Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6])=[N+]=[N-].[ClH:23].[H][H]>O1CCCC1.O.[Pd]>[ClH:23].[NH2:1][CH:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NC(C(=O)O)C1c2ccccc2CCc2ccccc21

Procedure:
To a solution of (R)-α-azido-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (3.5 g, 1.9 mmol) in tetrahydrofuran (75 mL), water (10 mL), and concentrated hydrochloric acid (1 mL) is added palladium on carbon (0.5 g, 20%). The mixture is shaken under 52 pounds per square inch (psi) of hydrogen at 25° C. for 6 hours. Solid is filtered. The filtrate is concentrated in vacuo to give a light green solid, which is recrystallized in 3N hydrochloric acid (with activated charcoal) to give the title compound as a white solid, 2.84 g; mp 313°-314° C. (dec), [α]D =-47.6° (c=1.0, methanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.Cl>>[CH:12]([N:8]1[C:6]2[N:7]=[CH:2][CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]=2[C:10]([CH3:11])=[N:9]1)([CH3:14])[CH3:13]
Reactant: Cc1nn(C(C)C)c2nc(Cl)cc(C(=O)O)c12
Agent: Cl
Product: Cc1nn(C(C)C)c2nccc(C(=O)O)c12

Procedure:
The title compound was prepared in the same manner as described for example 139 (step a) from 10% Pd/C(degussa) (0.457 g, 0.215 mmol), and 6-chloro-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1.09 g, 4.30 mmol) wherein the stir time was 4 h Upon acidification to pH 3 with 1M HCl, the contents were extracted with EtOAc (2×) and the combined organic layers dried over MgSO4, filtered, and concentrated in vacuo. The collected solid was dried in a vacuum oven at 45° C. for 3 h. The final product was collected as 0.826 g (84%). 1H NMR (400 MHz, DMSO-d6) d ppm 1.48 (d, J=6.57 Hz, 6 H), 2.63 (s, 3 H), 5.21 (quin, J=6.69 Hz, 1 H), 7.52 (d, J=4.55 Hz, 1 H), 8.63 (d, J=4.55 Hz, 1 H), 13.77 (br. s., 1 H). LCMS(ES) [M+H]+ 220.2
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]([NH2:29])[CH3:28])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][CH:24]([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH:27]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][CH:24]([F:25])[F:26])=[C:16]([Cl:15])[CH:17]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1cnc(OCC(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1cnc(OCC(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (157 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (155 mg, 0.57 mmol, Amine-16, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.O(S(C)(=O)=O)S(C)(=O)=O.C(O)(=O)C(O)=O.[NH2:52][C:53]1[CH:54]=[CH:55][C:56](=[O:60])[N:57]([CH3:59])[CH:58]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:52][C:53]2[CH:54]=[CH:55][C:56](=[O:60])[N:57]([CH3:59])[CH:58]=2)[C:9]2[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cn1cc(N)ccc1=O
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(Nc1ccc(=O)n(C)c1)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a stirred solution of Ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (Step 1.3) (423 mg, 1.020 mmol) and triethylamine (1.42 mL, 10.20 mmol) in CH2Cl2 under Ar was added Ms2O (355 mg, 2.039 mmol) at −10° C. The reaction mixture was stirred for 30 min at this temperature. 5-Amino-1-methyl-2(1H)-pyridinone oxalate salt (218 mg, 1.020 mmol) was added at 30° C. After 1 hr, the reaction mixture was quenched with a saturated aq. NaHCO solution, and extracted with CH2Cl2. The combined organic layers were washed a saturated aqueous solution of NaHCO3, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 1-2%) to afford the title product (147 mg, 0.282 mmol, 28% yield) as a greenish solid. tR: 4.68 min (HPLC 1); tR: 1.06 min (LC-MS 2); ESI-MS: 521 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc2ccccc12
Reactant: Nc1ccccc1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 197 °C
Yield: 85 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 10 parts of diphenyl phosphite are mixed and heated to 197° C. The elimination of water commences at this temperature and has ended when the internal temperature is 235° C. 31 parts of water are removed in the course of 8 hours. After distilling off excess α-naphthol and aniline, 372 parts of phenyl-α-naphthylamine are obtained at a boiling point of 202° - 204° C/5 mm Hg; the product has a melting point of 55° - 58° C and corresponds to a yield of 85% of theory.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-]>CO>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: COC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Yield: 5.9 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (75 mg, 0.23 mmol), methylurea (34 mg, 0.46 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. % , 0.49 mL, 0.35 mmol) and methanol (0.5 mL) was heated at 100° C. for 8 h. Over time, the reaction mixture turned cloudy in appearance. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and then filtered through a pad of silica gel. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 30/70 hexanes/ethyl acetate) afforded 1-[2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionyl]-3-methyl-urea (5 mg, 6%) as a colorless oil: FAB-HRMS m/e calcd for C17H24N2O5S (M+H)+ 369.1484. found 369.1495.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([Cl:20])=[N:13][C:14]([S:18][CH3:19])=[N:15][C:16]=1Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][O:42][C:16]2[C:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:12]([Cl:20])[N:13]=[C:14]([S:18][CH3:19])[N:15]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CSc1nc(Cl)c(C(=O)NCc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C(=O)NCc2ccccc2)c(OCCC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid benzylamide (3 mmol) in THF (20 mL) is added KOtBu (3.6 mmol) at 0° C. under N2. After stirred at 0° C. for 20 min, the above mixture is added dropwise to a solution of 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (3.3 mmol) in THF (20 mL) at −78° C. The resulting mixture is gradually warm up to −30° C. over 2.5 h. The reaction is quenched by the addition of H2O. The mixture is extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated to give 4-[2-(5-benzylcarbamoyl-6-chloro-2-methylsulfanylpyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester as a white solid; 1H-NMR (CDCl3), δ 1.07-1.17 (2H, m), 1.48 (9H, s), 1.62-1.70 (2H, m), 2.54 (3H, s), 2.64 (2H, br t), 4.06 (2H, m), 4.45 (2H, t), 4.64 (2H, d), 6.06 (1H, t), 7.30-7.34 (2H, m), 7.35-7.36 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[CH:23]=2)=[CH:4][CH:3]=1.[I:24]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[I:24])=[CH:4][CH:3]=1
Reactant: ClI
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)cn3n2)CC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(I)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution, cooled to about 5° C., of 31.0 g (99.6 mmol) of 2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in chloroform is rapidly added dropwise a solution of 64.7 g (398 mmol) of iodine monochloride in 150 mL of methanol. Mild exothermicity and the formation of a precipitate during the addition are observed. After cooling to room temperature and stirring for 30 minutes, the mixture is poured into 2 L of aqueous 5% sodium thiosulfate solution saturated with sodium bicarbonate. After vigorous stirring until the mixture has decolorized, the product is extracted with chloroform. The organic phase is separated out, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid. This solid is triturated in a mixture of 400 mL of diisopropyl ether and 50 mL of isopropanol at reflux. After cooling, 40 g of a beige-colored powder are isolated by filtration through a sinter funnel and drying under vacuum.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([N:16]3[C:20]([CH3:21])=[N:19][N:18]=[N:17]3)[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:22][CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.[ClH:44]>CO.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:44].[F:32][C:30]([F:31])([F:33])[C:28]1[CH:29]=[C:24]([CH2:23][O:22][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:15][C@H:14]3[N:16]2[C:20]([CH3:21])=[N:19][N:18]=[N:17]2)[CH:25]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:27]=1
Reactant: Cc1nnnn1[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: Cc1nnnn1[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(5-methyl-1H-tetrazol-1-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 110; 134 mg, 0.22 mmol) was dissolved in methanol (10 ml) and hydrochloric acid (2N) (1 ml) and 10% palladium hydroxide (50 mg) added and the mixture hydrogenated at 40 psi overnight. The reaction mixture was then filtered and concentrated in vacuo. The oil was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics dried (MgSO4) and concentrated in vacuo. The solid was purified by flash column chromatography [5% methanol in dichloromethane]. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether to a solution in diethyl ether. The title compound was filtered off and dried in vacuo (32 mg, 26%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)C(C)C)C>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3[nH]cnc23)CC1
Yield: 36 %

Procedure:
A solution of 6-chloro-9H-purine (1.19 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate. Suspension of the pre-purified material in ethyl acetate and filtration provided 0.89 g (36%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.31-1.43 (m, 2H), 1.40 (s, 9H), 1.87-1.90 (m, 2H), 2.74-2.88 (m, 2H), 3.92-3.96 (m, 2H), 4.32 (br s, 1H), 7.52 (br s, 1H), 8.08 (s, 1H), 8.18 (s, 1H). MS (ISP): 319.3 [M+H]+.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>ClC(Cl)C>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Clc1ccnc2ccsc12
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A mixture of thieno[3,2-b]pyridin-7-ol (2.50 g, 16.5 mmol) and POCl3 (3.1 mL, 33 mmol) in dichloroethane (10 mL) was stirred for 2 hours at reflux. The mixture was concentrated and the dark residue was resuspended in dichloromethane (50 mL). The solution was carefully neutralized with saturated NaHCO3 solution. The mixture was extracted with dichloromethane, dried over MgSO4, and concentrated to give the title compound (2.09 g, 74%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9]2[N:10]=[C:11]([NH:15][C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][CH3:24])[S:12][C:13]=2[CH3:14])=[C:5]([CH2:7][CH3:8])[N:6]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([NH:15][C:11]2[S:12][C:13]([CH3:14])=[C:9]([C:4]3[S:3][C:2]([NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6][C:5]=3[CH2:7][CH3:8])[N:10]=2)[CH:21]=1
Reactant: CCc1nc(N)sc1-c1nc(Nc2cc(Cl)ccc2OC)sc1C
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CCc1nc(NC(=O)C(C)(C)C)sc1-c1nc(Nc2cc(Cl)ccc2OC)sc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a suspension of 16z (0.50 g, 1.1 mmol) in DCM (55 mL) was added TEA (395 μL, 2.84 mmol). Pivaloyl chloride (174 μL, 1.42 mmol) was then added to the suspension in one portion and the reaction mixture was stirred at room temperature for 10 min at which time TLC indicated reaction completion. The reaction mixture was washed with cold water and extracted with DCM (2×). The organic layer was dried over anhydrous sodium sulfate and filtered and DCM was removed in vacuo. The resulting solid was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 eluent) to yield 17z as a light orange powder (0.34 g, 66%). Mp decomposition at 192° C. 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J=2.8 Hz, 1H), 7.13 (dd, J=8.8 Hz, 2.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 2.79 (q, J=7.6 Hz, 2H), 2.30 (s, 3H), 1.39 (s, 9H), 1.34 (t, J=7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 178.6, 164.6, 164.2, 163.8, 162.2, 149.1, 144.9, 128.9, 125.5, 120.5, 113.8, 112.3, 104.9, 56.3, 40.1, 26.7, 21.4, 13.5, 12.2. HRMS m/z (ESI) calcd. for C21H25ClN4O2S2 (M+H)+ 465.1180. Found 465.1181.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([OH:23])=O)[N:19]=1)=[O:13].[NH2:34][CH:35]1[C:59](=[O:60])[N:37]2[C:38]([C:43]([O:45][CH:46]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[S:44])=[C:39]([CH3:42])[CH2:40][S:41][C@H:36]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([NH:34][CH:35]2[C:59](=[O:60])[N:37]3[C:38]([C:43]([O:45][CH:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[S:44])=[C:39]([CH3:42])[CH2:40][S:41][C@H:36]23)=[O:23])[N:19]=1)=[O:13]
Reactant: CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 67.2 %

Procedure:
Vilsmeier reagent prepared from N,N-dimethylformamide (0.5 ml) and phosphorus oxychloride (0.58 ml) was suspended in dry tetrahydrofuran (20 ml). To a suspension was added 2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 2 g) under ice-cooling with stirring, and then the solution was stirred at the same temperature for an hour to prepare the activated acid solution. To the solution of benzhydryl 7-amino-3-methylthio-3-cephem-4-carboxylate (2.0 g) and trimethylsilylacetamide (5.0 g) in methylene chloride was added the activated acid solution obtained above all at once at -20° C., and then the mixed solution was stirred at -20° to -10° C. for an hour. Water and ethyl acetate were added to the resultant solution. The solution was adjusted to pH 7.5 with an aqueous saturated solution of sodium bicarbonate. The organic layer was washed with an aqueous saturated solution of sodium chloride, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give benzhydryl 7-[2-(2-formamidothiazol- 4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer, 2.4 g). mp. 151°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=4)[N:24]=3)[CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH:7]=[C:8]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[N:24]=1)[CH:9]=[C:10]2[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: COc1cccc(CNc2nccc(-c3cc(N4CCN(CCCO)CC4)c4cc(OC)ccc4c3)n2)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CNc2nccc(-c3cc(N4CCN(CCCN5CCCCC5)CC4)c4cc(OC)ccc4c3)n2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
A solution of 3-(4-(7-methoxy-3-(2-((3-methoxybenzyl)amino)pyrimidin-4-yl)naphthalen-1-yl)piperazin-1-yl)propan-1-ol (65 mg, 0.127 mmol) and triethlyamine (35 μl, 0.254 mmol) in dichloromethane (2 ml) was treated with methanesulfonyl chloride (10 μl, 0.133 mmol) and stirred for one hour. The mixture was diluted with water (2 ml), the organic layer removed and the aqueous layer extracted with dichloromethane (2 ml). The organic layer was concentrated under reduced pressure. The product was treated with acetonitrile (2 ml) and treated with piperidine (38 μl, 0.381 mmol) and heated to 50° C. for 1 hour then concentrated under reduced pressure. The mixture was diluted with saturated aqueous sodium bicarbonate (10 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and purified by flash column chromatography using a gradient of methanol-dichloromethane as eluent to afford 4-(6-methoxy-4-(4-(3-(piperidin-1-yl)propyl)piperazin-1-yl)naphthalen-2-yl)-N-(3-methoxybenzyl)pyrimidin-2-amine (194) (18 mg). M.p.=63-75° C.; 400 M Hz 1H NMR (DMSO-d6) δ: 8.35 (d, J=5.2 Hz, 1H), 8.30 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.81 (bm, 2H), 7.42 (s, 1H), 7.23 (m, 3H), 6.99 (bm, 2H), 6.78 (dd, J=2.0 and 8.4 Hz, 1H), 4.55 (d, J=6.4 Hz, 2H), 3.91 (s, 3H), 3.71 (s, 3H), 3.40-2.40 (m, 16H), 1.73 (bm, 2H), 1.57 (bm, 4H), 1.44 (bm, 2H); LCMS: 581 [M+H+].
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:45][C:46]([O:48][CH2:49][C:50]1[CH2:59][S:58][C@@H:53]2[C@H:54]([NH2:57])[C:55](=[O:56])[N:52]2[C:51]=1[C:60]([OH:62])=[O:61])=[O:47]>O1CCCC1.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:57][CH:54]2[C:55](=[O:56])[N:52]3[C:51]([C:60]([OH:62])=[O:61])=[C:50]([CH2:49][O:48][C:46](=[O:47])[CH3:45])[CH2:59][S:58][C@H:53]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: -20 °C
Yield: 88.7 %

Procedure:
A mixture of 801 mg of 2-tritylamino-4-thiazolyl-acetic acid, 10 ml of dry tetrahydrofuran and 2 ml of 1M solution of N-methyl-morpholine in tetrahydrofuran was stirred and cooled to -20° C and 2 ml of a 1M solution of isobutyl chloroformate in tetrahydrofuran were slowly added thereto. The mixture was stirred and then a solution of 544 mg of 7-amino-cephalosporanic acid in 24 ml of a 1 M solution of N-methyl-morpholine in tetrahydrofuran and 10 ml of water was added thereto. The mixture was stirred with reheating and the solvent was evaporated. The residue was diluted with water and 2 ml of 2N hydrochloric acid were added. The mixture was vacuum filtered to obtain 1.16 g of 7-[2-(2-tritylamino-4-thiazolyl)-acetamido]-3-acetoxy methyl-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].[C:13]([NH2:17])(=[O:16])[CH2:14]O>>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]1[NH:17][C:13](=[O:16])[CH2:14][O:6]1
Reactant: COc1cccc(OC)c1C=O
Reactant: NC(=O)CO
Product: COc1cccc(OC)c1C1NC(=O)CO1

Procedure:
prepared by reaction of 2,6-dimethoxybenzaldehyde with glycolamide; LC-MS: tR=0.41 min; [M+H]+=224.31.