Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:18](=[O:37])[C:19](=O)[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[C:23]=1[OH:35])C>CO>[OH:35][C:23]1[C:24]([C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]1[C:17](=[O:16])[C:18](=[O:37])[C:19]=1[NH:13][CH:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1([CH3:12])[CH2:9][O:10][CH2:11]1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc(C(=O)N3CCCC3)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CCCC4)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 95.1 %

Procedure:
385 mg (2.12 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in solution in 3 ml of methanol were added to a solution of 443 mg (1.40 mmol) of 3-ethoxy-4-[2-hydroxy-3-(pyrrolidine-1-carbonyl)phenylamino]cyclobut-3-ene-1,2-dione in 42 ml of methanol. The reaction medium was heated at 50° C. for 13 hours. The reaction medium was concentrated. The residue was taken up with ethyl acetate and was washed twice with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 0.62 g of product were obtained in the form of a beige solid. Yield=95%, HPLC=94.06%, Mp=210° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].CC([N:12]([C@@H:16]([CH2:30][CH3:31])/[CH:17]=[CH:18]/[C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20])C(=O)[O-])(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[N:21]1([C:19](=[O:20])/[CH:18]=[CH:17]/[C@@H:16]([NH2:12])[CH2:30][CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
TFA (25 mL, 324 mmol) was added to a solution of 1,1-dimethylethyl[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-2-buten-1-yl]carbamate (7.21 g, 21.82 mmol) in CH2Cl2 (25 mL). The reaction was stirred at RT. After 3.5 h, CH2Cl2 (200 mL) was added, and the reaction was concentrated under reduced pressure and dried under high vacuum. LC-MS m/z 231 (M+H)+, 0.69 (ret time).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1([CH2:29][CH2:28][CH2:27][CH2:26]1)[N:6]([S:8]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7])C.Cl>[OH-].[Na+].CO>[ClH:25].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([S:8]([N:6]([CH3:7])[C:5]3([C:4]([OH:30])=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:9])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CCOC(=O)C1(N(C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Yield: 44.3 %

Procedure:
A solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine ethyl ester (80 mg, 0.176 mmol) in NaOH (1 ml, 2N) and MeOH (10 ml) was stirred at 70° C. for 18 h. The cooled mixture was neutralised using HCl (2N), and the MeOH was removed in vacuo. The resulting precipitate was filtered off, washed with water and re-dissolved in concentrated HCl. This solution was evaporated in vacuo, azeotroped with toluene, the residue dissolved in EtOH and filtered. The filtrate was evaporated in vacuo and the resulting solid recrystallised from i-PrOH, to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine hydrochloride (18 mg, 0.039 mmol) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O: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[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:22]=2[CH2:33][C:34]([O:36]C)=[O:35])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O: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[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][C:22]=2[CH2:33][C:34]([OH:36])=[O:35])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cc(-c2ccccc2)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(-c3ccccc3)cc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 102.8 %

Procedure:
To a mixture of methyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetate (0.65 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (2.8 mL) and the mixture was stirred at 50° C. for 1.5 hrs. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.65 g, 92%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 102-103° C.
Reaction SMILES: [Br:1][C:2]1[S:9][C:8]2[C:7]([CH:10]=[O:11])=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:5][C:4]=2[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[S:9][C:8]2[C:7]([CH:10]=[O:11])=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]([CH3:17])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1[nH]c2cc(Br)sc2c1C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C=O)c2sc(Br)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of aldehyde 62 (515 mg, 1.70 mmol) in DMF (5 mL) was added potassium carbonate (707 mg, 5.12 mmol) and iodomethane (0.27 mL, 3.40 mmol) and the resulting mixture was stirred at room temperature for 2 hr. To the mixture was added H2O (30 mL) and EtOAc (50 mL) and the organic layer was separated and washed with brine and dried over Na2SO4. After removing the organic solvent under reduced pressure, the residue was purified by column chromatography (EtOAc/Hexane: 1/8) to give the desired N-methylated product 63 (440 mg, 82%) as a white solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH2:16][C:15]2=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].Cl>CCOCC>[N+:23]([CH:16]1[C:15](=[O:22])[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:13]=2)[C:17]1=[O:21])([O-:25])=[O:24]
Reactant: O=C1CC(=O)c2cc(OCCCOc3ccccc3)ccc21
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CCOCC
Product: O=C1c2ccc(OCCCOc3ccccc3)cc2C(=O)C1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 5-(3-phenoxypropoxy)-indan-1,3-dione (0.296 gm, 0.001 mole) was suspended in dry ether (10 ml) and cooled to 0° C. The stirred mixture was treated with fuming nitric acid (1 ml) added dropwise over 15 mins and stirred in the ice bath for 1 hr. The mixture was then stirred at r.t. for a further 11/2 hrs. During this time all the solid dissolved leaving a deep yellow solution. Dilute hydrochloric acid (20 ml) was added and the ether evaporated in vacuo. A yellow gum formed which solidfied on scratching to give 0.25 gm of yellow solid which had mp 77°-79° C.(d). (73%). (Found; C, 60.71; H, 4.58; N, 3.66; C18H15NO6.0.75H2O requires; C, 60.92; H, 4.69; N, 3.95%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2].IC.[CH3:25]C([O-])(C)C.[K+]>C1COCC1>[C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH3:25])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2]
Reactant: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]propanoate (0.065 g, 0.209 mmol) in THF (1 mL) was added iodomethane (0.59 g, 4.18 mmol), followed by dropwise addition of t-BuOK (1M in THF, 0.63 mL, 6.3 mmol). After 10 min, the mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to afford the title compound: MS (ES) m/z 325 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]([NH2:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCC(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
To a stirred solution of the crude 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanamide in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (2.0 mL, 2.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was carefully quenched with MeOH, poured into brine (100 mL), extracted with ethyl acetate (2×100 mL), dried (Na2SO4) and concentrated to give 50 mg (65% yield, 3 steps) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropan-1-amine
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22](=[O:30])[CH2:21]1)=[O:19].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:12])[CH2:14][C:15]2[CH:33]=[CH:32][CH:31]=[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22](=[O:30])[CH2:21]3)=[O:19])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CNCc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(Cc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1)S(=O)(=O)c1ccc(Br)cc1
Reaction time: 18 h
Yield: 66.1 %

Procedure:
4-Bromobenzenesulphonyl chloride (29 mg, 0.11 mmol) was added to a solution of 1-(3-(methylaminomethyl)benzoyl-1,2,3,4-tetrahydroquinoxalin-3-one (30 mg, 0.10 mmol) in dichloromethane (10 ml). The pH was adjusted to pH9 with triethylamine and the mixture stirred for 18 h. The mixture was reduced in vacuo, taken up in ethyl acetate, washed with water and brine, dried and reduced. Chromatography (50% EtOAc/50% 60-80 pet ether) afforded 4-bromo-N-methyl-N-(3-(1,2,3,4-tetrahydroquinoxalin-3-one-1-carbonyl)benzyl)-benzenesulphonamide (34 mg, 60%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:18][N:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[NH:26][C:27]([NH2:29])=[O:28])[CH2:16][CH:15]3[O:30]C(=O)C)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:17]2[CH2:16][CH:15]([OH:30])[CH:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]4[CH:34]=[CH:35][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:18]2)=[C:20]([NH:26][C:27]([NH2:29])=[O:28])[CH:21]=1
Reactant: CC(=O)OC1CN(c2ccc(Cl)cc2NC(N)=O)CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)Nc1cc(Cl)ccc1N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of acetic acid 4-[4-(4-chloro-benzoyl)-piperazin-1-yl]-1-(4-chloro-2-ureido-phenyl)-pyrrolidin-3-yl ester (60 mg, 0.11 mmol) in MeOH (2 mL), was added K2CO3 (30 mg). The mixture was stirred for 2 h. After concentrating, the residue was purified by column chromatography (ethyl acetate:MeOH:Et3N: 10:1:0.1)) to give the desired product (20 mg, 50% yield) as a yellow oil. MS (ESI), M/Z, 478 (M+1). Retention time: 1.68 min (FA-polar).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.C([Mg]Br)C.[O:23]=O>C1COCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([OH:23])=[CH:3][CH:2]=1
Reactant: O=O
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: CC[Mg]Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Oc1cccc2c1sc1ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a cooled (−78° C.) solution of dibenzothiophene (20.8 g, 113 mmol) in anhydrous THF (400 ml) was added tert-butyl lithium (1.7 M in pentane; 100 ml, 170 mmol). The reaction mixture was stirred at −78° C. for 1 hour and then allowed to warm to room temperature and stirred like this for 16 hours. The mixture was then cooled to 0° C. and ethylmagnesium bromide (1M in THF; 170 ml, 170 mmol) added to the amber reaction mixture in a slow stream via cannula. The reaction was again allowed to room temperature whereupon it was stirred like this for 30 minutes. A reflux condenser was attached to the reaction vessel before oxygen was bubbled through the solution for 40 minutes. The mixture was then stirred for a further 1 hour before carefully pouring onto crushed ice and acidifying to pH 3 with concentrated HCl. The mixture was then extracted using ethyl acetate (3×80 ml). The organic extracts were then treated with 3M sodium hydroxide solution until pH 10 was attained. The basic, aqueous layer was separated, acidified to pH 3 with 2M HCl which caused an oily solid to precipitate. This was dissolved in diethylether (150 ml), dried using MgSO4, filtered and concentrated in vacuo and then recrystallised from ethanol:water (1:1) (250 ml) to give a buff coloured solid that corresponded to the title compound (21.6 g, 96%) and required no further purification. m/z (LC-MS, ESP), RT=3.64 min, (M+H)=201.1.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:27]1[C:23]([C@H:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[O:17][C:13]2[CH:14]=[C:15]([F:16])[C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:9])=[O:8])=[C:11]([F:30])[CH:12]=2)=[CH:24][CH:25]=[N:26]1)[CH3:29]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 87.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (231 mg, 0.385 mmol) prepared in Example 50a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (151 mg, 87%) as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21]CC1>CS(C)=O.C(OCC)C>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:25]2[CH2:26][CH2:27][C:22](=[O:21])[CH2:23][CH2:24]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: FC(F)(F)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-Chloro-3-(trifluoromethyl)pyridine (11.92 g, 65.7 mmol)), K2CO3(19.10 g, 138 mmol), and 1,4-dioxa-8-azaspiro[4.5]decane (8.85 mL, 69.0 mmol) were combined in DMSO (65 mL) and stirred at 100° C. for 3 hours. The mixture was treated with additional 1,4-dioxa-8-azaspiro[4.5]decane (2.0 mL, 16 mmol), stirred for 2 hours, treated with additional 1,4-dioxa-8-azaspiro[4.5]decane (1.0 mL, 7.8 mmol), and stirred for 1 hour. The mixture was diluted with diethyl ether (200 mL), washed with water (250 mL), washed with brine (100 mL), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in concentrated HCl (25 mL), stirred for 3 hours, basified with concentrated NH4OH, extracted with CH2Cl2, and the phases separated. The organic phase was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified via flash chromatography (20% to 40% diethyl ether/hexanes) to provide the title compound.
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].Cl.[C:30]([NH:34][OH:35])([CH3:33])([CH3:32])[CH3:31].CC(C)([O-])C.[K+].CCOC(C)=O>C1COCC1.CCN(CC)CC.CO>[C:30]([NH:34][O:35][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=1[C:11](/[N:10]=[C:9]1/[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH3:28])[C:7]([C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:8]/1)=[O:23])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)NO
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2ONC(C)(C)C)cc(C(C)(C)C)n1C
Temperature: 40 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of Example 81C (0.45 g, 1.1 mmol) and N-(tert-butyl)hydroxylamine hydrochloride (0.28 g, 2.3 mmol) in THF (20 mL) was added potassium tert-butoxide (0.19 g, 1.7 mmol). The mixture was warmed to 40° C. and stirred for 18 hours then additional potassium tert-butoxide was added (0.40 g). The mixture was stirred for an additional 1 hour then partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 50% hexanes/EtOAc then 100% EtOAc then 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (0.41 g, 0.88 mmol, 78% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J=7.3 Hz, 3H) 1.20 (s, 9H) 1.34-1.43 (m, 2H) 1.42 (s, 9H) 1.64-1.72 (m, 2H) 3.72 (s, 3H) 4.27 (dd, J=7.5 Hz, 2H) 5.75 (s, 1H) 7.01 (s, 1H) 7.46 (dd, J=8.6, 1.9 Hz, 1H) 7.67 (d, J=8.8 Hz, 1H) 8.10 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 469 (M+H)+; Anal. calculated for C24H35F3N4O2: Calc: C, 61.52; H, 7.53; N, 11.96. Found: C, 61.18; H, 7.26; N, 11.92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C2CCNC2)CC1
Reaction time: 2 h

Procedure:
tert-butyl 3-(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)pyrrolidine-1-carboxylate (690 mg, 1.6 mmol) was dissolved in dichloromethane (50 ml) at room temperature. Trifluoroacetic acid (3 ml) was added and the mixture left to stir for 2 hours then concentrated in vacuo.
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[BH4-].[Na+].Br[CH2:16][CH2:17][C@@H:18]1[O:24][C@:23]([C:29]#[C:30][CH:31]2[CH2:33][CH2:32]2)([C:25]([F:28])([F:27])[F:26])[C:22]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:21]=2[NH:20][C:19]1=[O:39]>C1COCC1.C(O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:21]2[NH:20][C:19](=[O:39])[C@H:18]([CH:17]=[CH2:16])[O:24][C@:23]([C:29]#[C:30][CH:31]3[CH2:33][CH2:32]3)([C:25]([F:26])([F:27])[F:28])[C:22]=2[CH:34]=1
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O[C@H]1CCBr
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=C[C@@H]1O[C@](C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a room temperature solution of 409 mg (1.8 mmol) of 2-nitrophenylselenocyanate in 5.0 mL of THF was added 16 mL of ethanol and 90 mg of sodium borohydride. After stirring 1 h, a solution of 260 mg of rel-(3S,5S)-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 8 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 2 h, at which time an additional 20 for an additional 2 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 130 mg of the title compound as a pure solid: HRMS: Calcd. for C17H14NO2F3Cl (M+H)+: 354.0508. Found: 354.0487.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)on2)cc1OC
Yield: 90.2 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-phenylpiperazine (5.9, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 26.55 hr and followed the same processes as in Example 1 to obtain 14.7 mg (100%) of the target compound.
Reaction SMILES: C(=O)(O)[O-].[Na+:5].Cl.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:29][O:30][CH3:31])[C:14]([NH:16][CH:17]2[C:27](=[O:28])[N:19]3[C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1>O>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:29][O:30][CH3:31])[C:14]([NH:16][CH:17]2[C:27](=[O:28])[N:19]3[C:20]([C:24]([O-:26])=[O:25])=[CH:21][CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1.[Na+:5]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C

Procedure:
Sodium bicarbonate (1.04 g.) was added to a solution of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 2.6 g.) in water (100 ml.) under ice-cooling and stirred at room temperature. The resultant solution was lyophilized to give sodium 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).