Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:13][C:14](=[O:28])[CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17].Cl>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][CH2:13][C:14](=[O:28])[CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)CC(=O)OCCCc1ccccc1
Reactant: OCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
2-(1-Piperidinyl)ethanol (15 mL, 113 mmol) in THF (50 mL) was added dropwise to a suspension of sodium hydride (7 g, 175 mmol) in THF (200 mL) at 0° C. The mixture was then stirred for 1 h at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (22 mL, 103 mmol) in THF (50 mL) was added dropwise and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform. The combined extracts were washed with brine, dried and evaporated to give the title compound (24 g) as an oil. Electrospray MS m/z 348 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1cccc(O)c1
Reactant: BrCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cccc(N2CCCCC2)c1
Reaction time: 16 h

Procedure:
3-Aminophenol (500 mg) was dissolved in toluene (5.0 ml), the solution was added with sodium hydrogencarbonate (846.5 mg) and 1,5-dibromopentane (686.3 μl) at room temperature, and the mixture was stirred for 16 hours under reflux by heating. The reaction mixture was cooled, and then added with distilled water and ethyl acetate for extraction, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (513 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:8][C:7]=12)[CH3:24]
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNc1nnc(C)c2c1cc1ccccn12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 27 equivalents of 2-(aminomethyl)-1-ethylpyrrolidine gave the title compound as the free base which was converted to the dihydrochloride salt, mp. 128° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[N:15][CH:16]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[N:15][CH:16]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 393 (75 mg, 0.150 mmol) was taken in THF (3 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (31.47 mg, 0.75 mmol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1B(O)O.FC(F)(F)S(O[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][C@H:20]([N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][O:22]2)(=O)=O>>[CH2:35]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:20]1[CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[CH:26][C:17]=2[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[O:22][CH2:21]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: Cc1cnccc1B(O)O
Product: Cc1cnccc1-c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Yield: 76 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 76% yield, starting from 3-methylpyridine-4-boronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (d, 1 H), 8.46 (dd, 1 H), 7.25-7.32 (m, 8 H), 7.05-7.24 (m, 4 H), 6.76-6.83 (m, 1 H), 6.59-6.64 (m, 1 H), 4.26-4.34 (m, 1 H), 4.04-4.13 (m, 1 H), 3.55-3.68 (m, 4 H), 2.93-3.07 (m, 1 H), 2.34-2.43 (m, 1 H), 2.08-2.22 (m, 1 H), 1.92-2.02 (m, 3 H); MS (ESI) m/z 421[M+H+].
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.O>CS(C)=O>[S:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[N:15]1[CH2:16][CH2:17][CH:12]([N:5]2[C:6]3=[N:7][CH:8]=[CH:9][N:10]=[C:11]3[C:3]([CH3:19])([CH3:2])[C:4]2=[O:18])[CH2:13][CH2:14]1
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N(C2CCN(c3nc4ccccc4s3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 46.7 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.107 g, 0.378 mmol), potassium carbonate (0.183 g, 1.324 mmol), and 2-chlorobenzo[d]thiazole (0.077 g, 0.454 mmol) in DMSO (3 mL) was heated at 110° C. in 2 h. The reaction mixture was cooled, H2O was added, and extracted with DCM (3×). The organic extracts were dried over Na2SO4, filtered, concentrated, and purified by reverse phase HPLC. The pure fractions were concentrated to minimal H2O, neutralized with saturated aqueous NaHCO3. The white solid was collected, washed with H2O, and dried to afford the title compound (67 mg, 47%). MS (M+1): 380. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04-8.19 (2 H, m), 7.77 (1 H, d, J=7.4 Hz), 7.46 (1 H, d, J=8.0 Hz), 7.21-7.35 (1 H, m), 6.98-7.14 (1 H, m), 4.46-4.65 (1 H, m), 4.18 (2 H, d, J=13.1 Hz), 3.32-3.41 (2 H, m), 2.52-2.62 (2 H, m), 1.83 (2 H, d, J=10.8 Hz), 1.33 (6 H, s)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:48]2[CH2:53][CH2:52]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Si:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[C:2]([CH:52]2[CH2:53][CH2:48]2)[CH:7]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)c(C2CC2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 230.6 %

Procedure:
To a solution of benzyl (2-bromo-4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetate (250 mg) in toluene (5.00 mL) were added water (0.250 mL), potassium phosphate (366 mg), tricyclohexylphosphine (64.4 mg), palladium (II) acetate (25.8 mg), and cyclopropylboronic acid (98.6 mg), followed by stirring at 110° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylphenyl)acetate (210 mg).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:56]2[N:57]=[C:58]([NH:61]C(OC(C)(C)C)=O)[S:59][CH:60]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42]3[CH2:47][CH2:46][CH:45]([NH:48]C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][C:39]2[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]3[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]4([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]4)/[C:56]4[N:57]=[C:58]([NH2:61])[S:59][CH:60]=4)[C:29](=[O:30])[N:28]3[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=2)[CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ncc(CN3CCC(NC(=O)OC(C)(C)C)CC3)n2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ncc(CN3CCC(N)CC3)n2)cs1
Yield: 7.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (58 mg, 59 μmol), DCM (590 μL), anisole (13 μL, 0.12 mmol) and TFA (273 μL, 3.54 mmol). The crude residue was purified by reverse phase prep HPLC (Xselect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (2.7 mg, 7.3%) as an off-white powder. LCMS: Rt=0.50 min, m/z=613.4 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.93 (s, 1H), 7.12 (s, 1H), 5.59 (d, J=5.5 Hz, 1H), 5.07-5.00 (m, 1H), 4.99-4.96 (m, 1H), 4.93-4.90 (m, 1H), 4.39 (s, 2H), 3.75-3.62 (m, 2H), 3.63-3.51 (m, 1H), 3.28-3.08 (m, 2H), 2.33 (d, J=13.7 Hz, 2H), 2.04-1.89 (m, 2H), 1.38-1.11 (m, 4H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[N:20]([C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[N:26]=[CH:25][N:24]=1)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[N:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:26]=[CH:25][N:24]=[C:23]([NH:20][C:21]3[O:13][C@:5]4([CH2:4][N:3]=3)[CH:10]3[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]3)[CH2:6]4)[CH:28]=2)=[CH:34][CH:33]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: S=C=Nc1cc(-c2ccncc2)ncn1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1cc(-c2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncn2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.059 g, 0.257 mmol) in N,N-dimethylformamide (15 mL) was added Cs2CO3 (0.209 g, 0.642 mmol) and 4-isothiocyanato-6-(pyridin-4-yl)pyrimidine (0.055 g, 0.257 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-diisopropylcarbodiimide (0.12 mL, 0.77 mmol) was then added and the mixture was continued to stir at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (0-10% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford (R)—N-(6-(pyridin-4-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.014 g, 0.04 mmol, 16% yield) as a yellow film. 1H NMR (400 MHz, MeOD) δ ppm 8.85 (1 H, d), 8.67 (2 H, dd), 8.04 (2 H, dd), 7.34 (1 H, br. s.), 4.06 (1 H, d), 3.76 (1 H, d), 3.23 (1 H, d), 3.10 (1 H, d), 2.70-2.99 (4 H, m), 2.01-2.22 (2 H, m), 1.53-1.86 (3 H, m). LCMS R.T.=0.42; [M+H]+=337.14.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1.[Li]CCCC.[C:17](O)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2].CO.C(Cl)Cl>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:4]2[N:3]=[C:2]([C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:1][CH:5]=2)[CH:7]=1
Reactant: c1cncc(-c2cocn2)c1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCC(=O)c1nc(-c2cccnc2)co1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
(164) A solution of 3-(oxazol-4-yl)pyridine (6 mg, 0.041 mmol) in anhydrous THF (1 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.045 mmol, 18 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 0.082 mmol, 33 mL) was added at −75° C., and stirred for 45 min at 0C. Cul (1.0 equiv, 0.041 mmol, 8 mg) was added, and the solution was stirred for 10 min at 0° C. A separate flask was charged with oleic acid (2 equiv, 0.082 mmol, 23 mg) in anhydrous CH2Cl2 (0.5 mL), and to this solution cooled to 0° C. under N2 was added oxalyl chloride (5 equiv, 0.41 mmol, 52 mg, 37 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (0.5 mL). The solution of oleoyl chloride was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 1.5 cm×17.5 cm, 2% MeOH—CH2Cl2) afforded 1-(4-(pyridin-3-yl)oxazol-2-yl)octadec-9-en-1-one (164) (4 mg, 0.009 mmol, 23% yield) as a brown residue: 1H NMR (CDCl3, 250 MHz) d 8.99 (br s, 1H), 8.65 (br d, J=4.7 Hz, 1H), 8.04 (br d, J=7.5 Hz, 1H), 7.86-7.54 (m, 2H), 5.41-5.26 (m, 2H), 3.10 (t, J=7.4 Hz, 2H), 2.10-1.93 (m, 4H), 1.83-1.70 (m, 2H), 1.45-1.20 (m, 20H), 0.86 (br t, J=6.6 Hz, 3H); IR (CDCl3) umax 2926, 2871, 1700, 1601, 1564, 1510, 1421, 1382 cm−1; MALDI-FTMS (DHB) m/z 411.3012 (C26H38N2O2+H+ requires 411.3006).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([C:14]2[NH:18][C:17]([CH2:19][CH2:20][O:21][CH3:22])=[N:16][N:15]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([C:14]2[NH:18][C:17]([CH2:19][CH2:20][O:21][CH3:22])=[N:16][N:15]=2)=[CH:8][C:4]=1[C:5]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:7])[CH3:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(CC)c(-c2nnc(CCOC)[nH]2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(CC)c(-c2nnc(CCOC)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a round-bottom flask was added a solution of 2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid (compound 209.1, 300 mg, 0.940 mmol, 1.00 equiv, 95%) in N,N-dimethylformamide (20 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 243 mg, 1.09 mmol, 1.10 equiv), EDC.HCl (380 mg, 1.98 mmol, 2.00 equiv), and 4-dimethylaminopyridine (240 mg, 1.96 mmol, 2.09 equiv) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature, then diluted with 100 mL of ethyl acetate. The organic layer was washed with 3×15 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate as eluent. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (35% CH3CN up to 60% in 8 min, up to 100% in 1 min, down to 35% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 188 mg (42%) of the title compound as a white solid. m/z (ES+) 472 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]=[C:7]1[CH2:27][CH2:26][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH2:8]1.[Cl:28][CH2:29]Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:28][C:29]1[CH2:8][CH2:9][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:14][CH2:15]2)[CH2:26][C:27]=1[CH:7]=[O:6]
Reactant: O=C1CCC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)CCC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (2.33 mL) was added dropwise to a cooled (0° C.) solution of EXAMPLE 265D (7.5 g) in N,N-dimethylformamide (10 mL) and dichloromethane (30 mL). The mixture was then stirred overnight before it was diluted with ethyl acetate (300 mL) and washed with aqueous sodium acetate, water (3×), and brine and dried over Na2SO4. After filtration and concentration, the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O1CCOCC1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C1CCNCC1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and piperidine (0.14 mL, 1.42 mmol) in THF (20 mL) was stirred at room temperature for 4 hrs. 1,4-Dioxane (20 mL) was added and the mixture was refluxed for 18 hrs. After cooled to room temperature, the solvents were removed under vacuum. The residue was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous phase extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2) gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (147 mg, 84%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[S:15][C:16](=[C:22]([CH3:24])[CH3:23])[CH2:17][CH2:18][C:19]=2[CH:20]=O)=[CH:9][CH:8]=1.C(N(CC)CC)C.CS([Cl:36])(=O)=O>O>[Cl:36]/[CH:20]=[C:19]1/[C:14](=[N:13]/[C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)/[S:15][C:16](=[C:22]([CH3:24])[CH3:23])[CH2:17][CH2:18]/1
Reactant: CC(C)=C1CCC(C=O)=C(Nc2ccc(Cl)cc2)S1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)=C1CCC(=C\Cl)/C(=N/c2ccc(Cl)cc2)S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an N,N-dimethylformamide (10 ml) solution of 2-(4-chloro-phenylamino)-6-isopropylidene-5,6-dihydro-4H-thiopyran-3-carbaldehyde (0.44 g), triethylamine (0.23 g) and methanesulfonyl chloride (0.24 g) were added at 0° C. After raising the temperature to room temperature and further stirring for 1 hour, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain a crude product of {3-[1-chloro-(E)-methylidene]-6-isopropylidene-tetrahydro-thiopyran-(2Z)-ylidene}-(4-chloro-phenyl)-amine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]=[C:7]1[NH:11][C:10]([C:12](=[O:16])[C:13]([OH:15])=O)=[CH:9][S:8]1.[CH3:17][N:18]1[C:22]([S:23][CH2:24][C:25]2[CH2:26][S:27][C@@H:28]3[CH:35]([NH2:36])[C:34](=[O:37])[N:29]3[C:30]=2[C:31]([OH:33])=[O:32])=[N:21][N:20]=[N:19]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH3:17][N:18]1[C:22]([S:23][CH2:24][C:25]2[CH2:26][S:27][C@@H:28]3[CH:35]([NH:36][C:13](=[O:15])[C:12]([C:10]4[NH:11][C:7](=[O:6])[S:8][CH:9]=4)=[O:16])[C:34](=[O:37])[N:29]3[C:30]=2[C:31]([OH:33])=[O:32])=[N:21][N:20]=[N:19]1
Reactant: O=C(O)C(=O)c1csc(=O)[nH]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C(O)C(=O)c1csc(O)n1
Agent: O=C([O-])O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=O)[nH]3)[C@H]2SC1
Temperature: -20 °C

Procedure:
To dimethylformamide (3.74 g.) was dropwise added phosphorus oxychloride (6.46 g.) over 5 minutes under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C. To the mixture was added ethyl acetate (120 ml.) with stirring, and the mixture was cooled to -20° C. with stirring. To the mixture was added all at once 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylic acid, (6.05 g.) and to the mixture was added dimethylformamide (55 ml.) over 10 minutes at -20° C., and then the mixture was stirred for 40 minutes at the same temperature. Thus obtained mixture was added to the solution prepared in the similar manner as in Example 1 from 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (10.50 g.), bis(trimethylsilyl)acetamide (35 ml.) and ethyl acetate (150 ml.), at - 50° to -40° C. with stirring. The mixture was stirred for 30 minutes at -40° C. and further stirred for 30 minutes at -20° C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution (250 ml.), and the aqueous layer was separated. The aqueous layer was washed with ethyl acetate and adjusted to pH 1 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then treated with activated charcoal. After distillation of ethyl acetate from the extract, the residue was pulverized in diethyl ether, collected by filtration and dried to give pale yellow powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (9.2 g.).