Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1.CC(C)([O-])C.[K+].[C:24]([C:26]1([NH:29][C:30]([C@H:32]2[N:36]([C:37]([C:39]3([CH3:42])[CH2:41][CH2:40]3)=[O:38])[CH2:35][C@@H:34](OS(C3C=CC=CC=3)(=O)=O)[CH2:33]2)=[O:31])[CH2:28][CH2:27]1)#[N:25].O>O1CCCC1.CC(N(C)C)=O.C(OCC)(=O)C>[C:24]([C:26]1([NH:29][C:30]([C@@H:32]2[CH2:33][C@@H:34]([S:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[CH:6][C:7]=3[C:12]([F:13])([F:14])[F:15])[CH2:35][N:36]2[C:37]([C:39]2([CH3:42])[CH2:41][CH2:40]2)=[O:38])=[O:31])[CH2:27][CH2:28]1)#[N:25]
Reactant: CC1(C(=O)N2C[C@@H](OS(=O)(=O)c3ccccc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Reactant: FC(F)(F)COc1ccc(S)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1(C(=O)N2C[C@H](Sc3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
A solution of 4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenethiol (56.1 g, 196 mmol) in tetrahydrofuran (93 mL) was added at room temperature to a suspension of potassium tert-butoxide (22.8 g, 203 mmol) in tetrahydrofuran (370 mL). The orange-brown clear solution was stirred for 20 min and a solution of benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (74.4 g, 178 mmol) in dimethylacetamide (240 mL) was added. The mixture was stirred for 15 h at room temperature. Water (550 mL) and ethyl acetate (500 mL) were added and phases were separated. The aqueous layer was extracted with ethyl acetate (500 mL), the combined organic solution of 4-(2,2,2-trifluoro-eth sodium chloride (124 g) in water (1.1 L) (2×600 mL) and concentrated in vacuo to a volume of ca. 260 mL. Toluene (600 mL) was added, the mixture again concentrated in vacuo to a volume of ca. 260 mL and further toluene (240 mL) was added. The warm mixture (internal temperature 45° C.) was filtered, the precipitate was washed with toluene (120 mL) and the combined filtrate was allowed to slowly cool to room temperature (within 60 min). Crystallization started at 26° C. internal temperature. The suspension was stirred for 1 h at 22° C., heptane (620 mL) was added within 45 min and the suspension was stirred for 17 h at room temperature before it was filtered. The precipitate was washed with toluene/heptane 1:1 (v/v, 240 mL) and heptane (120 mL) and dried in vacuo at 40° C. to provide the title compound as off-white crystals (87.7 g, 96.1% purity, 88%). MS (ESI & APCI): m/z=536.1 [M+H]+. 1H NMR (CDCl3, 600 MHz): δ0.58-0.62 (m, 1H), 0.64-0.68 (m, 1H), 0.89-0.93 (m, 1H), 1.04-1.09 (m, 1H), 1.16-1.22 (m, 2H), 1.31 (s, 3H), 1.45-1.55 (m, 2H), 1.88-1.94 (m, 1H), 2.79-2.85 (m, 1H), 3.83-3.88 (m, 1H), 3.91-3.98 (m, 2H), 4.41 (q, J=7.9 Hz, 2H), 4.61 (dd, J=4.7 Hz, 8.0 Hz, 1H), 7.12 (dd, J=2.9 Hz, 8.6 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 8.04 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)[CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5].[BH4-].[Na+].Cl.[OH-].[Na+]>CO.O>[OH:1][CH:2]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)[CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5]
Reactant: CCC(C(=O)c1ccc2c(c1)CCC(=O)N2)N1CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C(O)c1ccc2c(c1)CCC(=O)N2)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.5 Grams of 6-(1-oxo-2-piperazinylbutyl)-3,4-dihydrocarbostyril was mixed in 80 ml of methanol and 1.6 g of sodium borohydride was added gradually under stirring at a room temperature in 15 minutes and further stirred at a room temperature for 2 hours. To the reaction mixture was added 5 ml of concentrated hydrochloric acid and the reaction mixture was concentrated under a reduced pressure to dryness. The residue thus obtained was dissolved by adding 10 ml of water and the pH of the solution was adjusted to 6-7 by adding 2N-sodium hydroxide aqueous solution at a room temperature and stirred to precipitate crystals. The crystals were collected by filtration washed with water and dried to obtain 1.2 g of 6-(1-hydroxy-2-piperazinylbutyl)-3,4-dihydrocarbostyril in colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:35][C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH2:38][S:39][CH3:40].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:35][C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH2:38][S:39][CH3:40])=[O:24])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@@H](CCSC)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (237 mg, 0.5 mmol) and L-methionine (149 mg, 1 mmol) in N,N-dimethylformamide (1 ml) was added triethylamine (0.21 ml, 1.5 mmol). The mixture was stirred at room temperature for 16 hours. After removal of the solvent, the residue was dissolved in ethyl acetate (10 ml) and the solution was washed with 1N hydrochloric acid (5 ml×3) and saturated aqueous sodium chloride (5 ml×3) in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was chromatographed on a column of silica gel (7 g). Elution was carried out with chloroform-methanol (4:1, v/v) and with chloroform-methanol-acetic acid (32:8:1, v/v) in the order mentioned. The fractions containing the desired compound were combined and the solvent was distilled off under reduced pressure to give 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-L-methionine (150 mg), melting at 83°-85° C.
Reaction SMILES: C1N(CCO)CCN([CH2:10][CH2:11]S(O)(=O)=O)C1.[F-].[K+].[CH2:18](S)[C@@H:19](O)[C@H:20](O)[CH2:21]S>>[CH3:18][C:19](=[CH:20][CH2:21][CH2:18]/[C:19](=[CH:20]/[CH2:21][CH2:10]/[C:11](=[CH:10]/[CH2:11][CH2:18]/[CH:19]=[C:20](/[CH2:21][CH2:18]/[CH:19]=[C:20](/[CH2:10][CH2:11][CH:10]=[C:10]([CH3:11])[CH3:11])\[CH3:21])\[CH3:21])/[CH3:20])/[CH3:19])[CH3:18]
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [F-]
Agent: [K+]
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C

Procedure:
Buffer mixture contains 270 mM HEPES, pH 7.5, 20 mM Potassium fluoride and 5.4 mM Dithiothreitol(DTT). 55 μl of this mixture was used per assay. The final concentrations of HEPES, KF and DTT in the assay are 150 mM, 11 mM and 3 mM respectively.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](B(O)O)=[CH:13][CH:14]=[CH:15][CH:16]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccccc2-c2cccc3[nH]ccc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a mixture of 4-bromoindole (1 g, 5 mmol), and 2-biphenylboronic acid (1 g, 5 mmol) in THF (17 mL) were added Palladium catalyst Pd(PPh3)4 (0.2 g, 0. 17 mmol) and the freshly prepared sodium hydroxide solution (0.6 g, 15 mmol in 7 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified on a silica gel column to give 1.26 g (93%) of 4-biphenyl-2-yl-1H-indole.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:21][C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[CH2:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=O)=[CH:28][C:27]=1[Br:35])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[CH2:14]([O:21][C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[CH2:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]#[N:32])=[CH:28][C:27]=1[Br:35])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(=O)c1ccc(CCc2ccccc2OCc2ccccc2)c(Br)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CCc2ccccc2OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
Trifluoroacetic anhydride (0.75 ml) was added to a mixture of 4-[2-benzyloxyphenethyl]-3-bromobenzamide (1.46 g) and pyridine (0.86 ml) in THF at -20° C. The mixture was stirred at ambient temperature for 18 hours, diluted with ethyl acetate and washed with water, dried (MgSO4), filtered and evaporated to dryness. The resulting residue was purified by MPLC on silica gel, eluting with CH2Cl2 to give 4-[2-benzyloxyphenethyl]-3-bromobenzonitrile as a white solid (1.34 g).
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[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[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:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)n1cc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of (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 (100 mg, 0.21 mmol) in 1,4-dioxane (2 mL) was added 5-bromo-1-isopropylpyridin-2(1H)-one (54.2 mg, 0.25 mmol). Then catalysts of Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (1 mL, 2 M) were added. The vessel was sealed with a septum and placed into the microwave cavity. Microwave irradiation of 100 W was used, the temperature being ramped from room temperature to 120° C. Once this temperature was reached, the reaction mixture was held at this temperature for 30 min. After the mixture cooled to rt, the mixture was filtered. The filtrate was extracted with EtOAc (20 mL×4), the organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by preparative HPLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (22 mg, 21%). 1H NMR (CDCl3): 1.13 (s, 3H), 1.19 (s, 3H), 1.40 (6H), 1.53 (d, 3H), 2.18-2.30 (m, 4H), 2.40 (m, 1H), 2.88 (m, 1H), 5.31 (m, 1H), 5.70 (m, 1H), 6.73 (d, 1H), 7.02 (d, 2H), 7.15 (d, 2H), 7.27-7.38 (m, 5H), 7.43 (d, 1H), 7.50 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.II.[F:15]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:15][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: FF
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Product: Fc1cc(Cl)c2ccc(Cl)cc2n1
Yield: 30.6 %

Procedure:
A solution containing 4,7-dichloroquinoline (1.0 g, 5 mmol) and iodine (1.28 g, 5 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture by volume in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added, the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to an oil (0.98 g). GC/MS analysis showed a 34% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2-fluoro-4,7-dichloroquinoline (0.33 g, 87%) as white crystals; other data were the same as that described in the following reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:2]=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].C(N(CC)CC)C>O1CCCC1>[C:18]1([O:17][C:15](=[O:16])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2cccnc2)c1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of 3-pyridin-3-ylaniline (500 mg, 2.94 mmol) in tetrahydrofuran (6 mL) was added at room temperature to a solution of phenyl chloroformate (450 mg, 2.94 mmol), then triethylamine (288 mg, 2.84 mmol) was added. After 15 min the reaction mixture was concentrated under vacuum, then the residue was partitioned between ethyl acetate and 1 M aq. sodium hydrogencarbonate solution. The organic layer was dried (MgSO4) and evaporated. The residue was taken up in tetrahydrofuran (1 mL), then heptane (10 mL) was added. The slurry was stirred for 30 min, then the precipitate was collected by filtration to afford the title compound (566 mg, 68%). Off-white solid, MS (ISP)=291.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:1][O:2][N:3]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[NH2:36])[N:29]([C@H:37]3[CH2:38][CH2:39][C@@H:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:41][CH2:42]3)[N:28]=2)=[CH:9][CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CON=C(c1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CON=C(c1ccccc1)c1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Temperature: 25 °C

Procedure:
A mixture of phenyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-methanone O-methyloxime (intermediate AQ) (0.701 g, 0.0021 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.80 g, 0.0018 mol), tetrakis-(triphenylphosphine)palladium (0.125 g, 0.00011 mol) and sodium carbonate (0.48 g, 0.0045 mol) was heated in a mixture of ethylene glycol dimethyl ether (40 mL) and water (20 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (70 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (96:3:1) as a mobile phase to give cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime as a white solid (0.700 g, 0.00133 mol). Cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime (0.201 g, 0.00039 mol) was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.178 g, 0.0015 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime dimaleate as a white solid (0.212 g, 0.00028 mol): 1H NMR (DMSO-d6, 400 MHz) 8.26 (s, 1H), 7.74 (d, 1H), 7.66 (d, 1H), 7.51 (m, 6H), 7.33 (d, 1H), 6.14 (s, 4H), 4.85 (m, 1H), 3.91 (s, 3H) 3.1 (br, 9H), 2.71 (s, 3H), 2.33 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H);
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[NH:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65](O)=[O:66])=[CH:59][CH:58]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[N:24]([C:65](=[O:66])[CH2:64][CH2:63][C:60]5[CH:61]=[CH:62][C:57]([O:56][CH2:49][C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[CH:58][CH:59]=5)[CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4C(=O)CCc3ccc(OCc4ccccc4)cc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(E)-3,5-diamino-6-chloro-N-(8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′-ylidene)pyrazine-2-carboxamide (prepared as described for Ex. 252) (280 mg, 0.798 mmol) is dissolved in DMF (8 ml) along with HATU (303 mg, 0.798 mmol) and 3-(4-benzyloxy-phenyl)-propionic acid (205 mg, 0.798 mmol). N-Methyl morpholine (0.263 ml, 2.394 mmol) is added and the solution stirred at room temperature for 6 hours. The mixture is then concentrated in vacuo. EtOAc (100 ml) is added and the solution washed with water (100 ml). The organic phase is dried (MgSO4) and concentrated. The residue is dissolved in MeOH (20 ml) and dry loaded onto silica (5 g). Purification by flash chromatography (SiO2, DCM/MeOH) gives the title compound as a tan solid; [M+H]+ 589.20, 591.19 for Cl isotopes.
Reaction SMILES: C1(C)C=CC=CC=1.N1C=C[C:9]=1[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[CH:18]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[C:19]([CH3:23])([CH3:22])[S:20](=[O:21])[C@H:16]12)=[O:13].[Cl:39]N1C(=O)CCC1=O>O>[CH3:22][C:19](=[CH2:23])[CH:18]([N:17]1[C:37](=[O:38])[CH:15]([NH:14][C:12](=[O:13])[CH3:9])[CH:16]1[S:20]([Cl:39])=[O:21])[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:25]
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C3=NC=C3)[C@H]2S1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(C)=O)C1S(=O)Cl

Procedure:
Toluene (500 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present. To the resulting dried toluene was added 1.0 gms. (2.4 mmol.) of p-nitrobenzyl 6-azetamido-2,2-dimethylpenam-3-carboxylate-1-oxide. The resulting mixture was refluxed again using a Dean-Stark water trap to remove any additional amounts of water which may be present. The mixture then was cooled, and 400 mg. (2.9 mmol) of N-chlorosuccinimide were added. The mixture then was refluxed for 1 hour. A sample of the reaction mixture was withdrawn, and the solvent was removed. The product which was obtain was consistent by nmr analysis with the structure of the title compound.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH3:46])[C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43]CC)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+]>CCO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[N:31]([CH3:46])[C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([OH:43])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:47])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)N(C)c2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N(C)C(=O)[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C

Procedure:
A stirred solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](methyl)amino]carbonyl}cyclohexyl)acetate (100 mg; 0.14 mmol) in EtOH (110 mL) was treated dropwise with 4 M KOH (1 mL). The reaction was stirred at room temperature and quenched with 10% citric acid after 2.5 h. The reaction was partitioned between EtOAc (50 mL) and H2O (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse-phase HPLC and the desired product was lyophilized to afford (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](methyl)amino]carbonyl}cyclohexyl)acetic acid as a white solid. LCMS=685.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.92 (s, 1 H), 7.80 (s, 1 H), 7.74 (s, 1 H), 7.29-7.21 (m, 2 H), 7.17-7.15 (m, 1 H), 5.67 (d, J=8.2 Hz, 1 H), 4.96 (d, J=14.7 Hz, 1 H), 4.22 (d, J=16.5 Hz, 1 H), 3.88 (d, J=15.1 Hz, 1 H), 3.41 (s, 3 H), 2.73-2.66 (m, 1 H), 2.28-2.24 (m, 1 H), 2.15-2.12 (m, 1 H), 2.01-1.50 (m, 8 H), 1.18-1.10 (m, 1 H), 0.76-0.68 (m, 3 H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:31](=[O:33])[CH3:32])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC1(C)CC(OC(C)=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 6,36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol (prepared as described in GB 2335190, example 7, compound 102) and 2.02 g (2 mmol) of triethylamine in 50 ml toluene are added 1,57 g (2 mmol) acetyl chloride at 0-5° C. and the reaction mixture is stirred for 2 hours at 20° C. The reaction mixture is then several times extracted with water. The organic phase is dried over Na2SO4 and after removing the solvent 6.9 g (96%) acetic acid 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester are obtained as yellowish liquid.