Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:24][C:25]([N:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]2=[O:36])=[CH:26][C:27]=1[CH3:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:24][C:25]([N:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)=[CH:31][C:30]2=[O:36])=[CH:26][C:27]=1[CH3:28])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1cc(-n2ccc(OCc3ccc(C(F)(F)F)cc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 42 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use 1-(bromomethyl)-4-(trifluoromethyl)benzene in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a colorless solid in 42% yield: mp 225-227° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (t, J=6.0 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.37-7.20 (m, 6H), 6.32 (dd, J=7.9, 2.8 Hz, 1H), 6.14 (d, J=2.8 Hz, 1H), 5.30 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.0, 162.4, 160.9, 140.3, 139.6, 138.7, 137.2, 135.2, 128.2 (d, JC-F=3.7 Hz), 127.4, 127.1, 126.6, 125.4 (d, JC-F=3.8 Hz), 120.7, 102.4, 97.5, 69.0, 42.5, 15.5; MS (ES+) m/z 499.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[C:19]([CH:26]=[O:27])=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:25][O:24][C:21]1[CH:20]=[C:19]([CH:26]=[O:27])[C:18]([O:17][CH2:2][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)=[N:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][N:22]=1
Reactant: COc1cccc(-c2ncccc2CCl)c1
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(-c2ncccc2COc2cnc(OC)cc2C=O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(3-methoxyphenyl)pyridine (234 mg, 1.00 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (153 mg, 1.00 mmol, 1.00 equiv), and potassium carbonate (278 mg, 2.01 mmol, 2.00 equiv) in CH3CN (30 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% TFA and MeCN (20% MeCN up to 40% in 10 min, up to 95% in 2 min, down to 20% in 1 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 100.8 mg (17%) of 2-methoxy-5-[[2-(3-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([Br:22])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[C:23]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([N:17]([CH3:23])[S:18]([CH3:21])(=[O:19])=[O:20])[C:14]([Br:22])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(C(C)=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 60 °C
Yield: 45.7 %

Procedure:
To a solution of 2-acetyl-5-bromo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.38 mmol) in DMF (3 mL) was added K2CO3 (160 mg, 1.16 mmol) and MeI (164 mg, 1.16 mmol). The mixture was heated at 60° C. for 1 hour, concentrated in vacuo to remove DMF and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude product. The crude product was purified by column chromatography to give 2-acetyl-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, yield: 45%). 1H-NMR (CDCl3, 400 MHz) δ 9.73 (s, 1H), 9.01 (s, 1H), 7.78 (s, 1H), 3.35 (s, 3H), 3.09 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 403/405.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[S:20]([O:1][CH2:2][C@H:3]1[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Commercially available (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (1.8 g, 9.61 mmol) in pyridine was treated with p-toluenesulfonyl chloride (1.83 g, 9.61 mmol). The reaction mixture was stirred at room temperature for 20 h then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water (3×75 mL) and then dried (MgSO4), filtered, and concentrated in vacuo to afford the titled compound. MS (DCI) m/z 342 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(COC2CCCCO2)cc1
Yield: 64.5 %

Procedure:
A solution of 8.5 g (35.9 mmol) of 2-(4-nitrobenzyloxy)-tetrahydropyran in 150 ml of methanol was hydrogenated at room temperature and atmospheric pressure in the presence of 800 mg of 10% palladium on carbon for 8 hours. The catalyst was removed by filtration and the filtrate evaporated to give a dark yellow oil. Purification by flash column chromatography on silica gel using 1:2 ethyl acetate/hexane as eluent gave 4.8 g (65%) of 4-(tetrahydropyran-2-yloxymethyl)aniline as a pale yellow oil. [Mass spectrum (ESI) [MH+MeCN]+ =249].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:19])=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc([N+](=O)[O-])cc1
Yield: 83.1 %

Procedure:
Using 3-nitroaniline (2.76 g, 16.5 mmol) and 4-nitrobenzoic acid (2.51 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 3.58 g (83.2%) of the title compound in the form of light yellow crystals.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1>>[Cl:3][C:2]1[N:4]=[C:5]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:7]=[C:8]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:1]=1
Reactant: Cc1cccc(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1

Procedure:
The reaction of cyanuric chloride with 1,3-xylene under Friedel-Crafts conditions to give 2-chloro-4,6-bis(2,4-dimethylphenyl)-s-triazine is known, e.g. from DE-A-1 169 947 and Helv. Chim. Acta 55, 1589 (1972). However, the product can also be obtained using an appropriate Grignard reagent, such as described in Helv. Chim. Acta 33, 1365 (1950) and U.S. Pat. No. 4,092,466.
Reaction SMILES: [NH2:1][C@:2]([C:6]([OH:8])=[O:7])([CH3:5])[CH2:3][CH3:4].[OH-].[Na+].[Cl:11][CH2:12][C:13](Cl)=[O:14].Cl>>[Cl:11][CH2:12][C:13]([NH:1][C@:2]([C:6]([OH:8])=[O:7])([CH3:5])[CH2:3][CH3:4])=[O:14]
Reactant: O=C(Cl)CCl
Reactant: CC[C@@](C)(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC[C@@](C)(NC(=O)CCl)C(=O)O
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a well-stirred mixture chilled to 0° C. to 5° C. (ice bath) of racemic isovaline ((R,S) 2-amino-2-methylbutanoic acid) (350 g, 2.99 mole) and 2N aqueous sodium hydroxide (1.5 L) were added simultaneously chloroacetyl chloride (373 g, 3.31 mole) and 2N aqueous sodium hydroxide (1,718 ml, 3.44 mole) over 1.5 hours . The base was added at such a rate as to keep the reaction mixture basic at all times. The reaction mixture was warmed up to room temperature, treated with concentrated aqueous hydrochloric acid until acidic to litmus paper. A white solid formed which was separated by filtration and dried to yield 454 g (78.5%) of the expected racemic N-chloroacetylisovaline ((R,S) 2-chloroacetamido-2-methylbutanoic acid).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25](OC)=[N:26][CH:27]=4)=[CH:18][C:17]=3[CH3:30])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].Cl.[NH+]1C=CC=CC=1.[OH2:39]>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:27](=[O:39])[NH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][C:17]=3[CH3:30])[CH:10]=2)[NH:5][CH:4]=1)#[N:2]
Reactant: O
Reactant: COc1ccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)c(C)c2)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Cc1cc(-c2ccc[nH]c2=O)ccc1C(=O)NCCc1ccc2[nH]cc(C#N)c2c1
Temperature: 160 °C
Reaction time: 0.05 h

Procedure:
A mixture of N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(2-methoxy-pyridin-5-yl)-2-methyl-benzamide (146 mg, 0.35 mmol) (reference example 1n) and pyridinium hydrochloride (3 g) is heated to 160° C. and stirred at this temperature for 3 minutes. The liquid is then cooled and mixed with water. The resulting precipitated solid is filtered, washed with water (3×) then dried under vacuum to give 133 mg of th title compound as a solid. This material is used without further purification. MS (ion spray) m/z 397 (M+H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:29][CH3:30])=[C:16]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([N:22]2[CH2:23][CH2:24][CH:25]([OH:28])[CH2:26][CH2:27]2)[C:15]([O:29][CH3:30])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1N1CCC(O)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1N1CCC(O)CC1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (5 mg, 0.03 mmol), 1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]piperidin-4-ol (7 mg, 0.02 mmol), and N,N-diisopropylethylamine (0.0082 mL, 0.047 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H26ClN6O2 (M+H)+: m/z=417.2. found: 417.1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[NH2:14].C(O)(=O)C>C(Cl)Cl.CO.CC(N(C)C)=O>[CH2:1]([NH:14][C:10]1[S:9][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CNc2nccs2)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, to a solution of benzaldehyde (40 mg, 0.38 mmol) in DCM/MeOH (1.4 mL) was added a solution of thiazol-2-amine (47 mg, 0.47 mmol) in DMA (1.8 mL). A solution of acetic acid (66 mg, 1.1 mmol) in DCM/MeOH (1.4 mL) was then added, followed by the addition of 470 mg of MP-CNBH3 resin (3 eq.; subst. 2.36 mmoles/g). The vial was capped and was then heated with shaking overnight at 65° C. The progress of the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH. Purification by reverse phase HPLC (TFA method) gave the title compound.
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]2([CH2:9][O:8][C:7]([CH2:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])([CH3:10])[CH2:6][CH2:5][CH2:4]2)[O:2]1>C(Cl)Cl.N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH2:18]1[CH2:1][O:2][C:3]2([CH2:9][O:8][C:7]([CH3:10])([CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[CH2:6][CH2:5][CH2:4]2)[O:17]1
Reactant: CC(O)CCCC1(C)CCCC2(CO1)OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CCCC1(C)CCCC2(CO1)OCCO2
Yield: 64 %

Procedure:
Dry celite (30 g) and 6,6-ethylenedioxy-2-(4'-hydroxypentyl)-2-methyloxepane (3.3 g, 0.0128 mol) in methylene chloride (50 ml) are added to a pyridine-chromium trioxide solution [prepared from pyridine (12.1 g, 0.153 mol) and chromium trioxide (7.67 g, 0.0767 mol)] in distilled methylene chloride (450 ml) at 10° C. in a nitrogen atmosphere. After 5 hours the mixture is filtered and the celite cake is washed with methylene chloride (10×50 ml). The solvent is removed at reduced pressure. The residue is diluted with ether (150 ml), filtered and the solvent is removed at reduced pressure. The crude product (3.3 g) is chromatographed on SilicAR CC-7 (60 g)in hexane. Elution with 12% ethyl acetate/hexane gives 6,6-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-oxepane as a clear colorless oil (2.1 g, 64%).
Reaction SMILES: C([Li])CCC.CC1CCCN(C)C1(C)C.[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1.[NH4+].[Cl-:27]>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([O:24][CH3:25])[N:20]=[N:19][C:18]=1[O:17][CH3:16]
Reactant: [Cl-]
Reactant: COc1ccc(OC)nn1
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(OC)nn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium (1.6 M in hexanes, 2.45 mL, 3.92 mmol) was added to a cold solution of THF (20 mL) at −78° C. Tetramethylpiperidine (0.67 mL, 3.92 mol) was introduced and the solution was warmed to 0° C. and kept at this temperature for 20 min; it was then cooled to −78° C. A solution of 3,6-dimethoxy-pyridazine (500 mg, 3.57 mmol) in THF (5 mL) was added slowly and the mixture was stirred at −78° C. for 45 min. This reaction mixture was transferred to a solution of achloroethane (1.268 g, 5.36 mmol) in THF (10 mL) at −78° C. and stirring was continued at −78° C. for 15 min. Saturated aqueous NH4Cl was added and the mixture was warmed to room temperature. The mixture was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo to give the crude product, which was purified by flash chromatography, eluting with 10-20% EtOAc in hexanes to afford, after evaporation, the title compound as a white solid (372 mg, 60%): 1H NMR (400 MHz, DMSO) δ 7.04 (s, 1H), 4.11 (s, 3H), 4.04 (s, 3H); LCMS (+ESI, M+H+) m/z 175.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[N:34]1([CH:39]2[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:41]4[CH2:42][CH2:43][CH:39]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:40]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: C1CCN(C2CCNC2)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N5CCCC5)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidin-yl-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H), 0.77 (m, 1H). m/z: 472 [M+H]
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([OH:13])=O)[N:9]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:21][N:22]1[C:26]([S:27][CH2:28][C:29]2[CH2:30][S:31][C@@H:32]3[CH:39]([NH2:40])[C:38](=[O:41])[N:33]3[C:34]=2[C:35]([OH:37])=[O:36])=[N:25][N:24]=[N:23]1.C[Si](CC(N)=O)(C)C.[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:21][N:22]1[C:26]([S:27][CH2:28][C:29]2[CH2:30][S:31][C@@H:32]3[CH:39]([NH:40][C:11](=[O:13])[CH2:10][C:8]4[N:9]=[C:5]([NH:4][C:3]([NH:2][CH3:1])=[O:14])[S:6][CH:7]=4)[C:38](=[O:41])[N:33]3[C:34]=2[C:35]([OH:37])=[O:36])=[N:25][N:24]=[N:23]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CNC(=O)Nc1nc(CC(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Temperature: -20 °C
Yield: 40.6 %

Procedure:
To a mixture of 2-(3-methylureido)thiazol-4-ylacetic acid (3.23 g.) in dried methylene chloride (50 ml.) was dropwise added a solution of phosphorus pentachloride in dried methylene chloride (80 ml.) with stirring under ice-cooling, and the mixture was stirred for 3 hours under ice-cooling. The precipitates were collected by filtration and washed with n-hexane. Thus obtained precipitates were added to a solution which was prepared by stirring a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (4.95 g.) and trimethylsilylacetamide (11.8 g.) in dried ethyl acetate (75 ml.) for 10 minutes at 40° C. and then by cooling it to at -20° C. The mixture was stirred for 1 hour at -20° to -10° C. and further stirred for 1 hour at -10° to 0° C. The mixture was cooled to at -20° C., and 10% aqueous solution of sodium chloride (7 ml.) was added therto, and then the mixture stirred for 10 minutes at room temperature. After the reaction, ethyl acetate layer was separated out, and the remaining precipitates were washed with ethyl acetate (50 ml.). To the precipitates was added water (30 ml.) and adjusted to pH 5 to 6 with sodium bicarbonate powder with stirring under ice-cooling. Thus obtained solution was subjected to alumina column chromatography, and the eluate was adjusted pH 2 with 17.5% hydrochloric acid. The precipitates were collected by filtration and dried over phosphorus pentachloride under reduced pressure to give white powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(3-methylureido)thiazol-4-yl]acetamido-3-cephem-4-carboxylic acid (3.20 g.)
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:34])([F:33])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:35][C:36]1[CH:37]=[CH:38][C:39](=O)[NH:40][N:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:35][C:36]1[N:41]=[N:40][C:39]([O:32][CH:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:16]([F:15])([F:33])[F:34])=[N:18][N:19]=4)[N:22]=3)[CH2:27][CH2:28]2)=[CH:38][CH:37]=1
Reactant: Cc1ccc(=O)[nH]n1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)nn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.3 %

Procedure:
DIAD (0.102 mL, 0.52 mmol) was added to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (obtained as described in Example 310, preparation of starting materials) (135 mg, 0.47 mmol), 6-methylpyridazin-3(2H)-one (56.9 mg, 0.52 mmol) and triphenylphosphine (136 mg, 0.52 mmol) in THF (5 mL). The resulting solution was stirred at ambient temperature for 3 days. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M ammonia in methanol and evaporated to give crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[(6-methylpyridazin-3-yl)oxy]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (22.00 mg, 12%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH2:14][OH:15])/[C:8]([OH:10])=O)[N:6]=1.[NH2:16][C@@H:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH2:14][OH:15])/[C:8]([NH:16][C@@H:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]23)=[O:10])[N:6]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Nc1nc(/C(=N/OCCO)C(=O)O)cs1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCCO)c3csc(N)n3)[C@H]2SC1

Procedure:
Starting from 2-(2-aminothiazol-4-yl)-2(Z)-(2-hydroxyethoxyimino)acetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, the titled compound is obtained by the procedure of Reference Example 3.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH2:28][CH3:29])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH2:28][CH3:29])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NCc1ccc(SC(F)(F)F)cc1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CCC(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 405 (M+H)+; MS (ESI−) m/z 403 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.21 (m, 1H), 3.39 (m, 1H), 4.34 (m, 2H), 7.31 (m, 2H), 7.58 (m, 2H), 7.62 (d, J 7.8, 1H), 8.00 (m, 2H), 8.22 (d, J 7.1, 1H), 8.45 (m, 1H), 8.77 (m, 1H), 8.82 (m, 1H), 9.06 (t, J 6.8, 1H), 9.87 (s, 1H), 10.30 (br s, 1H); Anal. Calcd for C21H19F3N2OS+0.65 HCl: C, 58.91; H, 4.63; N, 6.54. Found: C, 59.24; H, 4.30; N, 6.60.
Reaction SMILES: Br[C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].N1CCC[C@H]1[C:22](O)=[O:23].C[O-].[Na+].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CO.[Cu]I>[Cl:19][C:18]1[C:2]([O:23][CH3:22])=[CH:3][C:4]2[C:13]3[C:8](=[C:9]([CH3:14])[N:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[N:6]([CH3:16])[C:5]=2[CH:17]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(Br)cc21
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: C[O-]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Temperature: 80 °C

Procedure:
A mixture of 9-bromo-8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.05 g, 0.148 mmol), copper(I)iodide (0.031 g, 0.163 mmol), L-proline (0.020 g, 0.178 mmol), sodium methoxide (0.040 g, 0.741 mmol) and K2CO3 (0.041 g, 0.296 mmol) were stirred in DMSO (1.5 mL). The mixture was heated to 80° C. for 16 h. After cooling, the crude reaction mixture was diluted with methanol, filtered through diatomaceous earth (Celite®) and concentrated under reduced pressure to afford 8-chloro-9-methoxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one, as brown solid (40 mg). LC/MS (ESI) m/e 289.0 [(M)+, calcd for C15H14ClN2O2, 289.1]; LC/MS retention time (method D): tR=0.89 min.