Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]([N:22]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24][CH2:23]2)=[O:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:30]1COCC1.C[Mg]Br.O.O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]([N:22]2[CH2:28][CH2:27][CH2:26][C:25]([OH:29])([CH3:30])[CH2:24][CH2:23]2)=[O:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCOC1
Reactant: O=C1CCCN(C(=O)C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Agent: C[Mg]Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(O)CCCN(C(=O)C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydropyrazin-2-yl)acetyl)azepan-4-one (4) (0.0250 g, 0.054 mmol) in THF (8.00 ml, 0.054 mmol) under N2 was added methylmagnesium bromide (1.4M solution in THF/Toluene (75:25), 2.70 ml, 3.78 mmol) in thee times, and stirred overnight. The reaction mixture was cooled in ice-water bath and sodium sulfate dodecahydrate (10.0 g) was added slowly followed by AcOEt (20 ml). After stirring at r.t. for 1 h, the mixture was filtered and the solid was washed with AcOEt. The filtrate was concentrated under reduced pressure and the crude product was chomatographed on silica (CH2Cl2→CH2Cl2/MeOH=20/1) to yield the product. MS 476 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:22][CH2:23][CH3:24])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].C(N=C=NC(C)C)(C)C>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:15]2([OH:16])[CH:17]=[CH:18][CH:19]=[CH:20][CH:14]2[C:13]([O:22][CH2:23][CH3:24])=[O:21])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CCOC(=O)c1ccccc1O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)C1C=CC=CC1(O)C(=O)CCCc1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of 1.00 g of 4-phenylbutyric acid and 60 mg of N,N-dimethylaminopyridine in 20 ml of dichloromethane is added 0.75 ml of ethyl salicylate, followed by 0.95 ml of diisopropyl carbodiimide. After 18 hours, the mixture is concentrated under reduced pressure, and the residue triturated with ether. The organic phase is washed with aq. sodium bicarbonate and brine, dried (magnesium sulfate), and concentrated under reduced pressure. Flash chromatography on silica with 10% ethyl acetate in hexane affords 1.61 g of the title product as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13]>CN1CCCC1=O>[C:12]([C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1)#[N:13]
Reactant: N#C[Cu]
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(N)c(F)c1

Procedure:
reacting 4-bromo-2,6-difluoroaniline with copper (I) cyanide and N-methyl-2-pyrrolidone to yield 4-cyano-2,6-difluoroaniline;
Reaction SMILES: C([O:3][C:4]([C:6](=[CH2:25])[CH2:7][CH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:13]1)=[O:11])=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([C:6](=[CH2:25])[CH2:7][CH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[NH:13]1)=[O:11])([OH:5])=[O:3]
Reactant: C=C(CCCC(=O)N1CCC[C@@H](C(=O)OC(C)(C)C)N1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(CCCC(=O)N1CCC[C@@H](C(=O)OC(C)(C)C)N1)C(=O)O
Yield: 47.9 %

Procedure:
A solution of 8.2 g of tert.butyl 1-[5-(ethoxycarbonyl)-5-hexenoyl]-hexahydro-3-(S)-pyridazinecarboxylate in 25 ml of ethanol was treated with 23.7 ml of 1N aqueous sodium hydroxide solution for 16 hours. The solution was diluted with 80 ml of water and the volume was then reduced to 80 ml by evaporation. The solution was washed with diethyl ether and the pH of the aqueous solution was adjusted to 3 using 2N aqueous hydrochloric acid. The solution was then extracted with dichloromethane. The organic solution was evaporated and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution, whereby there were obtained 3.62 g of tert.butyl 1-[5-(carboxy)-5-hexenoyl]-hexahydro-3(S)-pyridazinecarboxylate in the form of a white solid of melting point 86°-88° C., from n-hexane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](O)[CH3:9])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.O=S(Cl)[Cl:23]>C(Cl)Cl>[Cl:23][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:5][CH:6]=1)[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C(C)O
Solvent: ClCCl
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C(C)Cl

Procedure:
0.530 g (1.89 mmol) of the above prepared [rac]-1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol was dissolved in 9.5 ml of CH2Cl2 and treated dropwise at 0° C. with 0.275 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with EtOEt, washing with water, drying over sodium sulfate and evaporation of the solvents yielded 0.586 g of pure title compound as light yellow oil.
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][C:5]#[C:4][CH:1]2[CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC#CC1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC#CC2CC2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3 h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:18](=[O:19])[N:17]3[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:18](=[O:19])[N:17]3[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[CH:11]2[OH:20])=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(N2C(=O)C3CCCCN3C2=O)c(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N2C(=O)N3CCCCC3C2O)c(F)cc1Cl
Temperature: 30 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
31.3 g (0.10 mol) of 8-(4-chloro-2-fluoro-5-methoxyphenyl)-7,9-dioxo-1,8-diazabicyclo[4.3.0]nonane were dissolved in 200 ml of methanol. 5.7 g (0.15 mol) of sodium borohydride were added in portions at a rate such that the temperature was kept at 30°-40° C. When the addition was complete, the mixture was stirred for a further 1 hour at 30° C. and poured into 500 ml of water. The precipitate which deposited was filtered off under suction and dried. 29.8 g (94% of theory) of 8-(4-chloro-2-fluoro-5-methoxyphenyl)-7-hydroxy-9-oxo-1,8-diazabicyclo[4.3.0]nonane were obtained in the form of colorless crystals having the melting point 155°-157° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])=O.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:12]([N:14]([CH2:1][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])[CH2:15][CH3:16])[CH3:13]
Reactant: Cc1cc(C(=O)O)sc1C=O
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)Cc1sc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
To a solution of 5-formyl-4-methyl-thiophene-2-carboxylic acid (6.90 g, 40.5 mmol) in THF (150 mL), diethylamine (5.93 g, 81.1 mmol) and acetic acid (10 mL) followed by sodium triacetoxyborohydride (14.32 g, 60.8 mmol) is added. The mixture becomes slightly warm. The reaction mixture is stirred at rt for 16 h before it is concentrated and separated by CC on silica gel eluting with EA containing 0-50% of methanol to give the title compound (4.95 g) containing large amount of diethylammonium salts. The material (4.94 g, 21.8 mmol) is therefore dissolved in methanol (70 mL) and treated with chloro trimethylsilane (23.7 g, 218 mmol). The mixture is stirred at 50° C. for 18 h before it is concentrated, dissolved in EA and washed with sat. aq. NaHCO3 solution. The organic extract is dried over Na2SO4, filtered, concentrated and dried to give 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid methyl ester (4.05 g) as a yellow oil; 1H NMR (CDCl3): δ 1.08 (t, J=7.0 Hz, 6H), 2.19 (s, 3H), 2.59 (q, J=7.0 Hz, 4H), 3.67 (s, 2H), 3.87 (s, 3H), 7.28 (s, 1H), 7.52 (s, 1H). This material is dissolved in 1 N aq. HCl (80 mL) and stirred at 65° C. for 214 h. The solvent is evaporated and the residue is dried under high vacuum to give the title compound (3.56 g) as a pale beige solid; LC-MS: tR=0.26 min; [M+1]+=228.20; 1H NMR (D6-DMSO): δ 1.28 (t, J=7.3 Hz, 6H), 2.31 (s, 3H), 3.12 (q, J=6.8 Hz, 4H), 4.48 (s, 2H), 7.59 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:31][CH:32]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Reaction time: 20 h
Yield: 87.5 %

Procedure:
To a solution of N1-(3-cyanobenzoyl)-1,2-benzenediamine (500 mg, 2.1 mmol), triethylamine (0.44 mL, 3.2 mmol) in methylene chloride (100 mL) was added 4-tert-butylbenzoyl chloride (0.41 mL, 2.1 mmol). After stirring for 20 hours, the reaction mixture was concentrated in vacuo. Chromatography (silica gel, 20% ethyl acetate/80% hexanes) yielded 730 mg (87%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[C:26]([F:38])=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:28]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(Cl)c2F)n1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-chloro-2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.321 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.066 g (40% yield) of pure product: MS (ES) m/z 530 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:4]([OH:6])=O.C(Cl)CCl.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([CH3:27])[CH:19]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:12][N:2]([CH3:1])[CH:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:4]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([CH3:27])[CH:19]=1)=[O:6]
Reactant: Cc1cc(N)ccc1C(N)=O
Reactant: CN(C)C(C(=O)O)c1ccsc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)C(c2ccsc2)N(C)C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 2-(dimethylamino)-2-(thiophen-3-yl)acetic acid in pyridine was added EDC, DMAP and 4-amino-2-methylbenzamide (E112) and the solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)-2-methylbenzamide (E113).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH2:32])[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH:32][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: CC(C)Oc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 94.4 %

Procedure:
Following a similar procedure to that described in Example (1a), 850 mg of 3-nitrophenyl 4-isopropoxyphenyl ketone, 936 mg of 1-(3,5-difluorophenyl)ethylamine, 1.66 ml of triethylamine, 0.39 ml of titanium tetrachloride, 788 mg of sodium cyanoborohydride and 0.26 ml of acetic acid were reacted, to obtain 1.20 g of the title compound as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=2[CH3:18])[CH:2]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:27]([Si:31](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28].N1C=CN=C1>ClCCl.O>[Si:31]([O:17][C:10]1[C:9]([CH3:18])=[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:13]([OH:14])=[C:12]([CH3:15])[C:11]=1[CH3:16])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1=C(C)C(=O)C(Cc2cccnc2)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: Cc1c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(Cc2cccnc2)c1O
Reaction time: 1 h

Procedure:
6-(3-Pyridylmethyl)-2,3,5-trimethyl-1,4-benzoquinone (241 mg, 1 mmol) was dissolved in dichloromethane (5 ml). The solution was stirred for 1 hour with a solution containing sodium hydrosulfite (400 mg, 2.3 mmol) in water (5 ml). The dichloromethane layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 ml), and tert-butylchlorodiphenylsilane (550 mg, 2 mmol) was added. Then imidazole (136 mg, 2 mmol) was added under a stream of nitrogen. The reaction mixture was stirred at 43° C. for 16 hours and washed with water (5 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 4-tert-butyldiphenylsilyloxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenol. This crude product was dissolved in dichloromethane (10 ml), and methyl 1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranosiduronate (1 g, 2.1 mmol) was added. Boron trifluoride diethyl ether (0.2 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then water (10 ml) containing sodium bicarbonate (1 g) was added, and the mixture was stirred for 5 minutes. The dichloromethane layer was separated and concentrated under reduced pressure. To the residue were added tetrahydrofuran (15 ml), methanol (10 ml) and 1N sodium hydroxide solution (20 ml), and the mixture was allowed to react at room temperature for 40 hours and concentrated under reduced pressure. The residue was extracted with ether, and the aqueous layer was subjected to Sephadex (trade mark) LH-20 column chromatography and eluted with water. The desired fraction was lyophilized to obtain the desired compound (210 mg) as white powder.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][CH:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:29]([CH:28]([OH:27])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)C(O)Cc1ccccc1
Product: CON=C1C[C@@H](c2noc(C(O)Cc3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2RS)-2-hydroxy-3-phenylpropanoic acid, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=483.3.
Reaction SMILES: O1CCCC1.[CH3:6][N:7]([CH3:29])[C:8]([C@@H:10]1[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])=[O:9].C([N-]C1CCCCC1)(C)C.Br[Mg+].C(N(CC)C(C1C=CC=CC=1S([C:55]1[C@H:56]([CH3:83])[C@@H:57]2[C@@H:74]([C@H:75]([O:77][Si:78]([CH3:81])([CH3:80])[CH3:79])[CH3:76])[C:73](=[O:82])[N:58]2[C:59]=1[C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=1)=[O:61])=O)=O)C>C(OCC)(=O)C>[CH3:6][N:7]([CH3:29])[C:8]([C@H:10]1[N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:17])[CH2:12][C@@H:13]([S:15][C:55]2[C@H:56]([CH3:83])[C@@H:57]3[C@@H:74]([C@H:75]([O:77][Si:78]([CH3:81])([CH3:80])[CH3:79])[CH3:76])[C:73](=[O:82])[N:58]3[C:59]=2[C:60]([O:62][CH2:63][C:64]2[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=2)=[O:61])[CH2:14]1)=[O:9]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]2[C@H]1C
Agent: CC(C)[N-]C1CCCCC1
Agent: [Mg+]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
2 ml of a tetrahydrofuran solution containing 68 mg (0.19 mmol) of (2S,4S)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine were cooled in an ice bath, and then 0.19 ml (0.19 mmol) of a 1M tetrahydrofuran solution of bromomagnesium N-isopropyl-N-cyclohexylamide were added dropwise over a period of 2 minutes. The mixture was stirred for a further 10 minutes at this temperature, and then 1 ml of a tetrahydrofuran solution containing 100 mg of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 38) was added. The mixture was stirred for a further 15 minutes at this temperature, after which ice water was added. The reaction solution was then diluted with ethyl acetate, washed with an aqueous solution of ammonium chloride then with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 10 g of silica gel, eluted with ethyl acetate, to give 94 mg (yield 78%) of the title compound as a foam-like solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH3:13])[C:3]=1[CH:14]=[O:15].CO[C:18]1C=C(C)C=C[C:19]=1C(=O)CC>>[Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH3:13])[C:3]=1[C:14](=[O:15])[CH2:18][CH3:19]
Reactant: Cn1c(-c2ccccc2)nc(Cl)c1C=O
Reactant: CCC(=O)c1ccc(C)cc1OC
Product: CCC(=O)c1c(Cl)nc(-c2ccccc2)n1C

Procedure:
The title compound is prepared from 5-chloro-3-methyl-2-phenyl-3H-imidazole-4-carbaldehyde analogously to 1-(2-methoxy-4-methyl-phenyl)-propan-1-one (Intermediate N).
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)=[N:9][N:10]=1)([CH3:5])[CH2:3][OH:4].C([O:32][P:33](Cl)([O:35]CC)=[O:34])C.C(N(CC)CC)C.Br[Si](C)(C)C>C(Cl)Cl>[P:33]([OH:35])([OH:34])([O:4][CH2:3][C@:2]([NH2:1])([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:28])([F:27])[F:29])[CH:12]=2)=[N:9][N:10]=1)[CH3:5])=[O:32]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)CO)s2)cc1C(F)(F)F
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)COP(=O)(O)O)s2)cc1C(F)(F)F
Reaction time: 36 h
Yield: 5.7 %

Procedure:
Crude product from E3 (30 mg, 0.069 mmol) was added to diethylchlorophosphate (100 μL, 0.69 mmol) and triethylamine (194 μL, 1.39 mmol,) in DCM and stirred for approx 36 hrs. The reaction mixture was then condensed and treated with bromotrimethylsilan (0.3 mL) in DCM (5 mL) to provide the title compound (˜2 mg). MS (ESI): 511.98 (MH+),
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:46])[CH2:32][C@@H:33]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[C:34]1[CH:38]=[CH:37][O:36][N:35]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:4][C:3]([CH2:2][O:45][C:42]3[CH:43]=[CH:44][C:39]([C@@H:33]([C:34]4[CH:38]=[CH:37][O:36][N:35]=4)[CH2:32][C:31]([N:26]4[C@@H:25]([CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:29][O:28][C:27]4=[O:30])=[O:46])=[CH:40][CH:41]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccc(-c2ccc(CCl)s2)cc1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A mixture of 60.5 (0.16 mmol), 7.5 (52 mg, 0.13 mmol), and Cs2CO3 (135 mg, 0.41 mmol) in DMF (1.6 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 60.6 (26 mg, 32%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.48 (d, 2H), 7.28 (m, 5H), 7.19 (m, 4H), 7.14 (d, 1H), 7.04 (d, 1H), 6.96 (d, 2H), 6.13 (d, 1H), 5.17 (s, 2H), 4.75 (t, 1H), 4.61 (m, 1H), 4.13 (m, 2H), 4.02 (dd, 1H), 3.54 (dd, 1H), 3.20 (dd, 1H), 2.76 (dd, 1H), 2.62 (t, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).