Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Br[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=1[F:54]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:8]1[CH2:12][C@@H:11]([NH:13][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=2[F:54])[CH2:10][C@H:9]1[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)[C@@H]1C[C@H](Nc2ccc(F)cc2F)CN1C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 10 h
Yield: 12.9 %

Procedure:
To a solution of (2S,4S)-1-Boc-4-amino[(dimethylamino)carbonyl]pyrrolidine (8 g, 31.5 mmol) prepared in Step C in toluene (100 ml) was added sodium t-butoxide (3.46 g, 36 mmol), 2-(di-t-butylphosphino)biphenyl (800 mg, 2.68 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.6 g, 1.79 mmol) and 1-bromo-2,4-difluorobenzene (6.94 g, 36 mmol), and the solution was stirred at 110° C. for 10 h. After the reaction finished, the solution was filtered through Celite, and extracted with water and EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent, EtOAc/Hex=1/4) to give the title compound (1.5 g, 78%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]O.[CH2:9]([N:24]=[C:25]=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CCCC>C(O)COCCO>[CH2:9]([N:24]=[C:25]=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: OCCCCCCO
Reactant: CCCCCCCCCCCCCCCN=C=O
Solvent: OCCOCCO
Product: CCCCCCCCCCCCCCCCCN=C=O

Procedure:
Following the procedure described in preparation 4, but using 1,6-hexanediol and n-pentadecylisocyanate, instead of diethylene glycol and n-heptadecylisocyanate respectively, the title compound was obtained in a similar yield.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[C:22]2[CH:23]=[C:24]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[C:11]=2[C:22]2[CH:23]=[C:24]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cccc(OCCN3CCCCC3)c2)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2-c2cccc(OCCN3CCCCC3)c2)cc1
Temperature: 0 °C

Procedure:
1.5 g (3 mmol) of 1-[2-[3-[2-(4-methoxyphenyl)-6-methoxynaphth-1-yl]phenyloxy]ethyl]piperidine hydrochloride was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. 0.7 mL (7.5 mmol) of BBr3 was slowly added and the reaction allowed to proceed for twenty-four hours. An additional 3 mL of BBr3 was added and the reaction was continued for two more hours. The reaction was quenched by pouring into water, followed by three extractions with EtOH--CHCl3 (1:9) (v/v). The organic extracts were combined, washed twice with brine, dried with Na2SO4, and evaporated to dryness. The final product was purified by chromatography on a silica gel column eluted with a linear gradient begining with CH2Cl2 and ending with CH2Cl2 --MeOH (9:1) (v/v). This yielded 0.5 g of the title compound as a white amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=[NH:36])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C([O-])(=O)C.[Na+].Cl.NO>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:36])[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@H]1C[C@@H](Oc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@H]1C[C@@H](Oc2cccc(N)c2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Combine 4-(3-bromo-phenoxy)-cis 2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 1 (preparation 22, 2.47 g, 6.67 mmol), benzhydrylideneamine (1.45 g, 8.0 mmol), toluene (100 mL), sodium-t-butoxide (0.9 g, 9.34 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.17 g, 0.27 mmol), stir and heat at 100° C. After 10 min., add tris(dibenzylideneacetone)-dipalladium(0) (0.12 g, 0.13 mmol), stir and heat at 100° C. After 4 hr., cool to ambient temperature and partition between water (200 mL) and 4:1 hexane:ethyl acetate (200 mL). Separate organic layer, wash with water (100 mL) and aqueous NaCl solution (100 mL). Dry organic layer over sodium sulfate, filter and concentrate to an oil. Dissolve residue in methanol (80 mL) and treat with sodium acetate (1.31 g, 16.01 mmol) followed by hydroxylamine monohydrogen chloride (0.83 g, 12.0 mmol) with stirring. After 1 hr., partition between 4:1 hexane:ethyl acetate (200 mL) and 0.5 M aqueous sodium hydroxide solution (200 mL). Separate organic layer, wash with aqueous NaCl solution (100 mL), dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 4:1 hexanes:ethyl acetate to obtain the title compound (1.17 g, 59%). 1H NMR (CDCl3): 7.05 (m, 1H), 6.3 (m, 2H), 6.25 (m, 1H), 4.6 (m, 1H), 4.35 (m, 1H), 3.85 (m, 1H), 3.7 (bs, 2H), 3.25 (m, 1H), 1.95 (m, 2H), 1.8 (m, 1H), 1.7 (m, 1H), 1.45 (s, 9H), 1.3 (d, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:34](=[O:41])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:18]2(=[O:33])=[O:32])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:18]2(=[O:32])=[O:33])[CH:11]=1)[C:34]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:41]
Reactant: CCCCCNC(=O)[C@H](Cc1cccc(CN2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNC(=O)[C@@H](N)Cc1cccc(CN2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of the title F compound, ((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamic acid t-butyl ester (77 mg, 0.127 mmol) in CH2Cl2 (1 mL) is added TFA (1 mL). After 30 min, the solvent is removed under stream of nitrogen. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The organic solution is washed with brine, dried over anhydrous MgSO4 and concentrated to yield (S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentyl-propionamide as a clear oil: [M+1]+=503.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][OH:15]>>[C:1]1(=[N:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCCCCCCCCCC1
Product: ON=C1CCCCCCCCCCC1

Procedure:
reacting cyclododecanone with hydroxylamine in an aqueous solution in the presence of an organic solvent (hereinafter, referred to as “oxime-formation solvent”) to produce cyclododecanone oxime (hereinafter, referred to as an “oxime-forming step”);
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[C:9](=[O:19])[N:10]3C(C4C=CC=CC=4)[O:12][C:3]=1[C:4]=23.B.[Na].[C:28](OCC)(=O)C.O>CO>[OH:12][C:3]1[C:4]2[NH:10][CH:9]([O:19][CH3:28])[CH:8]3[CH2:20][CH2:21][CH2:22][N:7]3[C:6](=[O:23])[C:5]=2[CH:24]=[CH:25][C:2]=1[CH3:1]
Reactant: Cc1ccc2c3c1OC(c1ccccc1)N3C(=O)C1CCCN1C2=O
Reactant: CCOC(C)=O
Agent: B
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Then, 1.43 g of the 6,8,9,10,10a,11-hexahydro-3-methyl-1-phenyl-1H-oxazolo[5,4,3-jk]pyrrolo[2,1-C] [1,4]benzodiazepin-6,11-dione was dissolved in 110 ml of methanol. To the solution, cooled to 0° to 5° C., was slowly added 820 mg of sodium boron hydride with stirring, and the whole mixture was stirred at 0° to 5° C. for 2.5 hours. 800 ml of ethyl acetate and 500 ml of water were added to the reaction mixture, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The both ethyl acetate layers were combined, dehydrated and concentrated under reduced pressure. The concentrate was dissolved in 375 ml of 2:1 mixture of methyl alcohol and 0.01 N hydrochloric acid and subjected to hydrolyzation at room temperature for 3 hours with stirring. The liquid reaction mixture was extracted with chloroform, the chloroform layer was washed with water and then it was concentrated under reduced pressure at a temperature not exceeding 40° C. The concentrate was dissolved in 50 ml of methanol and heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure at 40° C. or below. The concentrate was dissolved into 4 ml of hot methanol, cooled to -20° C. and allowed to stand at this temperature for 3 days. Thus, 0.35 g of 2,3,5,10,11,11a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo[2,1-C] [1,4]benzodiazepin-5-one was obtained in a colorless crystalline form. Recrystallization of the resulting product from methanol gave a colorless needle-like crystal having a melting point of 152.5° to 155.5° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[F:10][C:11]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:12]=1[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:10][C:11]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][S:4]([CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:6])=[O:5])=[CH:19][CH:20]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2F)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(CC(F)(F)F)Nc1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,2,2-Trifluoroethanesulfonyl chloride (10.0 g, 54.8 mmol) was added dropwise to a solution of 4-(2,4-difluorophenoxy)aniline (11.0 g, 50.0 mmol) and 4-dimethylaminopyridine (9.1 g, 74.6 mmol) in methylene chloride (100 mL) at 0° C. under nitrogen. The mixture was slowly warmed to room temperature, stirring for a total of 72 h. The mixture was washed with saturated aqueous sodium bicarbonate solution (200 mL), dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford the crude product as an orange oil. This residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/chloroform (1:4), to provide the title compound as a yellow solid: mp 105-108° C.; TLC Rf (1:9 ethyl acetate/chloroform)=0.75; 1H NMR (300 MHz, CDCl3) 7.23 (d, J=8.9 Hz, 2H), 7.14-6.87 (m, 3H), 6.93 (d, J=8.9 Hz, 2H), 3.76 (q, J=8.8 Hz, 2H) ppm; APCI MS m/z 366 [C14H10F5NO3S—H]−.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][N:22]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:21][CH2:20]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(O)(c4ccccc4)CC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 4-hydroxy-4-phenylpiperidine (25 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 95/5) to give a white solid. This solid was triturated in acetone and diethyl ether, filtered, washed with diethyl ether and then dried to give the title compound (18.5 mg, 41%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:37]([C:39]1[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=1)=O>CN(C)C=O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3](/[CH:2]=[CH:37]\[C:39]2[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(/C=C\c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.5 %

Procedure:
1-(Bromomethyl)-4-nitrobenzene (1.9 g), triphenylphosphine (2.31 g) and N,N-dimethylformamide (20 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 hours. Then potassium tert-butoxide (1.19 g) and N-(4-formyl-1,3-thiazol-2-yl)acetamide (1.5 g) were added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (1:1)-→(1:2) as an eluent, and triturated with ethyl ether to give N-{4-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (1.59 g) as a yellow solid.
Reaction SMILES: [C:1]([C@@H:3]([NH:21][C:22]([C:24]1([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][CH2:14]3)=[CH:7][CH:6]=1)#[N:2].N>C(O)=O.O>[NH2:30][C:24]1([C:22]([NH:21][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[NH:15][CH2:14]4)=[CH:9][CH:10]=2)=[O:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4c(c3)CNC4=O)cc2)CCOCC1
Agent: N
Solvent: O=CO
Solvent: O
Product: N#C[C@H](Cc1ccc(-c2ccc3c(c2)CNC3=O)cc1)NC(=O)C1(N)CCOCC1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-(1-oxoisoindolin-5-yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (ii), 160 mg) was stirred in formic acid (0.5 mL) at 50° C. for 20 min. The reaction mixture was cooled to room temperature and the mixture diluted with water (20 mL). The solution was basified with 0.880 ammonia and extracted into ethyl acetate (100 mL). The extract was dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica using methanol/ethyl acetate (1/9) to afford the titled compound as a solid (70 mg).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][NH2:7])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[F:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH:2]1([CH2:5][O:6][NH:7][S:26]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[C:23]([F:24])[C:18]=2[F:17])(=[O:28])=[O:27])[CH2:4][CH2:3]1
Reactant: NOCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NOCC1CC1)c1ccc(F)c(F)c1F
Reaction time: 0.2 h
Yield: 67.9 %

Procedure:
To a stirring suspension comprised of O-cyclopropylmethyl-hydroxylamine hydrochloride (5.40 g, 0.0437 mol) in dichloromethane (20 ml) at ambient temperature under a nitrogen atmosphere was added diisopropylethylamine (10.8 ml, 0.062 mol). A solution comprised of 2,3,4-trifluorobenzenesulfonyl chloride (Oakwood Products, Inc., 1.00 g, 4.34×10−3 mol) in dichloromethane (120 ml) was added dropwise to the reaction vessel containing the stirring suspension over a 12 minute period. The reaction mixture was stirred for another 12 minutes and was quenched with 10% aqueous hydrochloric acid (140 ml). The biphasic mixture was stirred vigorously for 16 hours. The layers were separated and the organic phase was dried (MgSO4) and concentrated to 6 ml volume. The concentrated solution was administered to a flash silica column (Biotage, 90 g of silica gel). Elution with dichloromethane afforded 0.8283 g of a white amorphous solid; 68% yield; 1H-NMR (400 MHz; CDCl3 signal offset to δ 7.03; values reported are uncorrected) δ 7.50 (m,1H), 7.10 (s,1H), 6.95 (m,1H), 3.59 (d, 2H, J═7.2 Hz), 0.80 (m, 1H), 0.31 (m, 2H), 0.02 (m, 2H); 19F-NMR (376 MHz; CDCl3) δ−122.65 (m, 1F), −129.37 (m, 1F), −156.20 (m, 1F); MS (APCl−) 280 (M−1, 100), 210 (55), 195 (45).
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:23]([Mg]Br)([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([CH3:26])([CH3:25])[C:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]([F:18])([F:19])[F:20])[O:13][N:12]=2)=[CH:9][CH:10]=1)=[O:21]
Reactant: CON(C)C(=O)c1ccc(-c2noc(C(F)(F)F)c2C)cc1
Reactant: CC(C)(C)[Mg]Br
Product: Cc1c(-c2ccc(C(=O)C(C)(C)C)cc2)noc1C(F)(F)F
Yield: 9 %

Procedure:
Prepared from N-Methoxy-N-methyl-4-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-benzamide and tert-butylmagnesium bromide as described in Example 5. Chromatographed on silica gel with EtOAc/hexanes (5%) as eluant to afford product as a colorless solid (53 mg, 9%). 1H NMR (CDCl3) 1.37 (s, 9 H), 2.29 (d, J=1.3, 3 H), 7.68 (d, J=7.9, 2 H), 7.81 (d, J=8.3, 2 H). 19F NMR −63.2. LC/MS 7.42 min, [M+1]+ 312.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10](N2CCOCC2)=[O:11])[CH:7]=1.[CH:21]([Li])([CH3:23])[CH3:22]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10](=[O:11])[CH:21]([CH3:23])[CH3:22])[CH:7]=1
Reactant: [Li]C(C)C
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C(C)(C)CC(=O)C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 3-(5-fluoro-2-methylphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (200 mg, 0.716 mmol) in 2 mL of THF was treated with i-PrLi (0.7 M in pentane, 1.28 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, allowed to warm to room temperature, quenched with 1 mL of methanol and 5 mL of saturated aqueous ammonium chloride solution, and extracted with three 50 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (100% hexanes to 25% ethyl acetate in hexanes, gradient) afforded 80.4 mg of the title product (48% yield).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[P:12](=[S:20])([NH2:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C(N(CC)CC)C>O>[C:4]1(=[O:6])[N:19]([P:12](=[S:20])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOP(N)(=S)OCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=S)(OCC)N1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
A mixture of the 74.06 g (0.5 mole) phthalic anhydride, 33.84 g (0.2 mole) O,O-diethyl phosphoramidothioate and 50.60 g (0.5 mole) triethylamine was heated at 55° C. for 3.5 hours. Eighty three mls of water were added to the stirred mixture and the system was stirred for 10 minutes and then cooled to 25° C. over a one hour period. The solid was filtered, washed with 150 ml water to give the desired compound, O,O-diethyl phthalimidophosphonothioate, purity by GLC. The yield was calculated to be 76% from the phosphoramidothioate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].C[N:25]([CH3:31])[CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>C1COCC1.CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:28]2[CH2:27][CH2:26][N:25]([CH3:31])[CH2:30][CH2:29]2)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH3:2]
Reactant: CN(C)C1CCNC1
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
To a solution of 4-bromomethyl-3-trifluoromethyl-benzoic acid ethyl ester 36 (120 mg, 0.386 mmol) in THF (4 mL) and DMF (1 mL) was added K2CO3 (80 mg, 0.579 mmol) and 3-(dimethylamino)pyrrolidine (0.043 mL, 38.6 mg, 0.386 mmol). The resulting mixture was stirred at rt for 4 h. The reaction mixture was poured out in water and extracted twice with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo. The crude material was purified by chromatography CH2Cl2/MeOH (95/5) to give pure 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid ethyl ester 37 (21 mg, 16%).
Reaction SMILES: Cl(O)(=O)(=O)=O.C(OC(NN=[C:13]([CH3:33])[C:14](=[N:30][O:31][CH3:32])[C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16])=O)C.[OH-:34].[Na+]>>[CH3:32][O:31][N:30]=[C:14]([C:13](=[O:34])[CH3:33])[C:15]([NH:17][CH:18]1[C:28](=[O:29])[N:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH2:23][S:24][C@H:19]12)=[O:16]
Reactant: [OH-]
Reactant: CCOC(=O)NN=C(C)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 2 h

Procedure:
70% Perchloric acid (4.1 ml.) was added to a solution of 7-(3-ethoxycarbonylhydrazono-2-methoxyiminobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 4.1 g.) at room temperature and stirred at the same temperature for 2 hours. After adjusting to pH 2.0 with 1 N sodium hydroxide aq. acetone was evaporated in vacuo from the resultant solution. Ethyl acetate (100 ml.) and a sodium chloride saturated aqueous solution (50 ml.) to the residue and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (100 ml.) and combined with the ethyl acetate layer. The solution was washed with a sodium chloride saturated aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diisopropyl ether and the precipitates were collected by filtration to give 7-(2-methoxyimino-3-oxobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 3.25 g.).