Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[OH:9].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:4][C@@H:5]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH2:17][CH2:18]3)=[O:12])[CH2:6][CH2:7][C:8](=[O:9])[OH:10])=[O:36])[CH:33]=2)[CH:28]=[CH:27]1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CCC(=O)O)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-(D-glutamyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and indole-6-carboxylic acid (46%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[F:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1F)[C:32]([N:34]1[CH2:37][CH2:36][CH2:35]1)=[O:33].N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C>CC(N(C)C)=O.CN(C=O)C.O>[N:34]1([C:32]([C:31]2[CH:38]=[CH:39][C:40]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[C:29]([F:28])[CH:30]=2)=[O:33])[CH2:37][CH2:36][CH2:35]1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Reactant: C[C@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (780 mg, 2.40 mmol) was added to a mixture of 3-hydroxy-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (350 mg, 1.2 mmol) and 1-(3,4-difluorobenzoyl)azetidine (235 mg, 1.2 mmol) in dimethylacetamide (5.0 mL) and the stirred-mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 2 hours. The mixture was allowed to return to ambient temperature and pressure and was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (5×50 mL) brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, and then chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant. A 10% impurity remained. This mixture (0.12 g, 0.26 mmol) was dissolved in DMF (3 mL) and imidazole (0.123 g, 1.79 mmol) and tert-butyldimethylsilylchloride (77 mg, 0.51 mmol) were added. After stirring at RT for 24 hours water (30 mL) was added and the material extracted into diethyl ether (2×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in chloroform, and then chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant. The chromatography fractions were allowed to stand overnight and the acetonitrile removed in vacuo. The aqueous residue was basified with saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate (2×50 mL) and the combined extracts reduced in vacuo to give the desired compound. (30 mg)
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=C)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=[O:27])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:2])[CH3:3]
Reactant: C=Cc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.300 g, 0.000894 mol) was dissolved in THF (20 mL) and H2O (10 mL). Osmium tetroxide (0.550 mL, 0.0716 mmol, 4% wt in water) was added followed by Sodium metaperiodate (0.383 g, 0.00179 mol). The reaction was stirred overnight at room temperature. The reaction was quenched using saturated sodium thiosulfate. 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbaldehyde (0.302 g, 95.1% yield) was isolated using an aqueous workup and carried on without further purification
Reaction SMILES: Cl.[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:53][C:52]([O:54][C:55]4[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=4[F:65])=[CH:51][C:50]3=[O:66])CC(C)C)=N2)CO1>C(#N)C>[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([N:17]2[CH2:53][C:52]([O:54][C:55]3[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=3[F:65])=[CH:51][C:50]2=[O:66])[CH2:13][CH:14]([CH3:15])[CH3:16])=[N:6]1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A suspension of (S)-2-amino-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]amide hydrochloride salt (2.0 g, 5.8 mmol) in acetonitrile (25 mL) was treated with N,N-diisopropylethylamine (4.0 mL) and stirred at 60° C. for 15 min. At this time N,N-diisopropylethylamine (2.5 mL) and a solution of (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 116, 1.37 g, 3.75 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 48 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (295 mg, 16%): HR-ES-MS (m/z) calculated for C25H32F2N4O5 [M+H]+ 507.2414, observed 507.2414; 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (br. s., 6H), 1.13 (br. s., 6H), 1.42 (br. s., 3H), 1.48-1.64 (m, 1H), 1.66-1.95 (m, 2H), 3.73 (br. s., 1H), 3.91 (br. s., 2H), 4.01-4.24 (m, 3H), 4.38 (d, J=17.8 Hz, 1H), 4.88 (br. s., 1H), 4.99 (br. s., 1H), 6.66 (br. s., 1H), 6.73-7.00 (m, 2H), 7.27 (br. s., 1H), 8.79 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1.CC1C=CC2C(=CC=CC=2N2CCNCC2)N=1.CS(OCCC1C=CC=C([Br:59])C=1)(=O)=O>>[Br:59][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCc1cccc(Br)c1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Agent: Cc1ccc2c(N3CCNCC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(Br)c4)CC3)cccc2n1
Yield: 56 %

Procedure:
The title compound was prepared in 56% yield using a similar procedure to description D5 starting from 2-methyl-5-(1-piperazinyl)quinoline (D3) and 2-(3-bromophenyl)ethyl methanesulfonate (D13).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[CH2:10][N:11]2[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][N:13]([C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[C:12]2=[O:30])=[CH:4][CH:3]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:32]1([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[CH2:10][N:11]3[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][N:13]([C:20]4[CH:21]=[N:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=4)[C:12]3=[O:30])=[CH:4][CH:3]=2)[CH2:34][CH2:33]1
Reactant: CC(C)C[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)Nc1ccc(Br)nc1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)Nc1ccc(C2CC2)nc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 5.4 %

Procedure:
A solution of N-(6-bromopyridin-3-yl)-2-{(5S)-5-(2-methylpropyl)-2-oxo-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}acetamide (50 mg), cyclopropyl boronic acid (17 mg), palladium acetate (1.1 mg), triphenylphosphine (2.6 mg), and potassium carbonate (41 mg) in toluene/water (=20:1, 1.5 mL) was stirred at 110° C. for 9 hr. Additional cyclopropyl boronic acid (35 mg) was added thereto, and the mixture was further stirred at 110° C. for 6 hr, followed by at 80° C. for 2 hr. The solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC. After further purification by PTLC(NH silica gel, hexane/ethyl acetate=1:1), the resulting solid was washed with isopropyl ether to afford the title compound (2.5 mg).
Reaction SMILES: C([N:9]1[CH2:17][CH2:16][C:12]([CH3:18])([C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1>Cl>[CH3:18][C:12]1([C:13]([OH:15])=[O:14])[CH2:16][CH2:17][NH:9][CH2:10][CH2:11]1
Reactant: CC1(C(=O)O)CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Product: CC1(C(=O)O)CCNCC1
Yield: 88.7 %

Procedure:
N-Benzoyl-4-methyl isonipecotic acid (1.21 g, 4.88 mmol) was dissolved in 20 mL of 6N HCl and refluxed overnight. The mixture was cooled and benzoic acid removed by filtration. The filtrate was evaporated and crystallization from acetone/dichloromethane provided 0.62 g of 4-methyl isonipecotic acid (90%). 1H NMR (300 MHz DMSO d6) δ9.0 (s, 1H), 3.1 (m, 2H), 2.7 (m, 2H), 2.0 (m, 2 H), 1.6 (m, 2H), 1.1 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:11][O:10]1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:10][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccccc1C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1C(O)COc1ccc(C=O)cc1
Temperature: 78 °C
Yield: 20.2 %

Procedure:
To a stirring solution of 2-(2-methoxyphenyl)oxirane (5.60 g, 37.3 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (6.80 g, 56.0 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction was allowed to cool to RT and it was then extracted with EtOAc (2×150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light oil was adsorbed onto silica gel and chromatographed eluting with 30-40% EtOAc/hexanes to give 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.71 g (17%) the regioisomer as a brown oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 2.05 g (20%) of the title compound as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[S:8][C:9]2[CH2:10][NH:11][CH2:12][CH2:13][C:14]=2[N:15]=1)=[O:6])[CH3:3].C(N(CC)CC)C.[C:23]1([N:29]=[C:30]=[S:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.O>[NH:29]([C:30]([N:11]1[CH2:12][CH2:13][C:14]2[N:15]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[S:8][C:9]=2[CH2:10]1)=[S:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: S=C=Nc1ccccc1
Reactant: CCOC(=O)c1nc2c(s1)CNCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1nc2c(s1)CN(C(=S)Nc1ccccc1)CC2
Reaction time: 0.25 h

Procedure:
5-tert-butyl 2-ethyl 6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate obtained in step V of example 1 was deprotected to get the hydrochloride salt of 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester. To a solution of a HCl salt of 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester (1 eq) in dichloromethane, triethyl amine (1.2 eq) was added at 0° C. and the reaction mixture was stirred for 15 min. To this, a solution of phenyl isothiocyanate (1 eq) in dichloromethane was added and the reaction was continued at room temperature for 3 h. Water was added and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded—ethyl 5-(anilinocarbonothioyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate.
Reaction SMILES: C1C=CC2N(O)N=[N:7][C:5]=2C=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:22]2[CH2:27][CH2:26][CH2:25]/[C:24](=[CH:28]\[C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]4)=[C:31]([O:41][CH3:42])[CH:30]=3)/[C:23]2=[O:43])[C:19](O)=[O:20])=[CH:14][CH:13]=1.CN.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:22]2[CH2:27][CH2:26][CH2:25]/[C:24](=[CH:28]\[C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]4)=[C:31]([O:41][CH3:42])[CH:30]=3)/[C:23]2=[O:43])[C:19]([NH:7][CH3:5])=[O:20])=[CH:14][CH:13]=1
Reactant: On1nnc2ccccc21
Reactant: COc1cc(/C=C2\CCCN(C(C(=O)O)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CNC(=O)C(c1ccc(F)cc1)N1CCC/C(=C\c2ccc(-n3cnc(C)c3)c(OC)c2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
A 1 N aqueous solution of sodium hydroxide (0.8 mL) was added to a solution of a solution of methyl (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)acetate synthesized by the method described in Example 924 (74 mg) in methanol (3 mL), and the reaction solution was stirred at room temperature for 13 hours. 2 N hydrochloric acid (0.4 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure to obtain 72 mg of crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)acetic acid. HOBT (16 mg) and EDC (23 mg) were added to a solution of the resulting crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)acetic acid (36 mg) and methylamine (2M THF solution, 0.4 mL) in DMF (3 mL), and the reaction solution was stirred at room temperature for 5 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: ethyl acetate->ethyl acetate:methanol=9:1) to obtain 32 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: Cl.[F:2][CH:3]([CH:7]([NH:10]CC1C=CC=CC=1)[CH2:8][F:9])[C:4]([OH:6])=[O:5].O.C(O)C>[Pd].C(O)(=O)C>[F:2][CH:3]([CH:7]([NH2:10])[CH2:8][F:9])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(F)C(CF)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NC(CF)C(F)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of 2,4-difluoro 3-benzylaminobutyric acid, hydrochloride prepared as in Step C (1.010 g, 3.84 mM) and 5% palladium on charcoal (type H, 0.150 g) in glacial acetic acid (30 ml) is shaken under hydrogen (60 psi) in a Parr hydrogenator for 16 hours at room temperature. Filtration of the catalyst, and removal of the solvent in vacuo yield a colourless oil. A first crystal crop was isolated by crystallisation from water/ethanol (0.185 g). A second crystal crop was obtained by passing the mother liquors on an ion exchange column (Dowex 50, H+, eluted with water) (0.190 g). Overall yield about 70%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8](Br)[CH:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cncnc3)cc(C(=O)OCC)n2n1

Procedure:
A mixture of 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (0.548 g, 1.54 mmol/prepared as in Example 6, Step 4) sodium acetate (0.63 g, 7.68 mmol), dppf (86 mg, 0.155 mmol), pyrimidine-5-boronic acid (0.289 g, 2.33 mmol) in toluene (30 mL)/water (6 mL)/ethanol (6 mL) was purged with nitrogen. PdCl2(PhCN)2 (60 mg, 0.156 mmol) was added and the mixture was purged with nitrogen then refluxed for 0.5 h. The reaction mixture was cooled and the resulting crystalline product was filtered and washed with water. The product was dissolved in hot methanol, filtered through celite and cooled to give 2-(3-ethyl-ureido)-7-pyrimidin-5-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester as a solid. ACPI-MS Found: [M+H]+=356.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[F:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].ClCCl.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>CN(C)C1C=CN=CC=1.CO>[C:39]([O:28][C:5]1[C:6]([CH2:25][CH2:26][CH3:27])=[C:7]([CH:23]=[CH:24][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[F:22])(=[O:41])[CH3:40]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2F)ccc(C(C)=O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2F)ccc(C(C)=O)c1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-fluorobenzoic acid (700 mg), dichloromethane (25 ml), triethylamine (2ml), acetic anhydride (2ml) and 4-dimethylaminopyridine (catalytic amount) was stirred at ice-cooling to room temperature for 6.5 hours. To the reaction mixture was added methanol (2ml), and the mixture was stirred for 30 minutes. After concentration, water was added to the residue. Solid materials were recovered by filtration and subjected to recrystallization from aqueous methanol to give crystals of 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-fluorobenzoic acid (723 mg). m.p. 144°-145° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:41])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:23]([O:25]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>C(Cl)Cl.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:41])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Benzhydryl 7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-methylthiomethyl-3-cephem-4-carboxylate (7.0 g) was dissolved in a solution of methylene chloride (70 ml), anisole (7 ml) and trifluoroacetic acid (14 ml), and the mixture was stirred at ambient temperature for an hour. After the solvent was removed by distillation under reduced pressure, the residue was dissolved in water, adjusted to pH 2.0 with conc. hydrochloric acid and then extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride and dried over magnesium sulfate, followed by evaporation. The residue was pulverized with diisopropyl ether to obtain 7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (3.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:43])[CH2:9][CH2:10][C@@H:11]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([B:27]5[O:31]C(C)(C)C(C)(C)[O:28]5)[CH:22]=4)=[CH:17][CH:16]=3)[N:13]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:12]2=[O:42])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:43])[CH2:9][CH2:10][C@H:11]2[C:12](=[O:42])[N:13]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@@H:14]2[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([B:27]([OH:28])[OH:31])[CH:22]=3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccccc4)cc3)c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(B(O)O)c3)cc2)N1c1ccccc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl]azetidin-2-one (0.020 g, 0.034 mmol) was dissolved in ethanol (3 mL) and water (1 mL) at room temperature. Solid sodium carbonate (0.10 g, 1.2 mmol) was added and the mixture was rapidly stirred 2 h at room temperature. The solution was poured into 0.5 N hydrochloric acid (4 mL) and extracted with ethyl acetate. The organic phase was washed successively with water (2×) and brine, then dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 40% to 75% acetonitrile-0.1% trifluoroacetic acid in water) to afford (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)boronic acid as a white powder (0.012 g, 70%); 1H NMR (300 MHz, CD3OD) δ 7.83 (br s, 1H), 7.0-7.7 (m, 16H), 4.92 (d, J=2.7 Hz, 1H), 4.63 (t, J=6.2 Hz, 1H), 3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M+HCO2−]− 540.
Reaction SMILES: CC1(C)O[C@@H:5]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[C:15]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=4[F:29])=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=3[N:10]=[CH:9]2)CO1.NC1C=C[C:35]([NH:38][C:39]2C3C(=O)NC=NC=3N(C)C(=O)C=2)=C(F)C=1.Br.BrCCN(C)C>>[CH3:35][N:38]([CH3:39])[CH2:5][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1
Reactant: Cn1c(=O)cc(Nc2ccc(N)cc2F)c2c(=O)[nH]cnc21
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H]3COC(C)(C)O3)cnc21
Agent: Br
Agent: CN(C)CCBr
Product: CN(C)CCn1cnc2c(c(Nc3ccc(I)cc3F)cc(=O)n2C)c1=O

Procedure:
The title compound was prepared following the same procedure for the synthesis of compound 5G using compound 5F and 2-bromo-N,N-dimethylethanamine hydrobromide as starting material. 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H) 7.68 (m, 2H) 7.33 (t, J=8.36 Hz, 1H) 5.78 (s, 1H) 4.51 (t, J=4.0 Hz, 2H) 3.69 (s, 3H) 3.66 (t, J=8.0 Hz, 2H) 3.09 (s, 6H).