Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]([C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)[N:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)=[CH:60][CH:59]=1>CN(C=O)C.C(OCC)C>[F:77][C:74]1[CH:73]=[CH:72][C:71]([CH:64]([C:61]2[CH:62]=[CH:63][C:58]([F:57])=[CH:59][CH:60]=2)[N:65]2[CH2:66][CH2:67][N:68]([C:5]([C@@H:4]([NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])[CH2:3][CH:2]([CH3:1])[CH3:23])=[O:7])[CH2:69][CH2:70]2)=[CH:76][CH:75]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 75.8 %

Procedure:
(S)-4-Methyl-2-[(4-phenyl-piperazine-1-carbonyl)-amino]pentanoic acid (0.300 g, 0.939 mmol, Example 17, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.327 mL, 1.88 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.356 g, 0.939 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.271 g, 0.939 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane, then 60% EtOAc in hexane) to provide 0.42 g (76%) of the pure titled compound as a light yellow foam: mp 83-91 ° C. APCI-MS m/z 590.4 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:12])[NH:9][N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:23][C:24]1[C:32]2[C:27](=[C:28]([NH2:33])[CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.O>CS(C)=O>[Cl:13][C:4]1[N:3]=[C:2]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[C:27]=2[NH:26][CH:25]=[C:24]3[CH3:23])[C:7]2[C:8](=[O:12])[NH:9][N:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: O=c1[nH]ncc2cc(Cl)nc(Cl)c12
Reactant: Cc1c[nH]c2c(N)cccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1c[nH]c2c(Nc3nc(Cl)cc4cn[nH]c(=O)c34)cccc12
Temperature: 140 °C

Procedure:
To 5,7-dichloro-3H-pyrido[3,4-d]pyridazin-4-one (180 mg, 0.833 mmol) in DMSO (1 ml) in a sealable vial, was added DIPEA (0.189 ml, 1.083 mmol) and 3-methyl-1H-indol-7-amine (158 mg, 1.083 mmol). The vial was capped to close and the mixture heated on a sandbath at 140° C. for 1 h. The resultant mixture was poured into water (20 ml), and extracted with EtOAc (20 ml). Organic phase was washed with water then brine, dried over Na2SO4, then concentrated under vacuum. The residue was triterated with DCM, then collected by filtration and dried to give title compound as a yellow-mustard coloured solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Si:28]([CH3:32])([CH3:31])[CH2:29][OH:30])=[CH:24][CH:23]=1)[CH3:20].Cl>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Si:28]([CH3:31])([CH3:32])[CH2:29][O:30][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:4]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Reactant: CCOc1ccc([Si](C)(C)CO)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOc1ccc([Si](C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g (0.0042 mole) of (4-fluoro3-phenoxyphenyl)methyl chloride in 5 mL of dry toluene was added 0.15 g (0.0063 mole) of sodium hydride. Dropwise a solution of 0.98 g (0.0047 mole) of 2-(4-ethoxyphenyl)-2-methyl-2-silapropanol in 5 mL of dry toluene was added to the reaction mixture. The reaction mixture was stirred at room temperature for one hour and then was heated at reflux for three hours. Aqueous 10% hydrochloric acid was added to the reaction mixture which was then extracted twice with diethyl ether. The combined extracts were dried, filtered through silica gel, and the solvent was evaporated under reduced pressure, leaving a residue. This residue was subjected to Kugelrohr distillation to remove remaining starting materials. The residue from this distillation was separated into two major fractions using a Chromatotron (eluant=ethyl acetate/ hexane (2:98). The smaller fraction, weighing 0.19 g, was determined to be (4-fluoro-3-phenoxyphenyl)methyl 2-(4-ethoxyphenyl)-2-methyl-2-silapropyl ether from its nmr spectrum.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH3:17])=[C:4]([CH:18]=[O:19])[C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]>CO>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([CH3:17])=[C:4]([CH2:18][OH:19])[C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: Cc1c(C=O)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Solvent: CO
Product: Cc1c(CO)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Yield: 93.8 %

Procedure:
To a −20° C. solution of 5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde (0.659 g, 1.40 mmol) in methanol (10 mL) was added, portionwise, solid sodium borohyride (3.6 g, 96 mmol) over one hour until complete consumption of starting material by LCMS analysis. Next, the reaction mixture was diluted with 500 mL of ethyl acetate and washed with 3×200 mL of water. The resulting organic extract was Na2SO4 dried, filtered, and concentrated in vacuo to approximately 100 mL volume. The resulting liquid was diluted with hexanes (100 mL) to furnish an amorphous solid that was collected and dried at 1 mm Hg vacuum to furnish (620 mg, 94%) of the desired product. 1H NMR (400 MHz, d4-MeOH) δ 7.70 (app q, J=8.3 Hz, 1H), 7.62 (app tt, J=10.4, 6.3 Hz, 1H), 7.25 (app t, J=8.6 Hz, 2H), 7.03 (app t, J=8.6 Hz, 1H), 6.88 (app t, J=8.5 Hz, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 2.17 (s, 3H); LC/MS C-18 column, tr=2.49 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 472 (M+H). ES-HRMS m/z 472.0152 (M+H calcd for C20H15BrF4NO3 requires 472.0166).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]([C:29](SC)=[N:30][C:31](=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[N:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1CCCCC1>[CH3:19][N:20]([C:29]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[N:30][C:31](=[O:39])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[N:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSC(=NC(=O)Cc1ccccc1)N(C)N=Cc1ccccc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: C1CCCCC1
Product: CN(N=Cc1ccccc1)C(=NC(=O)Cc1ccccc1)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 80.8 %

Procedure:
A mixture of 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (0.38 g) and methyl 1-methyl-N-phenylacetyl-2-(phenylmethylene)hydrazinecarboximidothioate (0.5 g) was heated at 50° under water pump vacuum during 4 h. The residue was dissolved in cyclohexane (20 ml) and light petroleum (b.p. 60°-80°) was added. The precipitate was removed by filtration and the filtrate was evaporated to give the title compound (0.65 g) as a colourless oil. tlc. System A Rf 0.7.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[N:27][CH:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:29][C:26]1[N:27]=[CH:28][C:23]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[C:8]3=[N:15][C:14]=2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1cn2nccc(N3CCOCC3)c2n1
Reactant: Clc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCOC(=O)Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(Cl)nc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
Compound 28c (867 mg, 2.99 mmol), 5-bromo-2-chloropyridine (888 mg, 4.48 mmol), Pd(OAc)2 (46.9 mg, 0.209 mmol), PPh3 (54.8 mg, 0.209 mmol), and KOAc (879 mg, 8.95 mmol) were placed in a 40 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMA (10 mL) was added via syringe and then the mixture was heated to 110° C. and stirred for 16 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and filtered. The solids were washed with EtOAc (30 mL) and then the combined filtrates were washed with water (2×20 mL) and brine (20 mL). The organic phase was dried over Na2SO4 and filtered, and then the solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-60% EtOAc/DCM to afford compound 28d. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.68 (d, J=2.2 Hz, 1H), 8.07 (dd, J=8.3, 2.4 Hz, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 6.11 (d, J=5.6 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.96-4.03 (m, 4H), 3.89-3.95 (m, 4H), 3.84 (s, 2H), 1.26 (t, J=7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C19H20ClN5O3: 402.1 (M+H). Found: 402.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][C:15](=O)[CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:15]1([CH2:16][CH:17]([CH3:19])[CH2:18][CH:13]([CH3:12])[CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC1CC(=O)CC(C)C1
Solvent: C1CCNC1
Solvent: CO
Product: CC1CC(C)CC2(CC(=O)c3cc(Br)ccc3O2)C1
Reaction time: 8 h
Yield: 110.5 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (6 g, 28 mmol), 3,5-dimethylcyclohexanone (7.12 g, 56 mmol) and pyrrolidine (3.8 g, 53.3 mmol) in methanol (120 mL) was stirred overnight. The reaction mixture was concentrated in vacuo, and H2O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6-bromo-3′,5′-dimethylspiro[chroman-2,1′-cyclohexan]-4-one (10 g, 100%). 1HNMR (CDCl3): 0.51 (m, 1H), 0.71 (m, 4H), 0.72 (m, 3H), 0.91 (m, 3H), 1.11 (d, 1H), 1.19 (t, 1H), 1.50 (s, 1H), 1.64 (t, 1H), 1.79 (m, 3H), 1.90 (m, 2H), 2.0 (m, 3H), 2.24 (t, 1H), 2.53 (s, 1H), 2.79 (s, 1H), 6.75 (t, 1H), 7.49 (t, 1H), 7.89 (d, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][N:7]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH-].[Na+]>C(OCC)C.O>[CH3:14][N:13]([CH2:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:1][NH2:2])[CH:11]=1)[CH3:15]
Reactant: CN(C)Cc1ccnc(CCCC#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN(C)Cc1ccnc(CCCCN)c1
Reaction time: 2.5 h
Yield: 100 %

Procedure:
2-(3-Cyanopropyl)-4-dimethylaminomethylpyridine (1 g) in diethyl ether (15 ml) was added dropwise to a rapidly stirred suspension of lithium aluminium hydride (0.76 g) in ether (45 ml). The solution was stirred for 2.5 hours. Wet tetrahydrofuran, followed by 16% sodium hydroxide (1 ml) and then water was added and the mixture was filtered. The filtrate was evaporated to give 4-(4-dimethylaminomethyl-2-pyridyl)butylamine (1.02 g) as a clear oil.
Reaction SMILES: [CH3:1][CH:2]([S:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([S:16](CCC(OC)=O)(=[O:18])=[O:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1)(=[O:6])=[O:5])[CH3:3].C[O-].[Na+].C1C(=O)N([Cl:35])C(=O)C1>C1COCC1>[CH3:1][CH:2]([S:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([S:16]([Cl:35])(=[O:18])=[O:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1)(=[O:6])=[O:5])[CH3:3]
Reactant: COC(=O)CCS(=O)(=O)c1ccc2c(cnn2S(=O)(=O)C(C)C)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1ncc2cc(S(=O)(=O)Cl)ccc21
Reaction time: 0.33 h

Procedure:
To a solution of methyl 3-{[1-(propan-2-ylsulfonyl)-1H-indazol-5-yl]sulfonyl}propanoate (300 mg, 0.80 mmol) in THF (4 mL) was added sodium methoxide (1.6 mL, 0.5 M, 0.80 mmol). The reaction mixture was stirred for 20 minutes, then the solvents were removed under reduced pressure and the residue was stripped down from heptanes to generate a white foam. This foam was suspended in DCM (4 mL) at 0° C. and then NCS (106 mg, 0.80 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was quenched by the addition of brine (4 mL) and the phases were separated using a phase separator. The aqueous layer was washed with DCM. The combined organic layers were concentrated under reduced pressure, and the crude was purified on silica gel eluting with hexanes and ethyl acetate to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([Br:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Br:10])=[CH:7][C:8]=1[Br:9])#[N:2].[OH-:17].[Na+]>O>[C:1]([C:3]1[C:4]([Br:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Br:10])=[CH:7][C:8]=1[Br:9])(=[O:17])[NH2:2]
Reactant: N#Cc1c(Br)cc(Br)c(CCC(=O)O)c1Br
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Br)cc(Br)c(CCC(=O)O)c1Br
Temperature: 60 °C
Reaction time: 3 h
Yield: 117.9 %

Procedure:
13 g of 3-(3-cyano-2,4,6-tribromophenyl)propionic acid is introduced into a solution of 3.2 g of caustic soda in 64 ml of water. The solution is then stirred for 3 hours at 60° C., filtered repeatedly over active carbon to decolorize, and subsequently the filtrate is brought to pH 1 by the addition of concentrated hydrochloric acid. The precipitate is vacuum-filtered, washed with water, and dried at 50° C., thus obtaining 16 g (95% of theory) of 3-(3-carbamoyl-2,4,6-tribromophenyl)propionic acid as a white powder, mp 197° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:28][CH2:27][CH2:26][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23](=[O:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.[CH2:29]1COCC1.C[Mg]Cl.[Cl-].[NH4+]>O.C(Cl)Cl.C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:28][CH2:27][CH2:26][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([OH:25])([CH3:29])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A 100 mL round bottom flask was charged with 1-(6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanone (2.74 g, 7.20 mmol). THF (36.0 mL) was added and the mixture was stirred at ambient temperature for about 15 min. The slurry was cooled to about −40° C. and a solution of methylmagnesium chloride (3 M in THF, 6.00 mL, 18.0 mmol) was added slowly while keeping the internal temperature between about −30° C. and −40° C. After about 15 min, the mixture was cooled to about −55° C. followed by the slow addition of a saturated ammonium chloride solution (about 10 mL). The mixture was then warmed to ambient temperature and diluted with water (50 mL), DCM (75 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL) then the combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give a foam. The material was dissolved in 95:5 DCM/MeOH (about 20 mL) with warming and sonication and then loaded onto a 120 g silica column and eluted with 94:6 DCM/MeOH (about 1 L) followed by 92:8 DCM/MeOH (about 500 mL). Evaporation of the fractions gave the title compound as a yellow foam (2.88 g, 91%) that contained about 9 wt % DCM by 1H NMR. This material was combined with a second batch of the title compound (3.4 g that also contained about 9 wt % DCM). The combined material (5.7 g) was dissolved into ACN (150 mL), followed by a rapid precipitation of the title compound as an off-white powder (4.69 g, 82% recovery): LC/MS (Table 1, Method g) Rt=1.58 min; MS m/z: 397.2 (M+H)+; 1H NMR (DMSO-d6) δ 8.18 (d, 1H), 7.65 (m, 1H), 7.29 (m, 1H), 7.19 (m, 1H), 6.93 (m, 1H), 5.46 (s, 1H), 4.36 (t, 2H), 2.90 (t, 2H), 2.68-2.54 (m, 2H), 1.70 (s, 6H); mp 221.6-222.7° C.; Anal. calcd. for C20H18F2N6O: C, 60.60; H, 4.58; N, 21.20; F, 9.59. found C, 60.43; H, 4.46; N, 21.38; F, 9.56.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4)c3O2)cc1
Yield: 67.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.367 g (68%) of (±)-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as an orange solid. mp 130-133° C.; Anal. calcd. for C22H19ClO4S: C, 63.69; H, 4.62. Found: C, 62.82; H, 4.56.
Reaction SMILES: C(NC1SC=C(/C(=N/OC(C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)C2C=CC(OC(=O)C)=C(OC(=O)C)C=2)/C(N[C@@H:30]2[C:57](=[O:58])[N:32]3[C:33]([C:45]([O:47]CC4C=CC(OC)=CC=4)=[O:46])=[C:34]([CH:37]=[CH:38][C:39]4[S:43][CH:42]=[N:41][C:40]=4[CH3:44])[CH2:35][S:36][C@H:31]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[F:100][C:101]([F:106])([F:105])[C:102]([OH:104])=[O:103]>C(Cl)Cl>[F:100][C:101]([F:106])([F:105])[C:102]([OH:104])=[O:103].[CH3:44][C:40]1[N:41]=[CH:42][S:43][C:39]=1[CH:38]=[CH:37][C:34]1[CH2:35][S:36][C@@H:31]2[CH2:30][C:57](=[O:58])[N:32]2[C:33]=1[C:45]([OH:47])=[O:46]
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3scnc3C)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Cc1ncsc1C=CC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Reaction time: 1.5 h

Procedure:
709 mg (0.558 mmol) of 4-methoxybenzyl 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(diphenylmethoxy carbonyl)(3,4-diacetoxyphenyl)methoxyl]imino]acetamido]-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboylate was dissolved in 7 ml of methylene chloride and 2.8 ml of anisole and then 11.2 ml of trifluoroacetic acid was added under and then 11.2 ml of trifluoroacetic acid was added under ice-cooling and the reaction was performed for 90 min. Methylene chloride and trifluoroacetic acid were evaporated under the reduced pressure and the resultant residue was powdered with ethyl ether-hexane(1:1). The powder collected by filtration was further dissolved in 40 ml of trifluoroacetic acid under ice-cooling and then 10 ml of water was added and the reaction was performed for 2.5 hrs. at the room temperature. Trifluoroacetic acid and water were evaporated under the reduced pressure and to the resultant residue was added ethyl ether to powder and collected by filtration to give 298 mg of 7β -[(Z)-2-(2-amino-4-thiazolyl)-2[[(R S)-carboxy)(3,4-diacetoxyphenyl)methoxy]imino]acetamido]-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid trifluoroacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=[CH:13][C:14]3[N:18]([CH3:19])[N:17]=[C:16]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:15]=3)[N:11]=[C:4]2[N:3]=1.C(Cl)Cl.CO>[Pd].CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:18]([CH3:19])[N:17]=[C:16]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:15]=3)[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(C=Cc3nc(N4CCCC4)nn3C)nc2n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)n2nc(CCc3nc(N4CCCC4)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.1 %

Procedure:
A mixture of 5,7-dimethyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrimidine (65 mg, 200 μmol, Eq: 1.00) and palladium on carbon 10% (42.6 mg, 40.1 μmol, Eq: 0.2) in methanol (10.0 ml) was stirred for 14 hours at 25° C. under hydrogen atmosphere. TLC (CH2Cl2/MeOH 19:1/UV 254 nm) showed complete reaction (spot to spot). palladium was filtered off and the filtrate was evaporated and dried under high vacuum to give 5,7-Dimethyl-2-[2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine (34 mg, 52%) as viscous oil
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]1[N+:30]([O-])=[N:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.O>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:28]5[N:29]=[N:30][CH:25]=[CH:26][CH:27]=5)[CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(-c3c[nH]c(C4CCNCC4)n3)cn2)cc1
Reactant: [O-][n+]1ncccc1Cl
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(-c2ncc(-c3c[nH]c(C4CCN(c5cccnn5)CC4)n3)cn2)cc1

Procedure:
The title compound is prepared in a similar manner described above using Buchwald-Hartwig amination conditions or as described in PCT International Application 2006/058338, 1 Jun. 2006. In this case, a solution consisting of 2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine and 6-chloropyridazine 1-oxide (preparation of this reagent can be found in PCT International Application 2007/106670, 20 Sep. 2007 and Chemical and Pharmaceutical Bulletin, 1963, 11, 261-263) in dimethylsulfoxide is heated at 80° C. for 18 hours. The reaction mixture is cooled, diluted with water and the organic material is extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica to afford the title compound.