Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=1)[C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([C:36]([N:8]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:7][CH:6]=3)[C:10]3([CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH2:11]3)[CH2:9]2)=[O:37])[CH:39]=[CH:40][N:41]=1
Reactant: Clc1ccc(/C=C/CN2CCC3(CNc4ccc(Cl)cc43)C2)cc1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccnc(Cl)c1)N1CC2(CCN(C/C=C/c3ccc(Cl)cc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] (150 mg) and triethylamine (0.24 ml) in dichloromethane (5 ml) at 0° C. under argon was treated with 2-chloro-isonicotinoyl chloride (147 mg). The resulting solution was stirred at room temperature for 1 hour, poured into saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried (Na2SO4) and concentrated in vacuo. Silica gel chromatography of the residue (eluent cyclohexane:ethyl acetate 6:4) afforded the title compound, 1-(2-chloropyridin-4-yl)carbonyl-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] (95 mg), which was characterised by its mass and NMR spectra. MS (ES+) 495/500 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([Br:15])[CH:3]=1.[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[F:43])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([Br:15])[CH:3]=2)=[CH:30][C:29]=1[F:43])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(OCCCOCc3ccccc3)c(F)c2)OC1(C)C
Reactant: COCCOCOc1cc(Br)cc(Br)c1
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1cc(Br)cc(-c2ccc(OCCCOCc3ccccc3)c(F)c2)c1

Procedure:
17.0 g (50.0 mmol) 1,3-dibromo-5-(2-methoxy-ethoxymethoxy)-benzene, 19.3 g (50.0 mmol) 2-[4-(3-benzyloxy-propoxy)-3-fluoro-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 41.3 g (150 mmol) sodium metaborate-tetrahydrate are suspended in 200 ml THF and 200 ml water and 1.6 g (2 mmol) palladium(dppf) are added. The mixture is heated overnight at reflux. After partial removal of the solvent and addition of 100 ml MTB ether, the mixture is acidified with 2M hydrochloric acid. The organic layer is separated and the aqueous layer is extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. The crude product is filtered through silica gel with toluene/ethylacetate (7:3 to 1:1) to yield 4-(3-benzyloxy-propoxy)-3′-bromo-3-fluoro-5′-(2-methoxy-ethoxymethoxy)-biphenyl as a yellow oil.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH2:17])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:18][CH2:19][CH3:20])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=3)[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:7]2[CH2:18][CH2:19][CH3:20])=[CH:24][CH:23]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCCc1[nH]c2cc(C(N)=O)ccc2c1C(=O)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 66.6 %

Procedure:
A mixture of 3-isobutyryl-2-propylindole-6-carboxamide (100 mg), 4-chlorobenzyl bromide (113 mg) and potassium carbonate (152 mg) in dimethylformamide (2 ml) was heated at 60° C. for 2 hours, and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was crystallized from a mixture of ethyl acetate and hexane. The crude crystals were recrystallized from a mixture of ethyl acetate and hexane to give 1-(4-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide (97 mg) as colorless crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[NH2:17][C@@H:18]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20]>>[CH2:38]([O:37][CH2:36][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([C:9]([F:10])([F:11])[F:12])=[C:3]([F:2])[CH:4]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cc1ccc(C(F)(F)F)c(F)c1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 42.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 101, (S)-3-(benzyloxy)-2-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (3 mg, 42.8%). MS (EI) for C31H25F5N2O4. found 585.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: O=C(CCc1ccc(O)c(F)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(2-fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-butanoate is prepared from 3-(3-fluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl 2-bromobutanoate according to general procedure D.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=O)[CH2:11]S(C)=O.[C:16]([C:18]1[CH:27]=[CH:26][C:21]([CH:22]=[CH:23][CH:24]=O)=[CH:20][CH:19]=1)#[N:17].COC1C2OC(C=CC3C=CC(C#N)=CC=3)=CC(=O)C=2C=CC=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:24]([CH:23]=[CH:22][C:21]3[CH:20]=[CH:19][C:18]([C:16]#[N:17])=[CH:27][CH:26]=3)=[CH:11][CH2:10][C:3]=2[CH:4]=1
Reactant: N#Cc1ccc(C=CC=O)cc1
Reactant: COc1ccc(O)c(C(=O)CS(C)=O)c1
Agent: COc1cccc2c(=O)cc(C=Cc3ccc(C#N)cc3)oc12
Product: COc1ccc2c(c1)CC=C(C=Cc1ccc(C#N)cc1)O2

Procedure:
This was prepared by reacting 11.4g of 2'-hydroxy-5'-methoxy-2-(methylsulfinyl)acetophenone with 7.85 g of p-cyanocinnamaldehyde in analogous fashion to 4-[2-(8-methoxy-4-oxo-4H-1-benzopyran-2-yl) ethenyl]benzonitrile. The material was recrystallized from toluene. mp 224°-26°; yield 6.5g (43%); λ max mμ (ε) 224 (20,600), 294 (21,900), 332 (43,500); ν max 820 (m), 980 (ms), 1080 (m), 1290 (m), 1580 (m), 1620 (s), 1645 (s), 2240 (m) cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[N:4]([OH:6])[CH3:5].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19]OS(C)(=O)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][CH2:19][O:6][N:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: COC(=O)N(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6 %

Procedure:
To a solution of N-Hydroxy-N-methyl-carbamic acid methyl ester (5.90 g, 56.2 mmol), as prepared in the previous step, in DMF (130 mL) at 0° C. was added NaH (1.35 g, 53 mmol) in one portion. The mixture was stirred at room temperature for 15 min, then stirred on an ice bath while a solution of methanesulfonic acid 2-tert-butoxycarbonylamino-ethyl ester (10.38 g, 43 mmol) (Clagett-Dame, M., et al; Biochim. Biophys. Acta, 986:271-280, 1989) in DMF (50 mL) was added in one portion. The ice bath was removed and the mixture stirred at room temperature 23 h. The DMF was removed by rotary evaporation, the residue was diluted with half-saturated NaHCO3 (100 mL), and extracted with EtOAc (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Flash chromatographic purification of the residue (3:2 hex/EtOAc) afforded 643 mg of the title compound as a colorless oil (2.59 mmol, 6% yield). 1H NMR (300 Hz, CDCl3) δ 5.38 (br s, 1H), 3.89 (t, J=5.1 Hz, 2H), 3.78 (s, 3H), 3.34 (q, J=5.5 Hz, 2H), 3.14 (s, 3H), 1.45 (s, 9H); LC/MS (m/z) [MH+−Boc] 149 (calculated for C5H13N2O3, 149.1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22][O:23][C:24](=[O:44])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]OS(C)(=O)=O>>[CH3:22][O:23][C:24](=[O:44])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Reactant: COC(=O)CCc1ccccc1OCCCCCOS(C)(=O)=O
Product: COC(=O)CCc1ccccc1OCCCCCOc1ccc2c(c1CCCc1ccccc1)OCCC2=O
Yield: 75.5 %

Procedure:
Using the procedure of example 11 and starting with 1.13 g (4 mmol) of 2,3-dihydro-7-hydroxy-8-(3-phenylpropyl)-4H-1-benzopyran-4-one (from example 194) and 1.38 g (4 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]benzenepropanoic acid methyl ester (from example 72), 2-[[5-[[3,4-dihydro-4-oxo-8-(3-phenylpropyl)-2H-1-benzopyran-7-yl]oxy]pentyl]oxy]benzenepropanoic acid methyl ester was obtained in 75.5% yield (1.6 g) as a pale-yellow oil. This diester (3 mmol) was saponified with 13.6 mL of 3N aqueous lithium hydroxide in 80 mL of tetrahydrofuran, at room temperature, for 96 hr. Work-up as in example 4 and recrystallization from ethyl acetate gave 0.6 g (38.5%) of the title acid, a colorless solid, mp 98°-99° C.
Reaction SMILES: C([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:45]2[N:46]=[C:47]([NH:50]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:48][CH:49]=2)\[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:22]([CH2:25]I)[CH2:23][S:24][C@H:19]23)=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.[S:70]1[C:78]2[CH:77]=[CH:76][N:75]=[CH:74][C:73]=2[N:72]=[CH:71]1>CS(C)=O.CCOCC>[NH2:50][C:47]1[S:48][CH:49]=[C:45](/[C:14](=[N:13]/[O:12][C:8]2([C:6]([OH:5])=[O:7])[CH2:11][CH2:10][CH2:9]2)/[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:75]4[CH:76]=[CH:77][C:78]5[S:70][CH:71]=[N:72][C:73]=5[CH:74]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:46]=1
Reactant: c1cc2scnc2cn1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: Nc1nc(/C(=N/OC2(C(=O)O)CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccc5scnc5c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 31 %

Procedure:
To a solution of diphenylmethyl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)-acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIe'] (482 mg, 0.45 mmole) in 2 mL of DMSO was added thiazolo[4,5-c]pyridine (68 mg, 0.5 mmole) in one portion. The mixture was stirred for 45 minutes at room temperature. The reaction mixture was then diluted with ether (50 mL) and the precipitated oil was triturated in ether (4×50 mL). The precipitate was mixed with anisole (0.5 mL), trifluoroacetic acid (5 mL) and water (0.5 mL), and the mixture was stirred with ice cooling for 30 minutes and at room temperature for 1 hour, and then was concentrated under reduced pressure (<30° C.). The residue was triturated with isopropyl ether (100 mL), and the resulting precipitate was collected by filtration to afford 395 mg of crude title compound, as a yellow powder. The crude product (387 mg) was purified on an HP-20 column (100 mL). The eluate containing desired product, which was eluted with 50% methanol, was concentrated and lyophilized to give 80 mg (31%) of the title product (Ie) as a pale yellow amorphous powder. Mp >170° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([O:7][C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[C:17]([F:20])([F:19])[F:18])[CH2:3]1.[H][H].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C.[Pt]>[CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([O:7][C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=2[C:17]([F:18])([F:19])[F:20])[CH2:3]1
Reactant: CN1CC[C@@H](Oc2cc([N+](=O)[O-])ccc2C(F)(F)F)C1
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CN1CC[C@@H](Oc2cc(N)ccc2C(F)(F)F)C1

Procedure:
A solution of 2-((R)-1-Methyl-pyrrolidin-3-yloxy)-4-nitrobenzotrifluoride (7.8 g, 26.9 mmol) in ethyl acetate (50 ml) was treated with 10% platinum on carbon (200 mg) then subjected to 40 psi hydrogen pressure for 3 hrs. The slurry was treated with anhydrous magnesium sulfate (5 g) then filtered through a pad of Celite. The filter cake was rinsed with ethyl acetate (2×25 ml) then the filtrate was evaporated under reduced pressure to an oil. This oil was evaporated twice for dichloromethane (50 ml) to remove trapped ethyl acetate. This gave the product as a clear light brown oil that solidified on standing (6.9 g, 99%): LCMS 249 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:14][O:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:2]2[NH:1][C:16](=[O:18])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Reaction time: 3 h

Procedure:
10.0 g (50.7 mmol) 2-Amino-4,5-dimethoxy-benzoic acid were dissolved in 150 ml tetrahydrofuran. 6.52 g (22.0 mmol) triphosgene were added and the solution was boiled for 3 h. After equilibration to room temperature the reaction mixture was poured on a water/ice mixture. The residue was filtrated and rinsed with methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9](Br)=[CH:8]2)=[O:4].[C:24]1([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2-c2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 120 °C
Yield: 65.5 %

Procedure:
A mixture of 3-bromo-5-hydroxy-2-oxo-1-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (300 mg, 0.8 mmol), PhSnBu3 (0.31 mL, 0.96 mmol), and PdCl2(PPh3)2 (112 mg, 0.16 mmol) in DMF (8 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (50 mL) were added. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-50% EtOAc/hexanes+2% AcOH) to give 195 mg of the title compound as a light yellow solid. MS: (−) m/z 371.32 (M−1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH:16]C(=O)OCC1C=CC=CC=1)[CH2:10]2.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:16][C@@H:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=3)[CH:8]=2)[CH2:12]1
Reactant: O=C(N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To (S)-benzyl 5-(3-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-ylcarbamate (2.94 mmol, 1.34 g) in Ethanol (35.4 mL) was added palladium hydroxide (2.51 mmol, 0.353 g). The reaction was placed under 2 bar of hydrogen gas and allowed to stir at room temp for 30 mins. The reaction mix was filtered through a dicalite cartridge before washing with EtOH. The solvent was removed before purifying further by SCX (20 g cartridge, 1:1 MeOH/DCM wash, 2M NH3 MeOH elution). The solvent was removed to give the product as a clear gum (810 mg, 86%). MS (ESI): m/z [M+H]+ 322.2
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:24][C:23]1[CH:25]=[CH:26][C:20]([S:17]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:16])(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: OCCOCCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCO)cc1
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
To a chilled (0° C.) solution of pentaethylene glycol (2.13 g, 8.92 mmol) in DCM (89 mL) were added TsCl (1.87 g, 9.81 mmol), Ag2O (3.10 g, 0.134 mmol), and KI (0.296 g, 1.78 mmol). After stirring for 20 min the reaction mixture was filtered through a 4 cm pad of celite and flushed with EtOAc. The resulted filtrate was concentrated under reduced pressure to give a yellow oil. The crude product was purified via silica flash chromatography using 3:2 DCM/acetone as an eluent, providing 26 (2.63 g, 75%): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.20-4.11 (m, 2H), 3.76-3.54 (m, 18H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[CH:6]=1)=[O:4].[CH3:13]OC(OC)N(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]([CH3:13])[C:7](=[O:12])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C)[nH]c(=O)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)n(C)c(=O)c1
Temperature: 60 °C
Yield: 48.6 %

Procedure:
A suspension of the title compound of Example 33.1 (0.80 g, 4.8 mmol) and dimethylformamide dimethylacetal (3.2 mL, 24 mmol) in DMF (10 mL) was heated at 60° C. for 48 hours. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed with water. The organic layer was concentrated. Recrystallization from ethyl acetate/heptane afforded the title compound (423 mg, 49%)
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:49]/[O:50][CH3:51])/[C:20]([NH:22][C@@H:23]2[C:30](=[O:31])[N:29]3[C@@H:24]2[CH2:25][O:26][C:27]([CH:44]2[CH2:48][CH2:47][CH2:46][O:45]2)=[C:28]3[C:32]([O:34]CC2C=CC(OC)=CC=2)=[O:33])=[O:21])[N:18]=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+:65].[Na+].[Na+]>ClCCl>[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:49]/[O:50][CH3:51])/[C:20]([NH:22][C@@H:23]2[C:30](=[O:31])[N:29]3[C@@H:24]2[CH2:25][O:26][C:27]([CH:44]2[CH2:48][CH2:47][CH2:46][O:45]2)=[C:28]3[C:32]([O-:34])=[O:33])=[O:21])[N:18]=1.[Na+:65]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C3CCCO3)OC[C@H]12)c1csc(N)n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C3CCCO3)OC[C@H]12)c1csc(N)n1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of anisole (2.38 ml) and dichloromethane (1.2 ml) under argon was cooled to -20° C. and treated with aluminium chloride (61 mg). The mixture was stirred at -20° C. for 15 min. and then a slurry of 4-methoxybenzyl (6S,7S)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-8-oxo-3-(tetrahydrofuran-2-yl)-1-aza-4-oxabicyclo[4.2.0]oct-2-ene-2-carboxylate (I) (88 mg) in dichloromethane (7.5 ml) was added. The mixture was stirred for 5 min. and then trisodium citrate (5.2 ml of 0.5M) was added and the mixture stirred for 10 min. The aqueous phase was separated and washed twice with dichloromethane, then evaporated. The product was purified by HP20SS chromatography of the residue (water with increasing proportions of acetone as eluent). Fractions containing product were combined and evaporated and the residue dissolved in water (4 ml) and freeze-dried to give the title compound (27 mg). νmax (KBr) 1757, 1662 and 1617 cm-1 ; δ[(CD3)2SO] 1.68-1.95 (4H, m), 3.58-3.77 (4H, m), 3.84 (3H, s), 4.35 (1H, m), 5.51 (1H, dd, J 3.91 and 8.83 Hz), 5.68 (1H, t, J 6.84), 6.78 (1H, s), 7.25 (2H, s), 9.91 (1H, d, J 8.83 Hz).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:32])[C@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[NH:13]C(OCC1C=CC=CC=1)=O.[NH2:33][C@H:34]([C:39]([OH:41])=[O:40])[C@H:35]([CH2:37][CH3:38])[CH3:36].CN(C)C=O.CN1CCOCC1>O>[NH2:13][C@H:12]([C:11]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[C@H:35]([CH2:37][CH3:38])[CH3:36])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Carbobenzoxytyrosine 2,4,5-trichlorophenyl ester (544 parts) is added to a suspension of 131 parts of isoleucine in 2000 parts by volume of dimethylformamide. After adding 101 parts of N-methylmorpholine, the mixture is stirred 48 hours at room temperature. Unreacted isoleucine is still present. Water (500 parts by volume) is added and stirring is continued for another 48 hours. The mixture is concentrated to dryness under high vacuum at 40°. The residue is dissolved in 2000 parts by volume of ethyl acetate, the ethyl acetate is washed with four 2000 parts by volume portions of 0.2 M potassium bisulfate, dried over sodium sulfate and stripped under reduced pressure. The residue is dissolved in 1 l. of chloroform and the solution added dropwise with violent stirring to 20 l. of ether. The resulting white powder, carbobenzoxy=tyrosylisoleucine, (42.8 parts) 0.1 mole, is dissolved in 500 parts by volume of 90% acetic acid and hydrogenated at 60 psi at room temperature over 4.3 parts of palladium black. Hydrogen uptake stopped after 2 hours. The catalyst is filtered off and the filtrate concentrated to dryness under vacuum. The residue is rubbed with ether yielding tyrosylisoleucine, Tyr-Ile.