Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)([CH3:7])[CH3:6])[CH3:2].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:7])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Yield: 90.3 %

Procedure:
Following General Procedure D and using 2-(3-bromo-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate 130, 0.77 g, 2.84 mmol), triethyl amine (5 mL), copper(I)iodide (0.044 g, 0.23 mmol), trimethylsilyl acetylene (2 mL, 14.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.159 g, 0.23 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane to 5% ethyl acetate in hexane as the eluent, the title compound (0.74 g, 90%) was obtained as an orange oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31]([CH3:35])=[N:30][C:29]=1[CH3:36]>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH2:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31]([CH3:35])=[N:30][C:29]=1[CH3:36]
Reactant: Cc1nc(C)c(C)nc1C
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(C)c(CCl)nc1C
Temperature: 0 °C

Procedure:
A reaction mixture containing N-chlorosuccinimide (6.67 g, 50.0 mmol), benzoylperoxide (50 mg) and TMPZ (6.81 g, 50.0 mmol), in 125 ml of reagent grade CCl4 was refluxed for 12 hours. The reaction solution was then cooled to 0° C. and filtered, removing succinimide. The solvent was evaporated in vacuo resulting in an oil (chloromethyltrimethylpyrazine). The oil was cooled to 0° C. and 25 ml of distilled n-amyl amine was dripped into the oil over a 20 minute period. The reaction mixture was stirred in an ice bath until an exothermic reaction ensured whereby the mixture was gently refluxed for 5 hours. Upon filtration of this reaction mixture, the resulting oil was chromatographed by flash column chromatography using 230-400 mesh silica gel (available from Fisher Scientific Co., King of Prussia, Pa.). Fractional separation was obtained by using a gradient solvent system (100% CHCl3 →25:1 CDCl3 /MeOH+1% NH4OH). Purification by Kugelrohr distillation at 90° C./15 mm Hg afforded 15% yield of a clear oil. m.p. 174°-175° C. Analysis: H-NMR(CDCl3) (ppm): 3.8(2H,S), 2.6-2.7(2H,t), 2.45-2.5(9H,t), 1.8-1.9(2H,m), 1.5-1.6(2H,m), 1.3-1.37(4H, sextet), 0.8-0.9(3H,t).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([F:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1.CS(C)=O>CN(C=O)C.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]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[C:21]([F:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Cl)c(F)c3)nc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(F)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-chloro-3-fluorophenyl)acetamide 168-2 (80 mg, 0.2 mmol) and 2-methyl-4-(tributylstannyl)pyridine (78 mg, 0.2 mmol) in DMF (0.6 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33 mg, 0.04 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-fluoro-4-(2-methylpyridin-4-yl)phenyl)acetamide 168 as white solid. MS m/z 448.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.57 (s, 1H), 8.52 (d, 1H), 8.04 (s, 1H), 7.93 (d, 1H), 7.59 (m, 1H), 7.44-7.29 (m, 5H), 3.77 (s, 2H), 3.58 (b, 2H), 3.14 (b, 2H), 3.08 (b, 2H), 2.55 (s, 2H), 2.51 (s, 3H), 2.04 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:16])=O)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CN=C1.S(Cl)(Cl)=O.[NH:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1>C(Cl)Cl.O.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:26]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]3)=[O:16])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC1CCNC1
Reactant: O=C(O)COCCc1ccc2ccsc2c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(COCCc1ccc2ccsc2c1)N1CCC(O)C1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
0.74 g of 2-(2-(1-benzothiophene-6-yl)ethoxy)acetic acid was dissolved in 7.4 ml of methylene chloride. Thereafter, 1.36 ml of triethylamine and 0.22 g of imidazole were added to the obtained solution. Subsequently, the mixture was cooled to 5° C. Thereafter, 0.24 ml of thionyl chloride was added dropwise thereto, and the obtained mixture was stirred at the same above temperature for 1 hour. After the reaction mixture was cooled to −50° C., 0.45 ml of triethylamine and 0.32 ml of 3-pyrrolidinol were added thereto. The mixture was stirred at the same above temperature for 1 hour and then at a room temperature for 1 hour. Thereafter, water was added to the reaction mixture, and an organic layer was separated. The organic layer was successively washed with 1 mol/l hydrochloric acid, then with a 2 mol/l aqueous sodium hydroxide solution, and then with a saturated saline solution. The resultant was then dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled away under a reduced pressure, so as to obtain a light yellow oil product, 2-(2-(1-benzothiophene-6-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone.
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[CH:7][CH2:8]2.[CH3:14][CH2:15][O-].[Na+].Cl>CS(C)=O>[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[C:6]([CH2:10][C:9]1[C:5]3[C:6](=[C:15]([CH3:14])[CH:11]=[CH:12][C:4]=3[CH3:3])[CH2:7][CH:8]=1)=[CH:7][CH2:8]2
Reactant: CC[O-]
Reactant: Cc1ccc(C)c2c1C=CC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C)c2c1CC=C2CC1=CCc2c(C)ccc(C)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
Formalin (37% aq. solution, 0.28 g, 3.47 mmol) was added to a mixture of 4,7-dimethylindene (1.0 g, 6.94 mmol) and EtONa (0.15 g, 2.20 mmol) in dimethylsulphoxide (10 mL) at 25° C. After stirring at room temperature for 12 hours, the reaction mixture was heated at 80° C. for further 4 hours and then cooled to room temperature. A solution of HCl (1 M, 10 mL) was added. The mixture was extracted with CH2Cl2 (2×50 mL); the organic phases were combined, washed with a saturated solution of NaCl and then with water, dried over anhydrous MgSO4, filtered and finally concentrated to yield a brown solid (GC analysis shows 75% conversion). After washing with MeOH, bis(4,7-dimethyl-3-indenyl)methane was isolated as a yellow solid (0.52 g; yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:10]#[N:11].CO.[BH4-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:10]#[N:11]
Reactant: Cc1ccccc1N=C(C#N)c1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1NC(C#N)c1c(Cl)cccc1Cl
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a stirred mixture of 2.9 parts of 2,6-dichloro-α-[(2-methylphenyl)imino]benzeneacetonitrile in 50 parts of methanol are added portionwise 0.2 parts of sodium borohydride. Upon completion the mixture is stirred during 0.5 hours and 100 parts of water are added. The precipitated produce is filtered off and recrystallized from 30 parts of 2-propanol, yielding 2.4 parts (82.1%) of 2,6-dichloro-α-[(2-methylphenyl)amino]benzeneacetonitrile; mp. 107.7° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]2[C:10]([C:11]=1O)=[CH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:21])=O>>[Cl:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]2[C:10]([C:11]=1[Cl:21])=[CH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1ccc2nc(C)c(Cl)c(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2nc(C)c(Cl)c(Cl)c2c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 3-chloro-4-hydroxy-2-methylquinoline-6-carboxylate (629 mg) and phosphoryl chloride (2 mL) was stirred in an oil bath at 100° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain ethyl 3,4-dichloro-2-methylquinoline-6-carboxylate (454 mg).
Reaction SMILES: [CH2:1]([N:3]([CH:14]1[CH2:19][CH2:18][C:17]([O:21][CH3:22])([CH3:20])[CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O-])=[O:8])[CH3:2].[OH-].[Na+].[NH2:25][CH2:26][C:27]1[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(O)C.O.CS(C)=O>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N:3]([CH2:1][CH3:2])[CH:14]2[CH2:19][CH2:18][C:17]([O:21][CH3:22])([CH3:20])[CH2:16][CH2:15]2)[C:5]=1[CH3:13]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cccc(C(=O)[O-])c1C)C1CCC(C)(OC)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCN(c1cccc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(C)(OC)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(ethyl(4-methoxy-4-methylcyclohexyl)amino)-2-methylbenzoate (300 mg, 0.94 mmol) and NaOH (56 mg, 1.41 mmol) in 5 ml of ethanol and water (4:1) was heated at 70° C. for 2 h. The reaction mixture was concentrated to dryness and the crude material was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 280 mg of the crude acid. A mixture of the crude acid (280 mg, 0.91 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (279 mg, 1.83 mmol), PyBOP (716 mg, 1.37 mmol) and triethylamine (0.12 ml, 0.91 mmol) in DMSO (3 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with 10% MeOH in DCM, dried over Na2SO4, and concentrated to a residue which was purified by silica gel column chromatography to afford the title compound N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(4-methoxy-4-methylcyclohexyl)amino)-2-methylbenzamide as a mixture of isomers (70 mg, 17%). LCMS: 440.45 (M+1)+; HPLC: 45.77 & 48.47% (@ 210-370 nm) (Rt; 4.297 & 4.430; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.03 (bs, 1H), 7.15 (bs, 2H), 6.91 (s, 1H), 5.85 (s, 1H), 4.25 (d, 2H, J=2.8 Hz), 3.10-2.90 (m, 7H), 2.19 (s, 6H), 2.10 (s, 3H), 1.72-1.10 (m, 8H), 1.08 & 0.99 (s, 3H), 0.77 (t, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][C:17]([CH3:21])([OH:20])[CH2:16][CH2:15]1)[CH3:3].[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25](Cl)[N:24]=1.CCN(CC)CC>CN(C=O)C>[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][C:17]([OH:20])([CH3:21])[CH2:18][CH2:19]2)[CH3:3])[N:24]=1
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-4-methylpiperidin-4-ol (56 mg, 0.194 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (32.9 mg, 0.194 mmol) and Et3N (0.054 mL, 0.388 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 5-30% ACN in water (with 0.05% ammonium carbonate). The fractions containing the desired product were combined and lyophilized to give the title compound (racemate) as a white solid (40 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.29 (m, 3 H), 1.32-1.43 (m, 3 H), 1.52-1.87 (m, 4 H), 2.57-2.72 (m, 2 H), 2.73-2.94 (m, 2 H), 3.16-3.29 (m, 1 H), 3.71-3.86 (m, 3 H), 4.24-4.32 (m, 1 H), 5.74-5.88 (m, 1 H), 6.34-6.44 (m, 2 H), 6.44-6.52 (m, 1 H), 6.53-6.65 (m, 3 H), 7.48-7.58 (m, 1 H), 7.77-7.84 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H27N9O, 422.2; found 422.5.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[NH2:35][C:36]1[NH:37][C:38]([SH:41])=[N:39][N:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:11][CH2:12][C@H:7]([CH2:6][S:41][C:38]5[NH:37][C:36]([NH2:35])=[N:40][N:39]=5)[CH2:8][CH2:9]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: Nc1nnc(S)[nH]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSc5nnc(N)[nH]5)CC4)c3)ncnc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (124.56 mg, 0.00024 mol), and 5-amino-4H-1,2,4-triazole-3-thiol (43.00 mg, 0.0003702 mol) were dissolved in DMF (1.20 mL) and potassium carbonate (0.122 g, 0.000887 mol) was added. The reaction was stirred at 50° C. for 18 h, at which time LCMS showed nearly complete reaction, and product present. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 526, 1H NMR(CDCl3): δ 8.90 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41 (m, 1H), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H), 1.70-2.10 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15]C(C)(C)C)=O)[N:8]1C(OC(C)(C)C)=O)=[O:6].FC(F)(F)C(O)=O.[C:36]([O:40][C:41](=[O:65])[CH2:42][C@@H:43](C(O)=O)[NH:44][C:45]([O:47][CH2:48][CH:49]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]2[C:50]1=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:46])([CH3:39])([CH3:38])[CH3:37].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(#N)C>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:15])[C@@H:43]([NH:44][C:45]([O:47][CH2:48][CH:49]2[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=3[C:56]3[C:61]2=[CH:60][CH:59]=[CH:58][CH:57]=3)=[O:46])[CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:65])[NH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl)ester (2.0 g, 4.3 mmol) in anhydrous dichloromethane (13 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (13 mL, 173 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo and the residue co-evaporated from toluene (3×). The resulting brown, viscous oil was dissolved in anhydrous acetonitrile (5 mL) and added to a solution of Fmoc-L-aspartic acid 4-tert-butyl ester (1.78 g, 4.3 mmol), N,N-diisopropylethylamine (3.0 mL, 17.3 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.60 g, 4.3 mmol) in anhydrous acetonitrile (25 mL) that had been previously stirred at 0° C. for 20 minutes. The reaction was warmed to room temperature and stirred for 16 h before being concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 2:1 to give the title compound (2.5 g, 88%) as a clear, viscous oil. 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 1.69-1.83 (m, 2H), 1.87-2.00 (m, 1H), 2.15-2.27 (m, 1H), 2.79-2.67 (m, 2H), 2.90-3.02 (m, 1H), 3.81-3.93 (m, 2H), 4.21-4.29 (m, 1H), 4.32-4.44 3H), 4.71 (d, J=12.0 Hz, 1H), 4.96 (d, J=12.0 Hz, 1H), 5.31-5.43 (m, 1H), 5.85 (d, J=8.5 Hz, 1H), 7.33 (app t, J=7.4 Hz, 2H), 7.41 (app t, J=7.4 Hz, 2H), 7.59-7.66 (m, 2H), 7.78 (d, J=7.6 Hz, 2H). LCMS (m/z)=654.2 [M+H], Tr=3.63 min.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([C:23]1[CH:24]=[C:25]([NH:45][C:46]([NH:48][C@@H:49]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C@H:52]([O:59][C:60]3[CH:61]=[CH:62][C:63]4[N:64]([C:66]([CH:69]([CH3:71])[CH3:70])=[N:67][N:68]=4)[CH:65]=3)[CH2:51][CH2:50]2)=[O:47])[N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][Si](C(C)C)(C(C)C)C(C)C)[CH:29]=2)[N:27]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([C:23]1[CH:24]=[C:25]([NH:45][C:46]([NH:48][C@@H:49]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C@H:52]([O:59][C:60]3[CH:61]=[CH:62][C:63]4[N:64]([C:66]([CH:69]([CH3:71])[CH3:70])=[N:67][N:68]=4)[CH:65]=3)[CH2:51][CH2:50]2)=[O:47])[N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[N:27]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(O[Si](C(C)C)(C(C)C)C(C)C)c4)c4ccccc43)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(O)c4)c4ccccc43)cn12
Reaction time: 1 h
Yield: 73.9 %

Procedure:
TBAF (1M in THF, 350 μL, 0.35 mmol) was added to a solution of Intermediate 22c (258 mg, 0.35 mmol) in THF (5.0 mL) at 0° C. The reaction was stirred for 1 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as an off-white solid (150 mg, 75%). LCMS (Method 1): Rt 4.11 min, m/z 580 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.42 (3H, d, J 6.9), 1.45 (3H, d, J 6.9), 1.88-2.16 (3H, m), 2.20-2.30 (1H, m), 3.51 (1H, sept, J 6.9), 4.90 (1H, dd, J 8.9, 5.6), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 6.84 (1H, ddd, J 8.3, 2.6, 0.8), 6.88-6.94 (2H, m), 7.19-7.26 (2H, m), 7.26-7.33 (4H, m), 7.61 (1H, d, J 10.0), 8.01 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[S:29][C:30]([CH2:33]Cl)=[CH:31][CH:32]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:33][C:30]3[S:29][C:28]([Cl:27])=[CH:32][CH:31]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2ccc(Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 25 °C

Procedure:
119 mg (0.39 mmol) of the compound from Example 5A and 107 mg (0.77 mmol) of potassium carbonate were dissolved in 5 ml of acetonitrile, and 65 mg (0.39 mmol) of 2-chloro-5-(chloromethyl)thiophene were added. The mixture was stirred under reflux for 2 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→8:1→5:1→1:1). This gave 114 mg (65% of theory) of the target compound.
Reaction SMILES: Cl.FC(F)(F)C(O)=O.C([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:40][O:41][CH:42]2[CH2:46][CH2:45][CH:44]=[CH:43]2)[C:18]([NH:20][C@@H:21]2[C:38](=[O:39])[N:23]3[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]4[N:30]([CH3:34])[CH:31]=[CH:32][CH:33]=4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:16]=1)=O.C(=O)(O)[O-].[Na+]>CO.O>[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:40][O:41][CH:42]2[CH2:46][CH2:45][CH:44]=[CH:43]2)[C:18]([NH:20][C@@H:21]2[C:38](=[O:39])[N:23]3[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]4[N:30]([CH3:34])[CH:31]=[CH:32][CH:33]=4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:16]=1
Reactant: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Conc. hydrochloric acid (4.1 g) was added to a solution of trifluoroacetic acid salt of 7β-[2-(2-formamidothiazol-4-yl)-2-(2-cyclopenten-1-yloxyimino)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (A isomer) (syn isomer) (5.8 g) in methanol (60 ml), and the mixture was stirred at ambient temperature for 2 hours. To the reaction mixture was added water (60 ml) and adjusted to pH 2.0 with 5% aqueous solution of sodium bicarbonate. The separated aqueous solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (120 ml) and eluted with 30% aqueous solution of methanol. The fractions containing the object compound were collected and concentrated in vacuo, then lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(2-cyclopenten-1-yloxyimino)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (A isomer) (syn isomer) (1.1 g).