Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH3:14])[C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])=[CH:17][CH:16]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][Cl:36].O>CCC(C)=O.C(OCC)(=O)C>[Cl:36][CH2:35][CH2:34][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]#[N:2])=[C:4]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:5]2[CH2:13][CH3:14])=[CH:10][CH:9]=1
Reactant: ClCCBr
Reactant: CCn1c(-c2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1c(-c2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(OCCCl)cc21
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide (4 g, 11.6 mmol) in 15 mL of MEK is added K2CO3 (8 g, 58 mmol) and 1-bromo-2-chloro-ethane (6.7 mL, 70 mmol). Then the mixture is heated at reflux overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2×), dried over anhydrous Na2SO4, filtered and concentrated to yield 81% of the crude cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}-amide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH3:2].C([Li])(CC)C.B(OC)(OC)[O:16]C.OO.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([OH:16])[CH:8]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCc1ccc(F)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1ccc(F)c(O)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
A 500 ml THF solution containing 15.5 g of 4-ethylfluorobenzene and 14.6 g of N,N,N′N′-tetramethylethylenediamine was cooled to −75° C. under a nitrogen atmosphere, and then 126 ml of s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture was stirred for 2 hours. Next, 28 ml of trimethyl borate was added, the reaction mixture temperature was raised to room temperature and 14.4 ml of acetic acid was added. After stirring for 30 minutes, the reaction mixture was cooled to 0° C., 28.4 ml of a 30% aqueous solution of hydrogen peroxide was added and stirring was continued at room temperature for 18 hours. Next, 500 ml of a saturated aqueous solution of sodium sulfite was added to the reaction mixture, which was then extracted with 11 of diethyl ether. The organic layer was washed with 500 ml of water and 500 ml of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was distilled to obtain the target compound (16.35 g) as a colorless liquid (boiling point: 76-80° C., 17 mmHg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][CH:8]([CH3:17])[CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClC1C=CC=CC=1Cl>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]([CH3:17])[N:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC(NC(=O)c1cccc(I)c1)C(O)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of amide 3b, 11.54 g, 30.3 mmol) and P2O5 (43 g) in o-dichlorobenzene (150 mL) was refluxed for 20 h. After it was cooled to room temperature, it was cooled to 0° C. by application of an external ice-water bath. To this cooled mixture was cautiously added 300 mL of H2O. After the vigorous reaction had subsided, the dark solution was washed with toluene (2×50 mL). The aqueous layer was cooled to 0° C. and made to pH >11 with 50% aqueous NaOH. The resulting mixture was extracted with toluene (4×50 mL). The organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from benzene, thereby affording a white solid (6.5 g, 62%) mp 77-78° C. 1H NMR (CDCl3) d 2.72 (s, 3 H, CH3), 7.23 (t, J=7.8 Hz, 1 H, aromatic), 7.40-7.52 (m, 2 H, aromatic), 7.57-7.66 (m, 2 H, aromatic), 7.71-7.85 (m, 2 H, aromatic), 7.92 (d, J=8.7 Hz, 1 H, aromatic), 8.02 (s, 1 H, aromatic). 13C NMR (CDCl3) d 24.31 (q, CH3), 94.31 (s, =CI--, aromatic), 118.36 (d, aromatic), 126.39 (d, 2C, aromatic), 126.92 (d, aromatic), 129.08 (d, aromatic), 129.83 (d, aromatic), 129.99 (d, aromatic), 137.34 (d, aromatic), 137.47 (s, aromatic), 138.53 (d, aromatic), 141.70 (s, aromatic), 150.80 (s, aromatic), 158.36 (s, =CCH3 --, aromatic). Anal. Calcd for C16H12IN: C, 55.67; H, 3.50; N, 4.06. Found: C, 55.53; H, 3.56; N, 4.05.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:76]1[N:81]=[CH:80][C:79]([CH2:82][CH3:83])=[CH:78][N:77]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH2:82]([C:79]1[CH:78]=[N:77][C:76]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[N:81][CH:80]=1)[CH3:83]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Reactant: CCc1cnc(Cl)nc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cnc(N[C@H]2CCC[C@@H]2NC(=O)c2cc(C)ccc2-n2nccn2)nc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 100 mg, 0.31 mmol), toluene (1 ml), BINAP (19 mg, 0.03 mmol), cesium carbonate (404 mg, 0.12 mmol) and 2-chloro-5-ethylpyrimidine (CAS number 111196-81-7; 48 mg, 0.34 mmol) was purged with nitrogen gas for 5 minutes before tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.02 mmol) was added. The reaction mixture was stirred at 100° C. for 15 hours and upon cooling poured into water (3 ml) and extracted with ethyl acetate (3×10 ml). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][O:12][CH3:13].C(N(C(C)C)CC)(C)C>>[CH3:11][O:12][CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCl
Reactant: O=Cc1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C=O)c1
Temperature: 0 °C

Procedure:
A solution of 3-hydroxybenzaldehyde (20 g), chloromethylmethyl ether (25 ml) and diisopropylethylamine (114 ml) intetrahydrofuran (300 ml) was stirred at room temperature overnight. To the reaction mixture was added ice water and was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=25:1) to give the title compound (23 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](O)=[O:19])(=[O:14])[CH3:13].NC1N=CC=CC=1C(OC)=O>N1C=CC=CC=1>[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:19])(=[O:14])[CH3:13]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: COC(=O)c1cccnc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccnc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1

Procedure:
Following the procedure of Example 1, but substituting an equivalent amount of methyl 2-amino-isonicotinate and 2-acetylthiomethyl-3-phenyl-propionic acid respectively for methyl 2-amino-nicotinate and 2-acetylthiomethyl-3-phenyl-propionic acid, using pyridine as reaction solvent, maintaining the reaction mixture at 50°-60° C. for five hours and purifying by chromatography on silica gel column (eluent, petroleum ether/ether 7:3), methyl 2-(2-acetylthiomethyl-3-phenyl-propionamido)-isonicotinate is obtained as an oil which is transformed into the corresponding hydrochloride with an alcoholic solution of hydrogen chloride; m.p. 137°-139° C., from acetone/ether.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[OH-].[Na+]>O>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 25 °C
Yield: 87 %

Procedure:
Conversion to high cis 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylic acid (compound C acid). Sodium hydroxide (20 g, 0.5 mole) in 100 ml of water was added to the reaction mixture above with vigorous stirring and the whole was heated at 100° for 5 hours under conditions allowing for the distillation of the tert-butanol present from the Phase (a) reaction. The mixture was allowed to cool to room temperature, then washed with ether and made acidic with concentrated hydrochloric acid. The acidified mixture was extracted with ether and the ether extracts were combined, washed with brine, dried over magnesium sulfate and concentrated to give, after distillation, 18.22 g (87% yield) of 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylic acid, bp 102°-105°/0.3 mm Hg, purity 97.3%, C/T=78/22.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].OCC1C=C([N+]([O-])=O)C=CC=1O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH:11]=1)[CH2:9][OH:10])([O-:3])=[O:2]
Reactant: CCCOc1ccc([N+](=O)[O-])cc1C=O
Agent: O=[N+]([O-])c1ccc(O)c(CO)c1
Product: CCCOc1ccc([N+](=O)[O-])cc1CO
Yield: 93 %

Procedure:
This compound was prepared by reduction of 5-nitro-2-propyloxybenzaldehyde using a method similar to that described for preparing 2-hydroxymethyl-4-nitrophenol in 93% yield: MP (No Sample left for MP); 1H NMR (400 MHz, DMSO-d6) 8.22 (d, 1H, J=2.6 Hz), 8.13 (dd, 1H, J=2.9 and 9.2 Hz), 7.14 (d, 1H, J=9.2 Hz), 5.41 (t, 1H, J=5.5 Hz), 4.52 (d, 2H, J=5.8 Hz), 4.08 (t, 2H, J=6.2), 1.75 (m, 2H), 0.98 (t, 3H, J=7.6 Hz).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(CCBr)cc1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccc(Cl)cc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-4-chlorobenzene and isolated as light-yellow gum. MS(m/e): 421.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:42][CH2:41]OCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[NH:19][C:20](=[O:21])[N:16]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:13]5[CH:14]=[C:41]([CH3:42])[N:16]=[CH:12]5)[CH:7]=4)=[C:14]([CH3:15])[N:13]=3)[N:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Reactant: C1COCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cc(Oc3ccc(-n4nc(-c5ccc(F)cc5)[nH]c4=O)nc3C)ccn2)cn1
Temperature: 25 °C
Yield: 18 %

Procedure:
A solution of Pd2(dba)3 (0.012 g, 0.013 mmol) and Me4tBuXPhos (0.012 g, 0.025 mmol) in toluene (2 mL) and dioxane (4 mL) was heated in a screw capped tube (10 mL) at 120° C. for 3 min. The reaction mixture was cooled to RT and the pre-formed catalyst was transferred to a re-sealable pressure tube (50 mL) containing a degassed suspension of Example A8 (0.250 g, 0.628 mmol), 4-methyl imadazole (0.100 g, 1.218 mmol) and potassium phosphate (0.250 g, 1.178 mmol) in a mixture of toluene (4 mL) and dioxane (8 mL) followed by heating at 110° C. for 8 hours. The solids from the reaction mixture was filtered and washed with DCM and THF. The filtrate was completely evaporated and the residue was subjected to chromatography using (0-15% MeOH/DCM) to provide 3-(4-fluorophenyl)-1-(6-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.050 g, 18% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 8.41 (d, J=1.4 Hz, 1H), 8.34 (d, J=5.8 Hz, 1H), 7.98-7.93 (m, 3H), 7.78 (d, J=8.8 Hz, 1H), 7.65 (t, J=1.3 Hz, 1H), 7.48 (br s, 1H), 7.40 (m, 2H), 6.82 (dd, J=5.8, 2.2 Hz, 1H), 2.38 (s, 3H), 2.13 (s, 3H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1>C(Cl)Cl>[CH:9]([CH:5]1[CH2:6][C:7](=[O:8])[C:2]([CH3:1])=[CH:3][CH2:4]1)([CH3:11])[CH3:10]
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Solvent: ClCCl
Product: CC1=CCC(C(C)C)CC1=O
Reaction time: 48 h
Yield: 97.4 %

Procedure:
According to the general procedure, a solution of carvone (45 μL, 0.29 mmol) and rac-32 (8.0 mg, 0.0051 mmol, 1.8 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 48 h. Filtration of the reaction mixture and evaporation of the solvent gave 49 as a colorless oil (43 mg, 96%). 1H NMR36 (300 MHz, CDCl3): δ 6.72-6.69 (m, 1H), 2.53-2.47 (m, 1H), 2.37-2.27 (m, 1H), 2.13-1.99 (m, 2H), 1.85-1.78 (m, 1H), 1.73-1.72 (m, 3H), 1.54 (quin, 1H, J=6.6 Hz), 0.87 (dd, 6H, J=6.9 Hz, 0.9 Hz); 13C NMR (75.5 MHz, CDCl3): δ 200.6, 145.2, 135.2, 42.0, 41.9, 31.9, 29.8, 19.5, 19.4 15.6.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1/[CH:21]=[CH:22]/[C:23](OC)=[O:24].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1/[CH:21]=[CH:22]/[CH2:23][OH:24]
Reactant: COC(=O)/C=C/c1ccc2ccccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.5M, 18 ml) was added dropwise to a solution of methyl (E)-3-(2-naphthyl)-acrylate (2.52 g) in CH2Cl2 at −78 ° C. and the mixture was stirred at −78° C. for 1 hour. Saturated aqueous solution of NH4Cl was added to the mixture and organic layer was washed with 1N HCl and brine, dried and concentrated. The residue was crystallized from CH2Cl2-hexane to give the titled compound (1.78 g) as a white solid.
Reaction SMILES: [N:1]1([C@@H:10]([C@@H:13]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[O:14][CH2:15][CH2:16][F:17])[CH2:11][OH:12])[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([O:23][CH2:22][C@@H:20]([OH:21])[C@@H:18]([OH:19])[C@@H:13]([O:14][CH2:15][CH2:16][F:17])[C@H:10]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH2:11][OH:12])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:29]2[CH:46]=[CH:47][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:36][CH:35]=1
Reactant: Cc1cn([C@H](CO)[C@H](OCCF)[C@H](O)[C@H](O)CO)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@@H](O)[C@@H](O)[C@@H](OCCF)[C@@H](CO)n2cc(C)c(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
Compound 5 (4.07 g, 12.79 mmol) was mixed with 4,4′-dimethoxytrityl chloride (4.56 g, 13.46 mmol) and dried over P2O5 under reduced pressure. The residue was dissolved in anhydrous pyridine (43 mL) and stirred at room temperature for 6 hours under an atmosphere of argon. The mixture was quenched with methanol (3 mL). The reaction mixture was diluted with EtOAc (200 mL), washed with aqueous NaHCO3 (saturated, 300 mL) and brine (200 mL) then dried over Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel column chromatography (eluted first with 70% EtOAc in hexanes and then increasing the polarity) to yield Compound 6 (7.1 g, 89%). ES MS m/z 643.2 [M+Na]+.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([CH2:7][S:8][C:9]2[CH2:10][S:11][C@@H:12]3[C@H:32]([NH:33]C(=O)CC4C=CC=CC=4)[C:31](=[O:43])[N:13]3[C:14]=2[C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4][O:3]1.CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:33][C@@H:32]1[C:31](=[O:43])[N:13]2[C:14]([C:15]([O:17][CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[C:9]([S:8][CH2:7][C:5]3[CH2:4][O:3][C:2](=[O:1])[CH:6]=3)[CH2:10][S:11][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CC(=O)OC3)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CC(=O)OC3)CS[C@H]12
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
A stirred solution of diphenylmethyl 3-(2,5-dihydro-2-oxofuran-4-ylmethylthio) -7β-phenylacetamidoceph-3-em-4-carboxylate (520 mg) in dry dichloromethane (8 ml) was cooled to -20° C., then N-methylmorpholine (0.202 ml) was added followed by a solution of phosphorous pentachloride in dichloromethane (7.2 ml of a solution containing 40 mg ml-1). The solution was stirred at -15° to -20° C. for 30 mins., then methanol (1.8 ml) was added and the mixture stirred at room temperature for 30 mins. Water (2.5 ml) was then added and the mixture vigorously stirred for a further 30 mins. The dichloromethane was then evaporated on a rotary evaporator and the residue partitioned between ethyl acetate and water. The pH of the aqueous phase was adjusted to 6.0 with saturated sodium bicarbonate solution and the organic phase was separated, washed with water, then brine, dried over magnesium sulphate and evaporated. The title compound (333 mg) was isolated by column chromatography of the residue (Kieselgel, ethyl acetate as eluent). υmax (CHCl3) 1780 and 1750 cm-1 ; δH (CDCl3) 1.86 (2H, broad s), 3.42 (1H, d, J 17.4Hz), 3.48 (1H, d, J 15.0Hz), 3.60 (1H, d, J 17.4Hz), 3.65 (1H, d, J 15.0Hz), 4.60 (2H, s), 4.78 (1H, d, J 5.1Hz), 4.95 (1H, d, J 5.1Hz), 5.89 (1H, s), 6.99 (1H, s), 7.2-7.5 (10H, m).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:11]=1[CH2:12][O:13][CH2:14][C:15]#[C:16][CH2:17]Br>O1CCCC1>[CH2:1]([NH:8][CH2:17][C:16]#[C:15][CH2:14][O:13][CH2:12][C:11]1[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:10]=1[F:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc(Br)cc1COCC#CCBr
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1COCC#CCNCc1ccccc1
Yield: 61.8 %

Procedure:
A solution of benzylamine (0.98 ml, 8.93 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (300 mg, 0.893 mmol) in tetrahydrofuran (4.5 ml). The cloudy reaction mixture was stirred for about twenty hours, at which time no starting material remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back extracted with methylene chloride (2×15 ml). The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 200 mg (62%) of the title intermediate.
Reaction SMILES: C1(C[O:8][C:9](=[O:51])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:26]=[C:25]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:24]=2)[CH2:12][C:13](=[O:22])[O:14]CC2C=CC=CC=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:26]=[C:25]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:24]=1)[CH2:12][C:13]([OH:22])=[O:14])([OH:51])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 74.8 %

Procedure:
A mixture of 10.2 g (0.0145 mol) of N-[3,5-bis(decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester and 1.5 g of 10% palladium on charcoal in 500 ml of THF was shaken in a hydrogen atmosphere at room temperature for 7 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to a solid which was recrystallized from acetonitrile to give 5.66 g (75% yield, mp 110°-114°) of N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([CH3:37])([CH3:36])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[N:25][N:26]=4)=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[O:23][C:22]([C:20]3[CH:19]=[CH:18][C:16]4[NH:17][C:13]([C:9]5[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][C:4]([CH3:36])([CH3:37])[C:3]([OH:38])=[O:2])=[CH:11][C:10]=5[CH3:12])=[N:14][C:15]=4[CH:21]=3)=[N:26][N:25]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3cc(-c4nnc(-c5ccc(OC)cc5)o4)ccc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2nnc(-c3ccc4[nH]c(-c5c(C)cc(CC(C)(C)C(=O)O)cc5C)nc4c3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(4-{5-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (340 mg, 0.667 mmol) and aqueous 1M NaOH (5 mL, 5 mmol) in MeOH (5 mL) was stirred at room temperature for 18 h and then heated at 50° C. for 1 h. After the mixture was cooled to room temperature, the mixture was slowly acidified to pH 2˜3 by addition of 3M HCl. The product precipitated and was separated from the solution. The solid was dissolved in a small quantity of DMSO and purified by HPLC (basic) to give the title compound as a solid. 1H NMR (CD3OD, 400 MHz) δ ppm 8.55-8.45 (m, 1H), 8.23 (d, J=8 Hz, 2H), 8.22 (d, J=8 Hz, 1H), 7.95-7.85 (m, 1H), 7.26 (d, J=8 Hz, 2H), 7.15 (s, 2H), 4.02 (s, 3H), 2.99 (s, 2H), 2.26 (s, 6H), 1.30 (s, 6H). m/z 497.2 (MH+).