Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[N:9]1)(C)(C)C.S(=O)(=O)(O)O>O>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:41])([CH3:42])[CH3:43])[NH:17][C@H:16]2[C:14]([NH:13][C:10]2[CH:11]=[CH:12][N:8]([CH2:7][C:6]([OH:44])=[O:5])[N:9]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC(=O)OC(C)(C)C)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC(=O)O)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of rac-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-acetic acid tert-butyl ester (25 mg, 0.039 mmol) was chilled to 0° C. Then concentrated sulfuric acid (1 mL) was added and the reaction was stirred for 2 hours. Ice and water added all at once, crystals filtered and washed with water. The crystals were azeotroped three times with toluene then treated to high vacuum overnight to yield rac-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-acetic acid as an off white powder (12.1 mg, 53%). HRMS (ES+) m/z Calcd for C28H27Cl2F2N5O3+H [(M+H)+]: 590.1532. found: 590.1531.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27]Br>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27][C:12]1([O:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:13]1[CH:14]=[N:15][OH:16]
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Reactant: Cc1cccc(C=CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(OC2(CC=Cc3cccc(C)c3)C=CC=CC2C=NO)n1
Yield: 64.1 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 4.2 g of 3-methylcinnamyl bromide were dissolved in 30 ml of acetonitrile containing 2.7 g of anhydrous potassium carbonate, and the solution was heated for 5 hours under stirring and reflux. After the reaction mixture was allowed to cool down, the acetonitrile was distilled out under reduced pressure and the resulting residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate:4:1) to obtain 5.2 g of 0-(3-methylcinnamyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as crystals.
Reaction SMILES: O=[C:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+]>CO>[OH:28]/[N:27]=[C:2]1\[CH2:3][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][C@H:6]\1[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@H](CNC(=O)OCc2ccccc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C/C(=N\O)[C@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 3 h

Procedure:
Dissolve 1,1-dimethylethyl(4R)-3-oxo-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.87 g, 2.49 mmol) in 5:1 MeOH/H O (10 mL). Add in hydroxylamine HCl (0.177 g, 2.54 mmol) and sodium acetate (2.04 g, 24.9 mmol). The mixture was heated to reflux and allowed to stir 3 hours. After the reaction was complete the solution was concentrated under reduced pressure and extracted with CHCl3 (3×). The organic layer was washed with 0.5 M HCl and brine. The solution was dried over Na2SO4, and evaporated to yield an oil. (0.90 g, quant). LCMS: m/z 364.6 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:49])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[CH2:32][O:33][CH2:34][CH:35]=C)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:37])[C:12]=2[C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:7][CH2:6]1)[CH:2]=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:45]([O:44][C@@H:38]([C:12]1[C:13]([CH3:37])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:49])([O:4][CH2:1][CH:2]=[CH:35][CH2:34][O:33][CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:24]2[N:23]=[N:22][N:21]([CH:25]=2)[CH2:20]3)[CH2:6][CH2:7]1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:46])([CH3:47])[CH3:48]
Reactant: C=CCOCc1ccccc1-c1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CCOCc1ccccc1-c1cn(nn1)C3
Yield: 16.89 %

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-((allyloxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.055 g, 0.082 mmol) in 1,2-dichloroethane (20 mL) was added at once Hoveyda-Grubbs catalyst 2nd generation (2.56 mg, 4.09 μmol) at 70° C. and refluxed for 5 h. Then, cooled, concentrated and purified by prep-HPLC to afford a mixture of products and one major isomer. Trans-isomer (0.0089 g, 0.014 mmol, 16.89% yield), off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 7.94 (dd, J=1.1, 7.7 Hz, 1H), 7.39-7.46 (m, 2H), 7.32-7.36 (m, 1H), 6.73 (s, 1H), 6.00-6.13 (m, 2H), 5.98 (s, 1H), 5.89 (d, JAB=14.3 Hz, 1H), 5.65 (d, JAB=14.3 Hz, 1H), 4.58 (dt, J=2.3, 12.4 Hz, 1H), 4.49 (d, JAB=10.5 Hz, 1H), 4.40 (d, JAB=10.5 Hz, 1H), 4.08-4.22 (m, 4H), 3.95-4.05 (m, 2H), 3.75-3.82 (m, 1H), 3.03 (td, J=2.0, 11.5 Hz, 1H), 2.73-2.79 (m, 1H), 2.61 (s, 3H), 2.00 (dd, J=2.4, 13.6 Hz, 1H), 1.90 (dd, J=2.1, 13.7 Hz, 1H), 1.67-1.74 (m, 2H), 1.31 (s, 3H), 1.24 (s, 9H), 1.18 (t, J=7.1 Hz, 3H). LCMS (M+H)=644.6. This is contaminated with minor isomer.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][C:10]=1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:21]([O-])=O.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([N:15]=[N+:16]=[N-:21])=[O:14])=[CH:11][C:10]=1[Cl:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 5 °C
Yield: 96.8 %

Procedure:
4-Benzyloxy-3-chlorobenzoic acid hydrazide (27.6 g., 0.1 mole) is suspended in 500 ml. 1N hydrochloric acid and the mixture cooled to about 0° C. A solution of sodium nitrite (7.0 g.) in 40 ml. water is added at such a rate as to keep the temperature below 5° C. The mixture is stirred at 5° C for 3/4 hr., filtered and the precipitate dried in vacuo to give 27.8 g., (96.8% yield) 4-benzyloxy-3-chlorobenzoyl azide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:18][CH:19]=2)[O:14]1)([O-])=O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:18][CH:19]=2)[O:14]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCOc1cccc([N+](=O)[O-])c1)CC2
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCOc1cccc(N)c1)CC2
Yield: 69.9 %

Procedure:
To a mixture of N-(2-{[3-(3-nitro-phenoxy)-propylamino]-methyl}-chroman-7-yl)-methanesulfonamide and hydrazine in ethanol at 5° C. was added Raney nickel (400 mg). After 0.5 hour another portion of Raney nickel (300 mg) was added and the reaction was heated to reflux for 1 hour. The catalyst was filtered and the solvent removed to afford N-(2-{[3-(3-amino-phenoxy)-propylamino]-methyl}-chroman-7-yl)-methanesulfonamide in 69.9% yield. The (2:1)oxalate, hemihydrate was prepared from tetrahydrofuran and triturated in methanol, mp 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[O:4][NH2:5].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>N1C=CC=CC=1.ClCCl>[C:15]1([O:14][C:12](=[O:13])[NH:5][O:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[Cl:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NOc1cccc(Cl)c1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NOc1cccc(Cl)c1Cl)Oc1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
9.10 g (51.1 mmole) of 2,3-dichlorophenoxyamine was dissolved in 7.5 ml of pyridine and 70 ml of dichloromethane, and the solution was cooled to -10° C. Then, 30 ml of a dichloromethane solution containing 7.28 g (46.5 mmole) of phenyl chloroformate was dropwise added thereto over a period of 1 hour, and the mixture was stirred at a temperature of from -10° to 25° C. for 6 hours. The solvent was distilled off under reduced pressure, and 300 ml of ethyl acetate was added. The mixture was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue thereby obtained was recrystallized from toluene/hexane, whereby 11.5 g of the desired product was obtained as light brown crystals (yield: 83%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl-].[Li+].C([Mg]Cl)(C)C.[C:13]([C@@H:16]1[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]1)(=[O:15])[CH3:14]>C1COCC1.[NH4+].[Cl-].C(OCC)C>[OH:15][C:13]([C@@H:16]1[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: c1cscn1
Reactant: COC(=O)[C@H]1CC[C@@H](C(C)=O)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](C(C)(O)c2nccs2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thiazole (501 mg, 5.88 mmol) was dissolved in THF (1.2 mL) and isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 5.88 mL, 7.64 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hr. Cis-methyl 3-acetylcyclopentanecarboxylate (1.2 g, 7.05 mmol) was then added as a solution in THF (2 mL) and the reaction mixture was stirred for 3 hrs at room temperature. The reaction mixture was diluted with saturated NH4Cl and diethyl ether. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (12% to 100% Et2O in Hexanes) to afford cis-methyl 3-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclopentanecarboxylate as a colorless oil; MS ESI calc'd. for C12H18NO3S [M+H]+ 256. found 256.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:15][Mg]Br>C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[CH2:15][C:14]1[CH:18]=[CH:19][C:20]([F:21])=[C:12]([F:11])[CH:13]=1
Reactant: Fc1ccc(C[Mg]Br)cc1F
Reactant: Nc1cccc(Cl)c1C=O
Solvent: CCOC(C)=O
Product: Nc1cccc(Cl)c1C(O)Cc1ccc(F)c(F)c1
Yield: 51.9 %

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from 2-amino-6-chlorobenzaldehyde (0.30 g, 1.9 mmol) and 3,4-difluorobenzylmagnesium bromide (generated from 3,4-difluorobenzyl bromide and magnesium in ether, 3.9 mmol, 2 equiv) to afford 0.28 g (57%) of (±)-1-(2-amino-6-chlorophenyl)-2-(3,4-difluorophenyl)ethanol after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClC1C=CC=CC=1>[NH2:8][C:6]1[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Solvent: Clc1ccccc1
Product: COc1cc(Cc2cnc(NC(=O)Cc3ccccc3)nc2N)cc(OC)c1OC

Procedure:
5.8 g of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine (trimethoprim) are suspended in 58 ml of chlorobenzene. At 125° C., 1.55 g of phenylacetyl chloride are dripped in, and the whole is maintained at this temperature for five hours. The difficultly soluble trimethoprim hydrochloride is filtered off and the filtrate is concentrated in vacuo. Upon recrystallization from ethanol there is obtained 4-amino-2-phenylacetamido-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 181° to 183° C.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][C:17]([Cl:34])=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([OH:23])=O)[N:19]=1)=[O:13].Cl.[NH2:36][CH:37]1[C:62](=[O:63])[N:39]2[C:40]([C:46]([O:48][CH:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[S:47])=[C:41]([CH2:44][CH3:45])[CH2:42][S:43][C@H:38]12.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][C:17]([Cl:34])=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([NH:36][CH:37]2[C:62](=[O:63])[N:39]3[C:40]([C:46]([O:48][CH:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[S:47])=[C:41]([CH2:44][CH3:45])[CH2:42][S:43][C@H:38]23)=[O:23])[N:19]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[N+](C)=CCl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nc(NC=O)sc3Cl)[C@H]2SC1
Yield: 378.3 %

Procedure:
Vilsmeier reagent prepared from N,N-dimethylformamide (0.42 ml) and phosphorus oxychloride (0.527 ml) was suspended in dry tetrahydrofuran (30.5 ml). To a suspension was added 2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 2.8 g) under ice-cooling with stirring and then the solution was stirred at the same temperature for an hour to prepare the activated acid solution. To the solution of benzhydryl 7-amino-3-ethylthio-3-cephem-4-carboxylate hydrochloride (2.0 g) and monotrimethylsilylacetamide (5.7 g) in methylene chloride (40 ml) was added the activated acid solution obtained above all at once at -0° C. and the mixed solution was stirred at -20° to -10° C. for an hour. After water and ethyl acetate (150 ml) were added to the resultant solution, the mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 12.8 g), mp. 143° to 148° C.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([O:54][C:55](=[O:66])[NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH2:65])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55](=[O:66])[NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH:65][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[NH:15][C:13](=[O:14])[NH:12][CH:11]2[CH2:10][S:9]1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 21 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A solution of biotin (0.59 g, 2.42 mmol, 1.5 eq), HBTU (0.79 g, 2.10 mmol, 1.3 eq) and DIEA (0.45 mL, 2.60 mmol, 1.6 eq) in DMF (15 mL) was stirred for 20 min at 21° C. before being added dropwise to a solution of tert-butyl-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (400 mg, 1.61 mmol, 1 eq) in DMF (10 mL). The reaction mixture was stirred for 2 h at 21° C., after which the DMF was removed in vacuo to give a yellow residue. The crude product was purified by column chromatography (gradient 2-10% MeOH/CH2Cl2) to yield the desired compound as a white solid (0.61 g, 1.29 mmol, 80% yield). m.p. 106-108° C.; [α]D20.0+23.0 (c 0.6, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.55 (dd, J=5.0, 7.5 Hz, 1H, NHC(O)NHCH), 4.36 (dd, J=5.0, 7.5 Hz, 1H, NHC(O)NHCH), 3.62 (bs, 6H, OCH2), 3.59-3.55 (m, 2H, OCH2), 3.46 (m, 2H, NCH2), 3.31 (m, 2H, NCH2), 3.17 (dt, 3.0, 5.0 Hz, 1H, SCH), 2.92 (dd, J=5.0, 13.0 Hz, 1H, SCHH), 2.79 (d, J=13.0 Hz, 1H, SCHH), 2.27 (t, J=7.0 Hz, 2H, NHC(O)CH2CH2CH2), 1.71 (m, 4H, NHC(O)CH2CH2CH2CH2), 1.47 (br, 11H, C(CH3)3 & NHC(O)CH2CH2CH2CH2); 13C NMR (125 MHz, CDCl3) δ 173.69 (s), 163.92 (s), 155.99 (s), 79.14 (s), 70.03 (t), 69.69 (br t), 61.58 (d), 60.06 (d), 55.19 (d), 40.16 (t), 39.96 (t), 38.91 (t), 35.44 (t), 28.09 (q), 27.80 (t), 27.67 (t), 25.23 (t), * 2 t absent; IR (neat) 3307, 2933, 1691 cm−; HRMS (ES) calcd for C21H38N4O6NaS [M+Na]+ 497.2410, observed 497.2423.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[C:24]([Br:25])=[CH:23][N:22]([CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:25][C:24]1[C:20]([C:16]2[CH:15]=[C:14]([NH:13][C:10]([O:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])[CH:19]=[CH:18][CH:17]=2)=[N:21][N:22]([CH3:26])[CH:23]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)Nc2cccc(-c3nn(C)cc3Br)c2)cc1
Yield: 52.2 %

Procedure:
To 4-methoxyphenylchloroformate (19 mg, 0.10 mmol) in CH2Cl2 (0.5 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (25 mg, 0.10 mmol) and triethylamine (14 μL, 0.10 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred for 16 H and concentrated. Chromatography on flash silica (40% EtOAc/hexane) gave the title compound as a colourless solid (21 mg, 52%), m.p. 140.3-141.8° C. (EtOAc/hexane).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:23][CH2:22][CH:21]([C@@:18]3([CH3:20])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:26][CH2:25]2)[O:29][N:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)C(=N)NO
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Product: CC(C)(C)c1noc(N2CCC([C@]3(C)Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 33; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Example 2. LC (method 4): tR=0.93 min; Mass spectrum (ESI+): m/z=497 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1ccccc1-3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(NCCN(C)C)COc1ccccc1-3
Reaction time: 0.08 h

Procedure:
To a solution of methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from Step 4) in 1,2-dichloroethane (0.08 M), were added 1.0 eq of N,N-dimethylethane-1,2-diamine and 1.5 eq acetic acid, followed by 1.5 eq. of solid sodium triacetoxyborohydride. NaOH (20 eq, 1 N) was added after 2 h, and after stirring for 5 min the mixture was taken into EtOAc and washed with water and brine. Drying over sodium sulfate and concentration in vacuo gave the crude product, which was used without further purification; MS (ES+) m/z 476 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([SH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[O-]CC.[Na+].[CH:20]12[O:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]2.O>C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:15][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[OH:26])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:1])[CH3:3]
Reactant: C1CCC2OC2C1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
3,5-Bis(1,1-dimethylethyl)benzenethiol (Example 2) (5.0 g, 0.0225 moles) was added to freshly prepared sodium ethoxide (0.0230 moles) in absolute ethyl alcohol (50 ml). After stirring for 1 hour, cyclohexene oxide (2.2 g; 0.0225 moles) was added by syringe over 5 minutes, and the reaction mixture was stirred for 60 hours at room temperature. Water (100 ml) was added, and the reaction mixture was extracted twice with 75 ml of ethyl acetate. The combined ethyl acetate extracts were washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated to give the title product as a yellow solid, which was recrystallized from cold pentane. The structure assignment was supported by NMR spectroscopy. The title compound was used in Example 4.