Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]12[CH:11]3[C:12]([CH3:18])([CH3:17])[CH:13]4[CH2:16][C:10]3([CH2:15][CH2:14]4)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]1[O:6]2)(=O)C.[OH-].[Na+].Cl>O.C(O)C>[OH:4][CH:5]1[CH:11]2[C:12]([CH3:17])([CH3:18])[CH:13]3[CH2:16][C:10]2([CH2:15][CH2:14]3)[C:9]([CH3:20])([CH3:19])[CH2:8][C:7]1=[O:6]
Reactant: CC(=O)OC12OC1CC(C)(C)C13CCC(C1)C(C)(C)C23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)C2CCC3(C2)C1C(O)C(=O)CC3(C)C
Reaction time: 8 h

Procedure:
2,2,8,8-Tetramethyl-5-oxatetracyclo[7.2.1.01.7.04.6]dodec-6-yl acetate (3, 14.5 g, 61% pure, 0.032 mol) was added at r. t. to a solution of sodium hydroxide (30 g, 0.75 mol) in water (0.75 l) and ethanol (0.75 l). After overnight stirring at r. t., the reaction mixture was neutralized to pH 7 with 2M aqueous HCl solution and extracted with MTBE (2×0.5 l). The combined organic phases were washed with water (2×0.2 l), dried (Na2SO4) and concentrated in vacuo to give crude 5-hydroxy-2,2,7,7-tetramethyltricyclo[6.2.1.01.6]undecan-4-one (4, 13 g, colourless oil, partly solidifying on standing) which was used without further purification in the next steps. Besides two isomeric hydroxyketones, the mixture contained tautomeric forms of the oxidised 4 (diketone).
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][CH2:10][CH2:11][N:12]([CH3:26])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.NC1C=CC(OCCN(CCC2C=CC(N[S:48]([CH3:51])(=[O:50])=[O:49])=CC=2)C)=CC=1.Cl.Cl.S(Cl)(C)(=O)=O>N1C=CC=CC=1>[CH3:51][S:48]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH3:26])=[CH:27][CH:28]=1)(=[O:50])=[O:49]
Reactant: CN(CCOc1ccc(N)cc1)CCc1ccc(NS(C)(=O)=O)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
The title compound was prepared by mesylation of 1-(4-aminophenoxy)-2-[N-methyl-N-(4-methanesulphonamidophenethyl)amino]ethane dihydrochloride hemihydrate (95 mg) with mesyl chloride ir pyridine according to the procedure of Example 19(C), yield 30 mg, m.p. 147°-149°, confirmed spectroscopically to be identical to the product of Example 7(C).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.O>CN(C)C=O>[I:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:25][CH:24]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(I)cc3)c2cc1OC
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of 4-chloro-6,7-dimethoxyquinazoline (224 mg, 1.00 mmol), potassium carbonate (152 mg, 1.10 mmol) and 4-iodophenol (244 mg, 1.10 mmol) in dimethylformamide (4 ml) was heated at 110° C. for 2 hours before the reaction was allowed to cool to ambient temperature. The reaction was poured into water and the solid which had precipitated was collected by suction filtration and washed with a mixture of diethyl ether (10 ml), ethyl acetate (10 ml) and isohexane (10 ml). Drying of this material yielded, yielded 4-(4-iodophenoxy)-6,7-dimethoxyquinazoline (340 mg, 83% yield) as a white solid:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of benzyl ester (1) (25.7 mg, 0.0664 mmol) in 1:1 THF/H2O (3 mL) at 0° C. was added LiOH (9 mg, 0.348 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h at room temperature. The desired product 3 was obtained in 99% yield after purification by column chromatography (CH2Cl2/MeOH=85:15). FABMS: 298 (M+1); HREIMS calcd. for C17H15NO4 298.1079, found 298.1078.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[N:17]/[O:18][CH3:19])/[C:14]([OH:16])=O)[N:12]=1)=[O:6])[CH:2]=[CH2:3].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[Cl-].[CH2:39]([O:46][C:47]([C:49]1[CH2:56][N:55]2[N:51]([C:52](=[O:58])[CH:53]([NH2:57])[CH2:54]2)[C:50]=1[C:59]([O:61][CH2:62][CH:63]=[CH2:64])=[O:60])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:39]([O:46][C:47]([C:49]1[CH2:56][N:55]2[N:51]([C:52](=[O:58])[CH:53]([NH:57][C:14](=[O:16])/[C:13](/[C:11]3[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[S:9][CH:10]=3)=[N:17]\[O:18][CH3:19])[CH2:54]2)[C:50]=1[C:59]([O:61][CH2:62][CH:63]=[CH2:64])=[O:60])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=CCOC(=O)C1=C(C(=O)OCc2ccccc2)CN2CC(N)C(=O)N12
Reactant: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)O)cs1
Agent: COc1nc(Cl)nc(OC)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)NC2CN3CC(C(=O)OCc4ccccc4)=C(C(=O)OCC=C)N3C2=O)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Under a nitrogen atmosphere, 2-[2-(allyloxycarbonylamino)thiazol-4-yl]-2-(Z)-methoxyiminoacetic acid (231 mg, 0.81 mmol) was suspended in methylene chloride (5 ml) and the suspension was cooled to 0° C. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (142 mg, 0.81 mmol) followed by N-methylmorpholine (0.09 ml, 0.81 mmol) were added and the solution was stirred at 0° C. for 30 minutes. A methylene chloride solution (10 ml) of allyl 3-(benzyloxycarbonyl)-7-(R,S)-amino-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate chloride (0.81 mmol) followed by additional N-methylmorpholine (0.09 ml, 0.81 mmol) were added and the solution was stirred and allowed to warm gradually to room temperature over 1.5 hours. The methylene chloride was removed in vacuo and the resultant residue was flash chromatographed on silica gel eluted with 10% hexane:ethyl acetate to give 340 mg, 67% yield of the title compound: n.m.r. (90 MHz, CDCl3): δ 3.08 (dd, J=10.8 and 10.8, 1), 3.96 (s, 3), 3.99, 4.43 (ABq, J=12.6, 2), 3.88-4.28 (m, 2), 4.56-4.92 (m, 4), 5.16 (s, 2), 5.23 (d, J=9, 2), 5.42 (d, J=10.8, 2), 5.50-6.16 (m, 2), 7.10 (s, 1), 7.28 (br. s, 5), 8.09 (br. d, 1), 9.38 (br. s, 1); i.r. (CDCl3): 3025, 1731, 1704, 1557, 1386, 1369, 1277 cm-1 ; f.d.m.s. (m/e): M+ +1=625; u.v. (EtOH): εmax =264 (ε=10926), 338 (ε=6493); Anal. Calcd for C28H28N6O9S1 : Theory: C, 53.84; H, 4.52; N, 13.45; Found: C, 53.68; H, 4.59; N, 13.21.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2=[CH:7][C:8]3[S:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]=3[CH:13]=[C:4]2[O:3]1.[Li]CCCC.[Mg+2].[Br-].[Br-].[C:25]([O:29]OC(=O)C1C=CC=CC=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C.CCCCCC>[C:25]([O:29][C:13]1[C:4]2[O:3][C:2]([CH3:16])([CH3:1])[S:6][C:5]=2[CH:7]=[C:8]2[S:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]=12)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1(C)Oc2cc3c(cc2S1)SC(C)(C)O3
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)Oc1c2c(cc3c1OC(C)(C)S3)SC(C)(C)O2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:5,4-d']bis(1,3)oxathiole (300 mg, 1.18 mmol) was dissolved in dry diethyl ether (30 mL) and the solution was cooled to -78° C. A solution of n-BuLi in hexane (2.5M, 0.52 mL) was added and the reaction was allowed to attain room temperature. After stirring for 1 hour, the mixture was cooled to -78° C. and transferred into a solution of MgBr2 in dry ether (prepared from magnesium, 60 mg and 1,2-dibromoethane, 0.2 mL in 2 mL ether) kept at -78° C. The mixture was stirred for 30 minutes at 0° C. and then, a solution of t-butylperbenzoate (0.24 mL, 0.12 mmol) in dry ether (2 mL) was added. After stirring for 1 hour at 0° C., the mixture was poured onto a mixture of ice and 0.1M aqueous HCl. The aqueous phase was extracted three times with ether and the combined organic phases were washed with aqueous NaHSO3, 2M NaOH, dried (MgSO4) and evaporated. The product was purified by preparative HPLC (RP-18, CH3CN: H2O 80:20). Yield 124 mg (32%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1)[CH2:22][CH3:23].[Cl-].[NH4+]>CS(C)=O>[CH2:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[CH:29][CH:30]=1)[CH2:22][CH3:23]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCCOc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(CN2CCC(C(=O)OCC)CC2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of 47.5 grams (0.30 mole) of ethyl piperidin-4-ylcarboxylate in 70 mL (0.40 mole) of N, N-diisopropylethylamine was added dropwise a solution of 52.5 grams (0.29 mole) of 4-propoxyphenylmethyl chloride in 50 mL of dimethyl sulfoxide. The reaction caused the reaction mixture temperature to rise to about 35° C. Upon completion of the addition the reaction mixture was stirred for 30 minutes, warmed to 40° C., and then allowed to cool to ambient temperature. After this time the reaction mixture was poured into 500 mL of aqueous 10% ammonium chloride. The mixture was extracted with three 250 mL portions of diethyl ether, and the combined extracts were washed with two 250 mL portions of an aqueous solution saturated with ammonium chloride, one 250 mL portion of water, and one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 80.0 grams of ethyl N-(4-propoxyphenylmethyl)piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=O)=[CH:13][CH:12]=1>>[C:1]1(=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Reactant: O=C1CCCCCC1
Product: COc1ccc(C(=C2CCCCCC2)c2ccc(C#N)cc2)cc1
Yield: 56.3 %

Procedure:
The general McMurry protocol, described for 14 was employed. The coupling was conducted between cycloheptanone (1.5 mL, 12.64 mmol), and 4-{[4-(methyloxy)phenyl]carbonyl}benzonitrile (1.0 g, 4.2 mmol) to afford 0.750 g (56%) of the title compound 207 as a white solid. IR (film): 2920, 2225, 1603, 1508, 1242, 825, cm1. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 3.80 (s, 3H), 2.36 (br s, 2H), 2.29 (br s, 2H), 1.60 (s, 8H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[N:45]1[CH:50]=[CH:49][N:48]=[C:47]([NH2:51])[N:46]=1.[H-].[Na+]>CN(C=O)C.CO>[N:45]1[CH:50]=[CH:49][N:48]=[C:47]([NH:51][C:37](=[O:39])[C:36]([NH:35][C:33]([C:32]2[CH:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:19]4[O:18][C:17]([C:14]5[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=5)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=4[CH:26]=3)[CH:44]=[CH:43][CH:42]=2)=[O:34])([CH3:41])[CH3:40])[N:46]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Reactant: Nc1nccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4nccnn4)c3)cc12
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
DIEA (28 μL, 0.158 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (25 mg, 0.053 mmol), 1,2,4-triazin-3-amine (11 mg, 0.105 mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263 mmol) was added and the reaction was allowed to stir overnight. The mixture was treated with a drop of MeOH and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7.4 mg, 25%). 1H NMR (500 MHz, CD3OD) δ ppm 8.58-8.63 (1H, m), 8.22-8.26 (1 H, m), 7.93-8.00 (3H, m), 7.85-7.93 (2H, m), 7.66-7.75 (2H, m), 7.59 (1H, t, J=7.63 Hz), 7.27 (2H, t, J=8.85 Hz), 2.98 (3H, s), 1.72 (6H, s). LC-MS retention time: 1.56 min; m/z (MH+): 553. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90%
Reaction SMILES: [NH2:1][C@@H:2]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[CH3:44][O:43][C:41](=[O:42])[CH2:40][NH:1][C@@H:2]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1
Reactant: N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-2-amino-1-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-3,3-diphenylpropane (8.6 g, Example 1i) and anhydrous K2CO3 (13.0 g)in dimethylformamide (50 ml) was added methyl bromoacetate (4.5 ml). The reaction was stirred at room temperature for 0.75 h then diluted with ethyl acetate (200 ml) and washed with water (4×100 ml), brine (100 ml), dried over MgSO4 and evaporated to dryness. The residual oil was purified on silica gel eluting with petroleum ether-ethyl acetate mixtures to give (S)-N-(1-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-3,3-diphenylprop-2-yl)glycine methyl ester as an oil (7.61 g) 1H NMR (360 MHz, CDCl3) δ7.77 (1H, s), 7.71 (2H, s), 7.42 (2H, d, J=7.4 Hz), 7.33-7.13 (8H, m), 4.44 (2H, s), 4.12 (1H, d, J=7.2 Hz), 3.73-3.69 (1H, m), 3.63 (3H, s), 3.57-3.52 (1H, m), 3.53 (2H, d, J=6.7 Hz) and 3.44-3.36 (1H, m).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CC(C)([O-])C.[Na+].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]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.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:40][C:39]2[CH:38]=[CH:37][C:36]([CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)=[CH:42][CH:41]=2)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)Cc1cnc(Nc2ccc(CN3CCOCC3)cc2)cc1NCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
20 mg of 4-(benzylamino)-6-chloropyridine-3-carboxyamide (the compound of Example 1), 3.1 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).methylene chloride adduct, 6.3 mg of 1,1′-bis (diphenylphosphino)ferrocene and 7.3 mg of sodium tert-butoxide were added to 1 mL of 1,4-dioxane, to which 18 mg of 4-(morpholinomethyl)aniline was added in an argon atmosphere, and stirred at 100° C. for 3 hours. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 9 mg (28%) of the title compound as a light yellow powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19](=[N:26][OH:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[C:30]1([C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N+]=[N-])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19](=[N:26][OH:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([O:14][CH:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid (syn-isomer)(2.0 g) in tetrahydrofuran (50 ml.) maintained at 37° was added portionwise a solution of diphenyldiazomethane in petroleum (b.p. 60°-80°) until the purple colour persisted for one hour. After addition of acetic acid to destroy excess diphenyldiazomethane, the solution was evaporated to dryness, taken up in ethyl acetate, then washed with sodium bicarbonate, and brine, dried and evaporated. The residue was triturated with petroleum spirit, and the resulting solid filtered and dried to give diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (syn-isomer) (1.93 g 69%), [α]D +24° (c 1, DMSO), λmax. (EtOH) 253 nm (ε 16,150), νmax. (CHBr3) 3610 (OH), 1796 cm.-1 (β-lactam), τ (DMSO-d6) values include 0.27 (doublet, J 9 Hz; NH), 8.03 (singlet; OCOCH 3).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]OCCCCC1C=CC([N+]([O-])=O)=CC=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:33][CH2:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Product: O=[N+]([O-])c1ccc(CCOCCCCCCBr)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 52, using 2-(4-nitrophenyl)ethanol in place of 4-(4-nitrophenyl)butan-1-ol. ES/MS calcd. for C14H21BrNO3+ 330.1. Found m/z=330.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]#[C:12][C:13]([F:16])([F:15])[F:14]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][CH2:12][C:13]([F:14])([F:16])[F:15]
Reactant: COc1cccc(OC)c1C#CC(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CCC(F)(F)F
Yield: 87 %

Procedure:
41.5 g (0.18 mole) of 1,3-dimethoxy-2-(3,3,3-trifluoroprop-1-ynyl)-benzene are dissolved in tetrahydrofuran and hydrogenated in the presence of palladium-on-charcoal at room temperature under normal pressure. The catalyst is filtered off over diatomaceous earth and washed with tetrahydrofuran and the filtrate is concentrated. Drying under reduced pressure gives crystalline 1,3-dimethoxy-2-(3,3,3-trifluoropropyl)-benzene (yield 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1C(C(O)=O)=C(C)N(C2C=CC(C(F)(F)F)=CN=2)[N:24]=1>>[Si:15]([O:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:24])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2ccc(Br)cn2)CC1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)c(C)c1C(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2ccc(N)cn2)CC1

Procedure:
trans-5-Bromo-2-[4-(tert-butyldimethylsilyloxy)cyclohex-1-yl]pyridine (1.54 g) described in Reference Example 103 (3) was used in place of 1-(5-bromopyridin-2-yl)-c-4-(tert-butyldimethylsilanyloxy)-r-1-cyclohexanecarbonitrile in Reference Example 144 (2) and (3), and reacted and treated in a similar manner to give the titled compound (1.11 g) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14](Cl)=O.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:14]([C:13]3[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:12]=3[F:11])[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: O=C(Cl)c1c(F)ccc(F)c1F
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1ccc(F)c(-c2nc(-c3ccnnc3)no2)c1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 2,3,6-trifluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.28-7.37 (m, J=9.5, 9.5, 3.7, 2.4 Hz, 1H), 7.67-7.79 (m, J=9.6, 9.6, 8.7, 4.9 Hz, 1H), 8.39 (dd, J=5.3, 2.2 Hz, 1H), 9.46 (dd, J=5.3, 1.2 Hz, 1H), 9.88 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z=279 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[C:34]([C:36]1[CH:51]=[CH:50][C:39]([O:40][C:41]2[C:42]([C:47](O)=[O:48])=[N:43][CH:44]=[CH:45][N:46]=2)=[CH:38][CH:37]=1)=[O:35].C(N(C(C)C)CC)(C)C.[C:61]1([CH2:67][CH2:68][NH2:69])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:25]=[C:26]1[C:34]([C:36]1[CH:37]=[CH:38][C:39]([O:40][C:41]2[C:42]([C:47]([NH:69][CH2:68][CH2:67][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[O:48])=[N:43][CH:44]=[CH:45][N:46]=2)=[CH:50][CH:51]=1)=[O:35]
Reactant: O=C(c1ccc(Oc2nccnc2C(=O)O)cc1)c1nc2ccccc2[nH]1
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Oc2nccnc2C(=O)NCCc2ccccc2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (123 mg, 0.324 mmol) was added to a mixture of 3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazine-2-carboxylic acid (106 mg, 0.294 mmol) and diisopropylethylamine (102 μL, 0.588 mmol) in DMF (1 mL) and the mixture was stirred at RT for 10 min. 2-Phenylethylamine (55.8 μL, 0.441 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was purified by chromatography on silica gel to deliver 3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-phenethylpyrazine-2-carboxamide as a white solid. MS (ESI, pos. ion) m/z: 464.0 (M+1). IC50 (uM) +++++.