mole) and cooled to -30° C. Pyridine (53 g, 0.67 mole) was then added to the stirred reaction mixture at such a rate that the temperature did not rise above -20° C. The reaction was then allowed to warm to room temperature over 16 h. The reaction was then concentrated in vacuo to a gum and the residue partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum. The gum was dissolved in dichloromethane and treated with decolourising charcoal filtered and reconcentrated to a gum. Recrystallisation from ether afforded 1-azabicyclo[2.2.1]hept-4-yl-N-methoxy-N-methyl carboxamide (D21) (21.2 g, 0.115 mole, 84%) as needles.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]2[C:8]([NH:10][NH:11][C:12](=[O:13])[C:3]=2[CH:2]=1)=[O:9].[Cl:14][CH2:15][C:16](Cl)=[O:17].N1C=CC=CC=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Cl:14][CH2:15][C:16]([NH:7][C:5]1[CH:6]=[CH:1][CH:2]=[C:3]2[C:4]=1[C:8](=[O:9])[NH:10][NH:11][C:12]2=[O:13])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2c(=O)[nH][nH]c(=O)c12
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cccc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C

Procedure:
Luminol (1.55 g; 8.75 mmol) was reacted with 2-chloro-acetylchloride (1.24 g; 10.99 mmol), in the presence of pyridine (1.07 g, 13.6 mmol) in acetic:acid (45 ml). Contents were stirred and refluxed for 1 h, allowed to cool to RT, and transferred to a refrigerator for precipitation of the product to obtain 2-Chloro-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazine-5-yl)acetamide. Thereafter, acetic acid (20 ml) was added to the cold precipitates prior to filtration (for uniform transfer into the filtration unit). Finally, precipitates were filtered, washed with methylene chloride (three times) and dried under vacuum to yield 2-Chloro-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazine-5-yl)acetamide (1.6 g; 6324 mmol; 72.2%). 1H NMR (300 MHz, DMSO-d6) δ: 8.82-8.87 (t, 1H), 7.71-7.89 (dd, 1H), 7.61-7.69 (dd, 1H), 4.34 (s, 2H), 2.16 (s, 3H, Methyl for Acetic Acid); ESMS: Calcd for C10H8ClN3O3: 253.0, Found, 253.8.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:27][C:28](O)=[O:29]>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:29]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)ccc1F
Product: O=C(Cc1cc(F)ccc1F)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.90-7.93 (m, 1H), 7.36 (ddd, J=9.0, 5.8, 3.2 Hz, 1H), 7.12-7.29 (m, 2H), 3.82-3.84 (m, 4H), 3.75 (s, 2H), 3.09-3.11 (m, 4H); MS (ESI+) M/Z 401 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:30][N:31]1[C:35]([C:36]2[CH:41]=[CH:40][N:39]3[C:42]([C:45](OC)=[O:46])=[CH:43][N:44]=[C:38]3[CH:37]=2)=[CH:34][CH:33]=[N:32]1>C1COCC1.CO.C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:45]([C:42]2[N:39]3[CH:40]=[CH:41][C:36]([C:35]4[N:31]([CH3:30])[N:32]=[CH:33][CH:34]=4)=[CH:37][C:38]3=[N:44][CH:43]=2)=[O:46])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: COC(=O)c1cnc2cc(-c3ccnn3C)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(-c6ccnn6C)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (46.7 mg, 0.185 mmol) in anhydrous THF (2 ml) was added under a nitrogen atmosphere at ambient temperature lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.38 mL). The resulting mixture was stirred at ambient temperature for 10 minutes, then added dropwise to a chilled (ice-water bath) solution of methyl 7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (47.4 mg, 0.185 mmol) in anhydrous THF (2 mL). The cold bath was removed, and the reaction mixture was allowed to warm to ambient temperature, and quenched with water. The resulting suspension was extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford the dried product. The crude product was subjected to preparative thin-layer chromatography on silica with 8% MeOH/DCM as eluent to afford 45.7 mg of pure, desired product as a yellow-brown solid. MS (ES+APCI) m/z=477 (M+H) detected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:25]=[C:24]([CH3:26])[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:21]([C:20]1[CH:19]=[N:18][C:17]([NH2:16])=[CH:25][C:24]=1[CH3:26])=[O:22])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Cc1cc(N)ncc1C(=O)O
Product: Cc1cc(N)ncc1C(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Yield: 55.3 %

Procedure:
Following general amide formation method 1, 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (279 mg, 1.31 mmol, 1.0 eq) was combined with 6-Amino-4-methylnicotinic acid (200 mg, 1.31 mmol, 1.0 eq) to give 3-(6-Amino-4-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (251 mg) in 55% yield. MS m/z 347.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](N)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].C(#N)C.N([O-])=[O:26].[Na+]>OS(O)(=O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([OH:26])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)nc(-c2ccc(Cl)c(OC)c2F)n1
Yield: 60 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (300 mg, 0.97 mmol, see U.S. Pat. No. 7,300,907 B2 for preparation) was slurried in 10 mL 1M H2SO4 plus 3 mL acetonitrile, heated to 75° C. and treated in portions with sodium nitrite (350 mg, 5 mmol) over a period of 10 minutes. After 40 minutes the mixture was cooled and the yellow precipitate was taken up in 40 mL ethyl acetate, washed with 10 mL water, washed with 10 mL brine, dried, and evaporated to give 170 mg (60% yield) 6-hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester; MS m/z 312, 1H NMR (DMSO-d6): δ 7.49 (m, 3H), 3.95 (s, 3H), 3.86 (s, 3H)
Reaction SMILES: [ClH:1].Cl.FC1C=CC(C2C=NC(N3CCNCC3)=NC=2)=CC=1.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[N:32]1([C:35]2[N:36]=[CH:37][C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:45][CH:46]=3)=[CH:39][N:40]=2)[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Agent: Cl
Agent: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Product: FC(F)(F)c1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Yield: 69 %

Procedure:
Prepared according to the-method for the preparation of 5-(4-fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride, from 4-[5-(4-trifluoromethyl-phenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (0.392 g), to furnish the title compound as an off-white solid (0.250 g, 69%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:49])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][C@@H:21]1[C@@H:25](/[CH:26]=[CH:27]/[C@@H:28]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:29][CH2:30][C:31]#[C:32][CH3:33])[C@H:24]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:23][C@@H:22]1[OH:48].[N+](=C)=[N-].C(=O)(O)[O-].[Na+]>CCOCC.O.N1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:49])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][C@@H:21]1[C@@H:25](/[CH:26]=[CH:27]/[C@@H:28]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:29][CH2:30][C:31]#[C:32][CH3:33])[C@H:24]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:23][C@@H:22]1[O:48][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC#CCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC#CCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OS(=O)(=O)c2ccc(C)cc2)C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At 0°, 1.38 g. of p-toluenesulfonyl chloride is added to a solution of 2 g. of (5Z,13E)-(9S,11R,15S)-11,15-bis(tetrahydropyran-2-yloxy)-9-hydroxy-5,13-prostadien-18-ynoic methyl ester (prepared from the corresponding acid with ethereal diazomethane solution) in 4 ml. of pyridine. The mixture is stirred for 6 hours at room temperature and then allowed to stand at 5° for 60 hours. The mixture is then diluted with ether, shaken in succession once with water, once with ice-cold 3% sulfuric acid, once with water, once with 5% sodium bicarbonate solution, twice with water, and dried over magnesium sulfate and evaporated under vacuum, thus obtaining 2.45 g. of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])/[CH:11]=N/O)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:15]S(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:15])[C:10](=[O:14])[NH:9]2)=[C:6]([F:8])[CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(/C=N/O)Nc1cc(F)cc(Br)c1
Product: O=C1Nc2cc(Br)cc(F)c2C1=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
(E)-N-(3-bromo-5-fluorophenyl)-2-(hydroxyimino)acetamide (6.13 g, 23.6 mmol) was slowly added to a solution of conc. H2SO4 (30 mL) in an ice bath. The temperature of the reaction mixture was maintained below 50° C. After completion of the addition, the solution was heated to 90° C. for 1 h. After it was cooled to rt, the mixture was poured into ice-water and stirred vigorously for 1 h. The insoluble solid was filtered and washed with water, dried under vacuum to provide 7.4 g of crude product, which was used into the next step without further purification. MS (ESI): 242, 244 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[NH:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][CH:7]=1.[C:18](OCC1N(C)C(C(C)C)=C(SC2C=CC=CC=2)N=1)(=O)N>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([CH3:18])[C:12]([CH3:14])=[N:11][C:10]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(Sc2ccccc2)nc(COC(N)=O)n1C
Reactant: Cc1nc(C(C)C)c(Sc2cccc(Cl)c2)[nH]1
Product: Cc1nc(C(C)C)c(Sc2cccc(Cl)c2)n1C

Procedure:
Compound I-3 was obtained from 5-(3-chlorophenylthio)-4-isopropyl-2-methylimidazole by the same synthetic process as that for Compound I-1 in Example 1 (yield 47%). mp 91 to 94° C.
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(Cl)(Cl)(Cl)Cl>[CH2:17]([NH:19][C:20]([N:8]1[CH:7]2[C:16]3=[C:3]([O:2][N:1]=[C:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=3)[CH2:4][CH2:5][CH2:6]2)=[O:21])[CH3:18]
Reactant: CCN=C=O
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Solvent: ClC(Cl)(Cl)Cl
Product: CCNC(=O)N1c2ccccc2-c2noc3c2C1CCC3

Procedure:
In 20 ml CCl4 were combined 5.00 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine and 9 ml ethyl isocyanate. The mixture was refluxed for two days. After the first day, 9 ml more ethyl isocyanate was added. The reaction mixture was then cooled in ice and the precipitate filtered. The precipitate was recrystallized from 1:1 DCM/hexanes and dried in vacuo at 80° C. to yield 3.91 g crystals, m.p. 189° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:48])[CH2:36][O:37][C:38]1[C:43]([F:44])=[C:42]([F:45])[CH:41]=[C:40]([F:46])[C:39]=1[F:47])[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:48])[CH2:36][O:37][C:38]1[C:43]([F:44])=[C:42]([F:45])[CH:41]=[C:40]([F:46])[C:39]=1[F:47])[CH2:27][C:28]([OH:30])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)O)C(=O)COc2c(F)c(F)cc(F)c2F)n(C)c2ccccc12
Yield: 66.6 %

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-cabonyl)leucinyl]-3-amino-4-oxo-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (47.6 mg, 0.070 mmol) with TFA as described in Example 80 gave the titled product (29.0 mg, 67%) as a white powder. MS C35H43F4N3O6, [M+Na]+=644, [M−H]−=620. TLC (CH2Cl2/MeOH, 90/10): Rf=0.19.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1COCC1>[CH2:4]([C:17]1([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1CCOCC1
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(CCc2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Magnesium turnings (2.34 g, 97.6 mmol) and THF(100 mL) are placed under N2. A small crystal of I2 and a 1 mL portion of phenethyl bromide are added, and the mixture is stirred at rt for 30 min. The reaction mixture is briefly heated with a heat gun until the iodine color is discharged. An exothermic reaction commences. Thereafter, the remaining bromide (10.5 mL, total=11.5 mL, 84.6 mmol) is added at a rate to maintain a gentle reflux (ca. 10 min). When the mixture reaches rt, the reaction apparatus is placed in an ice water bath, and tetrahydropyran-4-one (6.0 mL, 43.4 mmol) is added to the reaction mixture neat via syringe over a five minute period. The cooling bath is removed, and the reaction mixture is allowed to reach rt. The reaction mixture is worked up and purified as above with compound 17 to give the product 18. Recrystallization from hexane/CH2Cl2 gives 18 as white needles (1 crop), mp 74-75° C. (5.0 g, 37%) . 1H NMR (CDCl3) 7.40-7.10(m,5), 3.90-3.70(m,4), 2.80-2.65(m,2), 1.90-1.70(m,4), 1.55(br d,2, J=11.9), 1.46(s,1); 13C NMR (CDCl3) 142.14, 128.47, 128.28, 125.87, 68.86, 63.78, 45.13, 37.58, 28.91; MS(CI/CH4, eE=70eV) m/z 207(M+H)+,205, 190, 189 (base peak), 171, 161, 143, 119, 101, 91, 83, 71; Anal. Calcd for C13H18O2 (MW=206.3): C,75.69 H,8.80. Found: C,75.46 H,8.80.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2S[CH2:7][CH2:8][C:4]=2[CH:3]=1.O[O:12][S:13]([O-:15])=O.[K+]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[S:13](=[O:15])(=[O:12])[CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=S([O-])OO
Reactant: Brc1ccc2c(c1)CCS2
Agent: [K+]
Solvent: CO
Product: O=S1(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Dissolve 5-bromo-2,3-dihydro-benzo[b]thiophene (J. Am. Chem. Soc, 1973, 1916-1925, 4.3 g, 20 mmol) in MeOH (100 mL) and add oxone (36.9 g, 60 mmol). Stir the reaction mixture at room temperature overnight, and then remove the solid by filtration. Concentrate the filtrate and purify the residue by flash column chromatography (silica gel, 20-40% EtOAc/Hexane) to give 4.24 g of 5-bromo-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (86%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:68][C:69]([CH3:71])=[O:70])[C:5]([C@@:7]1([CH3:67])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[O:57][C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O)=[O:6].C1(NN)C=CC=CC=1>C(#N)C.O>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:68][C:69]([CH3:71])=[O:70])[C:5]([C@@:7]1([CH3:67])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@]2(C)[C@@H](O[C@@H]3OC[C@@H](O)[C@H](O)[C@H]3O)C[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c3ccccc3)c3ccccc3)C(C)=C1C2(C)C
Solvent: NNc1ccccc1
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
In the manner of the procedure of EXAMPLE 1, 0.5 g of taxol-7-xyloside was oxidatively cleaved. The product, after treatment with phenylhydrazine, was taken up in 25% acetonitrile in water and applied to a column of 10 g of C-18 reverse phase silica. The column was eluted with a gradient of acetonitrile in water (30, 35, 40, 45 and 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12](Cl)(=[O:14])=[O:13])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].CC[N:18]([CH:22]([CH3:24])C)[CH:19]([CH3:21])C.N1CCCC1>O1CCOCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([N:18]2[CH2:19][CH2:21][CH2:24][CH2:22]2)(=[O:14])=[O:13])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)Cl)c1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)N2CCCC2)c1
Reaction time: 2 h

Procedure:
To a solution of 3-Bromo-5-chlorosulfonyl-4-fluoro-benzoic acid (3.0 g) in dioxane/water (9/1 (v/v), 30 ml) was added DiPEA (5 ml) and pyrrolidine (1.55 ml). After stirring for 2 h, the mixture was diluted with EtOAc and washed with 2 M aq. HCl. The organic layer was dried (Na2SO4) and concentrated in vacuo. Yield: 2.3 g.