Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)[C@]5(O)[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:30]([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)#N>>[OH:2][C@:49]12[CH2:48][C:47](=[O:50])[CH2:46][CH2:45][C@:44]1([CH3:51])[C@@H:43]1[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]1)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33][C:32]2=[CH2:30]
Reactant: C=C1C[C@H]2[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCCC[C@]12O
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Yield: 78 %

Procedure:
The title compound II-bo was prepared in 78% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-methyleneandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.93 (s, 1H), 4.83 (m, 1H), 4.60 (m, 1H), 2.83 (d, 1H), 2.90-1.10 (m, 18H), 0.95 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23](O)=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23]([Cl:30])=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)O)O2
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)Cl)O2
Yield: 105 %

Procedure:
Reaction of 11.8 g (33.3 mmol) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid with oxalyl chloride according to Cohen et al Helv. Chim. Acta. 1978 61, 837 afforded 13.0 g (105%) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetyl chloride as a yellow oil. This acid chloride was reacted according to Org. Synth., 1984, 63, 198 with 4.94 g (34.3 mmol) of Meldrum's acid and 6.58 g (6.73 mL. 83.2 mmol) of dry pyridine as described above for the racemic series to afford 16.5 g of crude adduct i.e. (S)-5-[2-[3,4-dihydro-2,5,7,8-tetramethyl-6-phenylmethoxy-2H-1-benzopyran-2-yl]-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a brownish foam. Crystallization attempts from several solvents or solvent mixtures failed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:28])[CH2:15]C3CCC4OCC(=O)CC=4OC3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].[OH2:31].Cl.[CH3:33][OH:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:28])[CH2:15][CH:9]3[O:34][C:33]4[CH2:5][CH2:6][CH2:7][CH2:2][O:31][C:3]=4[CH:4]=[C:8]3[OH:12])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: CC(CC1CCC2=C(CC(=O)CO2)OC1)N1CC(c2cccc(Cl)c2)OC1=O
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(CC1OC2=C(C=C1O)OCCCC2)N1CC(c2cccc(Cl)c2)OC1=O

Procedure:
One equivalent of 5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727 Example 1, is treated with one equivalent of 1,3-dibromoacetone and excess potassium carbonate in acetonitrile. The mixture is stirred at room temperature for 18 hours, filtered and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,5-dioxabenzocycloheptan-3-one. One equivalent of this ketone is reduced, at room temperature for one hour, with excess sodium borohydride in methyl alcohol. The reaction mixture is poured into water, made acidic with 1N hydrochloric acid and extracted with methylene chloride. The organic extracts are dried and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-1,5-dioxabenzocycloheptan-3-ol. Hydrolysis with 2.5N sodium hydroxide gives the title compound.
Reaction SMILES: C(O)(=O)C(O)=O.C([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22]([C:24]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]3[CH2:33][CH2:34][CH2:35][O:36][C:25]=23)=[O:23])[CH2:16][CH2:15]1)C1C=CC=CC=1>C(O)C.C(O)(=O)C>[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22]([C:24]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]3[CH2:33][CH2:34][CH2:35][O:36][C:25]=23)=[O:23])[CH2:16][CH2:15]1
Reactant: O=C(NCC1CCN(Cc2ccccc2)CC1)c1c2n(c3ccccc13)CCCO2
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Yield: 105.4 %

Procedure:
A stirred suspension of N-[(1-benzyl-4-piperidyl)methyl] 3,4-dihydro-2 H-[1,3]oxazino[3,2-a]indole-10-carboxamide oxalate salt (E20, 2.25 g, 0.0046 mole) in ethanol (100 ml) and glacial acetic acid (4 ml) was hydrogenated over 10% Pd--C (0.8 g) at atmospheric pressure and 45° C. for 18 h. The mixture was filtered and the filtrate concentrated in vacuo. The majority of the product was in the solid which had been filtered off. This material was shaken with concentrated potassium carbonate solution (50 ml) and chloroform (50 ml) together with the residue from the filtrate. The mixture was filtered, the chloroform layer separated and dried (Na2SO4), then concentrated in vacuo to afford the title compound as a white solid (1.52 g, 100%). This was recrystallised from chloroform/60-80 petrol mp 139°-141° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32]C)=[O:31])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([OH:32])=[O:31])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a mixture of methyl 2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]-phenyl]acetate (1.05 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at 50° C. for 2 hrs. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration and dried with air to give crystals (0.91 g, 88%) of 2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23]Br)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Yield: 121.9 %

Procedure:
A mixture of 1.9 g of 4-hydroxybenzaldehyde, 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 8.3 g of potassium carbonate and 50 ml of butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave 6.0 g of pure 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde.
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([Mg]Cl)[CH2:18][CH2:17]1.[Cl-].[NH4+].[O:26]1CCCC1>>[OH:26][C:12]1([CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: C1CCOC1
Reactant: CN1CCC([Mg]Cl)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: CN1CCC(C2(O)c3ccccc3-c3ccccc32)CC1
Reaction time: 8 h

Procedure:
A solution of 0.412 mol of fluorenone in 300 ml of tetrahydrofuran is added at 20° C. to a solution of 0.659 mol of (1-methyl-4-piperidyl)magnesium chloride in 600 ml of tetrahydrofuran. The mixture is left stirring overnight and then hydrolyzed in the cold state with ammonium chloride solution. The reaction medium is concentrated and the residue is taken up in one liter of water. The product is extracted with chloroform. The organic phase is dried over anhydrous sodium sulfate and then concentrated. After crystallization of the expected product, the latter is washed with ethyl ether and filtered off.
Reaction SMILES: C(S)C.B(F)(F)F.CCOCC.[C:13]1([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][S:29]([CH:32]4[CH2:37][CH2:36][N:35](C(OCC5C=CC=CC=5)=O)[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH:26]=3)[NH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:13]1([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][S:29]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH:26]=3)[NH:21][N:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)CC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCS
Solvent: CCOCC
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3ccccc3)c2c1)C1CCNCC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
N-(3-Phenyl-1H-indazol-5-yl)piperidine-4-sulfonamide can be obtained in the following way: 1.89 g of ethanethiol, then 1.45 g of boron trifluoride etherate, are added dropwise to a solution, under argon, of 0.5 g of benzyl 4-(3-phenyl-1H-indazol-5-ylsulfamoyl)piperidine-1-carboxylate in 5 ml of dichloromethane. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 10 ml of water, basified with 5 ml of an aqueous 32% ammonium hydroxide solution, and then extracted successively with 30 ml and 15 ml of ethyl acetate. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 40-63 μm), eluting successively with dichloromethane/methanol (99/1; 95/5 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue taken up in 6 ml of acetonitrile in the presence of 3S black, and dissolved under hot conditions, and the mixture is filtered under hot conditions through sintered glass and then recrystallized. The crystals are filtered off through sintered glass, washed with 2 times 0.5 ml then 1 ml of acetonitrile, partially dried and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. 0.04 g of N-(3-phenyl-1H-indazol-5-yl)piperidine-4-sulfonamide is thus obtained in the form of a white crystalline solid melting at 230° C. (analysis: C18H20N4O2S, % calculated C, 60.65, H 5.66; N, 15.72; O, 8.98; S, 9. % found C, 60.62; H, 5.85; N, 15.39; S, 8.72).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1([CH3:19])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)C.CO.[OH-].[K+]>O>[CH3:19][C:6]1([CH2:5][C:4]([OH:20])=[O:3])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Reaction time: 8 h

Procedure:
Hydrolysis of this ester to the title compound is effected as follows: The ester is dissolved in 230 ml. of methanol. To this is added 10 g. of KOH in 30 ml. of H2O and the solution is allowed to stand at room temperature overnight. The methanol is evaporated, water added and the solution washed with benzene. The aqueous phase is acidified with 6N HCl, and extracted with benzene. This organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give an oil, which is crystallized from benzene containing a trace of petroleum ether to afford the title compound, m.p. 150 - 152° C., νmaxCHCl3 3325 and 1705 cm-1.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:8]([SH:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>[OH-].[Na+].C1COCC1>[CH2:8]([S:24][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: O=C1C=CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSC1CCCC(=O)C1
Yield: 70 %

Procedure:
2-Cyclohexenone (0.14 mol, 13.4 mL) was dissolved in 10 mL of 10 percent sodium hydroxide and 50 mL of THF. An equimolar amount of hexadecyl mercaptan (0.14 mol, 42.9 mL) was added to the unsaturated ketone and the mixture refluxed to produce 3-hexadecylthiocyclohexanone (70 percent yield). This product (5.23 mmol, 1.851 g) was dissolved in methanol and reduced with sodium borohydride (5.23 mmol, 0.199 g) to give a racemic mixture of 3-hexadecylthiocyclohexanol (yield 62 percent; cis:trans ratio 4:1). The phosphorylating agent was prepared by refluxing phosphorus oxychloride (0.65 mol, 60.8 mL) and 2-bromoethanol (0.38 mol, 27.0 mL) in 25 mL of trichloroethylene to produce 2-bromoethyl dichlorophosphate (yield 53 percent). The 3-hexadecylthiocyclohexanol (0.56 mmol, 0.200 g) was dissolved in diethyl ether:THF (2:1) and refluxed with the 2-bromoethyl dichlorophosphate (222 mmol, 0.3 mL) to produce 3-hexadecylthiocyclohexyl phosphoethyl bromide (yield 54 percent). The latter (0.276 mmol, 0.150 g) was dissolved in isopropyl alcohol chloroform:DMF (5:3:5) and heated at 65° C. with trimethylamine (0.042 mol, 2 mL) to produce the desired product, 3-hexadecylthiocyclohexyl-phosphocholine (yield 38 percent).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.CO.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:8][C@@H:9]4[O:15]3)=[O:19])[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude dihydroartemisinin in chloroform (40 mL) and methanol (1 mL, 24.8 mmol) was added boron trifluoride etherate (0.16 mL, 1.24 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes, slowly warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was monitored by TLC until all starting material was consumed. The reaction mixture was quenched with water (50 mL) and diluted with chloroform (25 mL). The two phases were separated, and the aqueous layer was extracted with chloroform (30×2 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude product which was further purified by column chromatography on Florisil (1%-10% EtOAc/hexanes) to give two artemisinin isomers as white solids: β-isomer (0.29 g, 0.98 mmol, 79%) mp 73°-74.5° C.; α-isomer (0.05 g, 0.17 mmol, 14%), with each having a 1H NMR spectrum identical to that reported in the literature. ##STR33##
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](O)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21].C1C=[C:26]2[N:28]=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:28][CH3:26])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid (73 mg, 0.252 mmol), methylamine, HCl (25.5 mg, 0.377 mmol), HOBT hydrate (65.5 mg, 0.428 mmol) and EDC hydrochloride (87 mg, 0.453 mmol) at r.t. under N2 was added N,N-diisopropylethylamine (0.220 mL, 1.258 mmol). The mixture was stirred at r.t. for 16 hours. After concentration, the mixture was added with 5 ml 1N HCl, and then 14 ml H2O. The white solid was filtered and washed with 3×5 ml H2O and dried (64 mg). 1H NMR (500 MHz, CD3OD) δ 7.89 (dd, J=8.09, 5.34, 2H), 7.25 (t overlapping with dd, 2H), 7.23 (dd, 1H), 6.99 (t, J=8.55, 1H), 2.96 (s, 3H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH—90% H2O—0.1% TFA, Solvent B=90% MeOH—10% H2O—0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=304.06, HPLC Rt=1.262 min.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=O)[CH2:11][C@H:10]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:8])=[CH:3][CH:2]=1.[CH3:26][O:27][NH3+:28].[Cl-].C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:28][O:27][CH3:26])[CH2:11][C@H:10]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:8])=[CH:3][CH:2]=1
Reactant: CO[NH3+]
Reactant: COC(=O)C[C@@H]1CC(=O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C1C[C@@H](CC(=O)OC)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 84 %

Procedure:
A solution of methyl [(2S)-1-(biphenyl-4-ylcarbonyl)-4-oxopyrrolidin-2-yl]acetate (43 mg, 0.13 mmol), hydroxylamine methyl ether hydrochloride (32 mg, 0.38 mmol) and triethylamine (53 μl, 0.38 mmol) in chloroforme (3 ml) was stirred at 70° C. for 5 days. The reaction mixture was diluted with dichloromethane and washed with HCl 1N. The organic phase was dried (MgSO4) and concentrated to afford methyl [(2S,4EZ)-1-(biphenyl-4-yl-carbonyl)--4-(methoxyimino)pyrrolidin-2-yl]acetate (40 mg). Yield: 62%. HPLC purity: 94%
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:22])[N:4]=[C:3]1[N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C1COCC1.[H][H]>[Pd].CCOC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:38])([CH3:1])[C:3]([N:23]([C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[N:4][C@:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To an argon flushed flask was added tert-butyl N-[(4aR,11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.94 g, 3.50 mmol) and THF (35 ml), followed by a slurry of palladium on carbon (0.75 g, 0.70 mmol) in EtOAc (5 ml). The gas in flask was replaced with hydrogen balloon for three times. The mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was filtered through celite plug and concentrated to give tert-butyl N-[(4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.80 g, 98% yield) as an off-white solid. m/z (ESI) 524.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][C@@H:37]2[CH3:42])[CH3:35])=[CH:4][N:3]=1.CCN(CC)CC.[CH3:50][S:51](Cl)(=[O:53])=[O:52].[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:38][C@@H:37]2[CH3:42])[CH3:35])=[CH:4][N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNC[C@@H]4C)cnc3F)nc(C)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A solution of 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.350 mmol) in CH2Cl2 (3 mL) at −20° C. was treated with NEt3 (0.488 mL, 3.50 mmol) followed by methanesulfonyl chloride (0.083 mL, 1.051 mmol). The mixture stirred at −20° C. for 30 minutes. 1 M NaOH (aq.) and CH2Cl2 were then added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 60% to 100% EtOAc in hexane, to provide 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.130 g, 0.200 mmol, 57.2% yield) as a white foam. m/z (ESI, +ve) 649.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, J=9.29, 2.45 Hz, 1H); 8.14 (d, J=1.17 Hz, 1H); 7.18 (d, J=7.82 Hz, 4H); 6.81-6.89 (m, 5H); 4.74 (br. s., 4H); 4.04 (q, J=6.78 Hz, 1H); 3.79 (s, 6H); 3.28-3.37 (m, 1H); 3.16-3.24 (m, 1H); 3.12 (dd, J=10.95, 2.93 Hz, 1H); 2.85-3.01 (m, 2H); 2.77 (s, 3H); 2.63-2.70 (m, 2H); 2.62 (s, 3H); 1.44 (d, J=6.85 Hz, 3H); 1.10 (d, J=6.26 Hz, 3H).