Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24][CH3:25])=[O:23])=[CH:12][CH:11]=2)=[C:4]([CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.Cl[CH2:31][C:32](=O)[CH3:33]>CN(C=O)C>[CH2:26]([C:4]1[N:3]2[CH:32]([CH3:33])[CH:31]=[N:1][C:2]2=[N:7][C:6](=[O:8])[C:5]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:15]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1nc(N)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: CC(=O)CCl
Solvent: CN(C)C=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c(=O)nc2n1C(C)C=N2
Temperature: 100 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A solution of 0.3 g of 2-amino-6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl) methyl]pyrimidin-4-one in 6 ml of DMF is added under stirring with 61 μl of chloroacetone. After 18 h under stirring at 100° C., the solvent is evaporated under reduced pressure. The residue is taken up into water to separate a solid which is filtered and purified by FC (eluent CH2Cl2 --CH3OH 97:3), to obtain 90 mg of a spongy solid (27% yield).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NC1CCCCC1
Yield: 100 %

Procedure:
32 g (0.11 mol) of N-cyclohexyl-2-nitro-4-trifluoromethylaniline dissolved in 250 ml of methanol were hydrogenated under a pressure of about 1 bar of hydrogen in the presence of 1.5 g of palladium/active carbon (10% by weight Pd) at room temperature. The reaction mixture was filtered. Conventional workup of the filtrate gave a 100% yield of the abovementioned compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].[Cl-]>C(N(CC)CC)C.[Cu]I>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#C[Si](C)(C)C)cc1
Yield: 79.5 %

Procedure:
A solution of 20 g of 4-bromophenylacetic acid methyl ester and 10.3 g of trimethylsilylacetylene in 650 ml of triethylamine is refluxed in the presence of 1.46 g of bis-triphenylphosphinepalladium(II) chloride and 227 mg of copper(I) iodide for 5 hours. The reaction mixture is concentrated by evaporation, the residue is spread between water and ethyl acetate, the organic phase is washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/0-5% ethyl acetate. 17.1 g of 4-(2-trimethylsilylethinyl)-phenylacetic acid methyl ester is obtained as oily crude product.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([NH:26][C:27]([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])=[O:28])[CH3:25]>>[CH2:24]([NH:26][C:27](=[O:28])[CH2:29][CH2:30][CH2:31][C:32]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:33])[CH3:25]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCNC(=O)CCCC(=O)O
Product: CCNC(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-ethylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(ethylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+H]=910; RT=1.13 min; UPLC Method I
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)[O:3]1.CC(O)=O>C(O)C.[Fe]>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]2[O:3][C:2]([CH3:1])([CH3:35])[C:6](=[O:7])[C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=[CH:27][CH:28]=1
Reactant: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(4-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.6 g, 1.28 mmol) in ethanol (10 mL) was added AcOH (1.28 mL) at RT under N2 atmosphere. After being stirred for 10 min at RT, the reaction mixture was heated to 70° C. and Fe (0.524 g, 9.04 mmol) and FeCl3 (0.062 g, 0.38 mmol) were added under N2 atmosphere. The reaction mixture was stirred at 70° C. for 2 h. After completion of starting material (by TLC), reaction mixture was cooled to RT, and the volatiles were evaporated in vacuo to obtain the crude product. The crude product was extracted in EtOAc (25 mL), washed with water (2×10 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (400 mg, 71%), as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][NH:3]1.[CH3:24][S-:25].[Na+].O>CN1CCCC1=O>[O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[C:18]([S:25][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: C[S-]
Reactant: O=c1[nH]cccc1CN1CCC(CCc2cccnc2Cl)CC1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1ncccc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
168 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in Example 117 and 354 mg of sodium thiomethoxide were suspended in 5 ml of 1-methyl-2-pyrrolidinone, and the mixture was stirred at 150° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (methanol:ethyl acetate=1:19), to give 20 mg of the title compound as colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24]>O1CCCC1>[Cl:22][C:23](=[CH2:24])[CH2:25][CH:14]([CH:15]([CH3:17])[CH3:16])[C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=C(Cl)CCl
Reactant: CCOC(=O)CC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(Cl)CC(C(=O)OCC)C(C)C
Temperature: -4 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A 1 liter flask was equipped with a mechanical stirrer, reflux condenser, nitrogen inlet, addition funnel, and thermometer. The flask was charged with 200 ml of tetrahydrofuran (THF) and 31.37 g (0.300 mol) of diisopropylamine and cooled to -4° C. The n-butyllithium solution (265 ml of 1.6M, 0.424 mol) was added dropwise at -4° to -6° C. over 22 minutes. The reaction mixture was then stirred for 30 minutes at -4° C. and then 39.06 g (0.300 mol) of ethyl isovalerate added over 15 minutes. The reaction mixture was cooled to -78° C. and 44.39 g (0.400 mol) of 2,3-dichloro-1-propene added dropwise. During the addition of the halide, the temperature was maintained at -78° C. to -74° C. The reaction mixture was stirred for 2 hrs. at -78° C. to give a clear, tan colored solution. The temperature of the reaction mixture was then allowed to rise to -40° C., and stirred at -40° C. to -30° C. for 2 hours. The reaction mixture was then allowed to stand at room temperature over the weekend. The reaction mixture was quenched with 25 ml of water and then poured into 300 ml of ice water. The aqueous mixture was extracted twice with 250 ml portions of ether. The combined ether extracts were washed with saturated sodium chloride solution, dried (MgSO4), and the ether removed. The residue was vacuum distilled through a vigreux column to give 28.02 g (46% yield) of ethyl 4-chloro-2-isopropyl-4-pentenoate, bp 53°-63° C./0.70 mm.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([NH:12][C:13]2([C:27]#[N:28])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:29].[NH4+]>>[C:6]1([NH:12][C:13]2([C:27]([NH2:28])=[O:29])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [OH-]
Reactant: N#CC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To 4500 parts of sulfuric acid are added portionwise 710 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarbonitrile, while keeping the temperature below 25° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto a mixture of 10,000 parts of crushed ice and 3600 parts of ammonium hydroxide. The product is extracted with trichloromethane (7500 parts). The extract is dried, filtered and evaporated. The residue is stirred in 140 parts of 2,2'-oxybispropane. The product is filtered off and dried, yielding 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxamide; mp. 182.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[Br:21]Br>O.[OH-].[Na+]>[Br:21][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: BrBr
Reactant: CC(CO)Nc1ccnc2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(CO)Nc1c(Br)cnc2cc(Cl)ccc12
Yield: 57 %

Procedure:
A mixture of 12 g of 7-chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine and 112 ml of acetic acid was stirred at room temperature and to it 8 g of bromine was added dropwise over a thirty minute period. The product precipitated from the solution as the hydrobromide salt and it was isolated by filtration, dissolved in water and basified with sodium hydroxide. The free base was extracted into dichloromethane and evaporation of solvents resulted in a solid which was purified by HPLC using 95:5 dichloromethane/methanol as the eluent. Recrystallization from isopropanol yielded 9 g of crystalline solid with a melting point of 145°-147° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+]>O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
(R)-4-[6-(4-tert-Butylcyclohexyloxy)naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.03878 g, 0.0001016 mol) was dissolved in ethanol (1.00 mL, 0.0171 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M Lithium hydroxide, monohydrate in water (1.00 mL) was added and the reaction was refluxed overnight. TLC analysis showed that the reaction was complete. The solvent was removed under vacuum. The product was diluted in methylene chloride (5 mL) and water was added (5 mL). The layers were separated and the organic phase was then concentrated to dryness under vacuum, and purified by HPLC to give 0.0048 g of the title compound (13% yield). MS: m/z=339.47 [M-NH2]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:20])[CH3:17]>N1C=CC=CC=1.O1CCCC1>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25]([C:24]3[CH:28]=[CH:29][C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:22][CH:23]=3)=[O:26])=[CH:11][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:6][C:7]1=[O:13]
Reactant: CN1C(=O)CC(C)(C)c2cc(N)ccc21
Reactant: CCOC(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CC(=O)N3C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
37.2 g of 6-amino-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 600 ml of pyridine and treated dropwise at room temperature with a solution of 43 g of 4-ethoxycarbonylbenzoyl chloride in 80 ml of tetrahydrofuran. After stirring at room temperature for 20 hours, the reaction mixture was poured on to ice-water, extracted several times with ethyl acetate, the organic phase was washed with cold 2N hydrochloric acid and water, dried and evaporated. Chromatography of the crude product (silica gel, eluent hexane/ethyl acetate 2:1, then ethyl acetate) and recrystallization from ethyl acetate/hexane, yielded 45.5 g of ethyl p-[(1,2,3,4-tetrahydro-1,4,4-trimethyl-2-oxo-6-quinolinyl)carbamoyl]-benzoate, m.p. 197°-199° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([NH2:57])[CH:54]=[CH:55][CH:56]=1.[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][C:68]2[N:71]([CH3:92])[C:72]([C:75]3[CH:80]=[CH:79][N:78]=[C:77]([N:81]4C(=O)C5C(=CC=CC=5)C4=O)[N:76]=3)=[C:73](I)[C:67]=2[C:66]1=[O:93])=[O:64])([CH3:61])([CH3:60])[CH3:59]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][C:68]2[N:71]([CH3:92])[C:72]([C:75]3[CH:80]=[CH:79][N:78]=[C:77]([NH2:81])[N:76]=3)=[C:73]([NH:57][C:53]3[CH:54]=[CH:55][CH:56]=[C:51]([O:50][CH3:49])[CH:52]=3)[C:67]=2[C:66]1=[O:93])=[O:64])([CH3:61])([CH3:60])[CH3:59]
Reactant: Cn1c2c(c(I)c1-c1ccnc(N3C(=O)c4ccccc4C3=O)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Reactant: COc1cccc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cccc(Nc2c3c(n(C)c2-c2ccnc(N)n2)CCN(C(=O)OC(C)(C)C)C3=O)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 22.4 %

Procedure:
Cesium carbonate (0.154 g, 0.473 mmol), 4,5-bis(diphenylphoshino)-9,9-dimethylxanthene (0.027 g, 0.047 mmol), Pd2(dba)3 (0.0217 g, 0.023 mmol), 3-methoxy-phenylamine (0.038 g, 0.308 mmol) were added under argon to a solution of 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-pyrimidin-4-yl]-3-iodo-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.142 mg, 0.237 mmol) in dry dioxane (4.0 ml) and the reaction mixture was stirred at 100° C. for 24 h under argon atmosphere. The solvent was removed under vacuum, the residue was taken up into DCM (5.0 ml), filtered, and the organic layer was washed with purite water (1×5.0 ml), dried over Na2SO4. The filtrate was purified over silica, using DCM/MeOH (9.5:0.5) as eluent, affording 2-(2-Amino-pyrimidin-4-yl)-3-(3-methoxy-phenylamino)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.025 g, 0.053 mmol, 23%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:45][O:46]C2CCC=C2)[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:45][OH:46])[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Reaction time: 0.58 h
Yield: 53.7 %

Procedure:
To a suspension of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl) oxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (1.06 g) in anisole (2 ml) was added trifluoroacetic acid (4 ml) under ice-cooling and the mixture was stirred for 35 minutes at the same temperature. The mixture was poured into diisopropyl ether (250 ml). The precipitate was collected, washed with diisopropyl ether and dried over phosphorus pentoxide. The precipitate was dissolved in a mixture of tetrahydrofuran (50 ml), sodium bicarbonate (242 mg), water (40 ml) and ethyl acetate (50 ml). The aqueous layer was separated and adjusted to pH 2 with 1N hydrochloric acid. The resultant precipitate was collected, washed with cold water and dried over phosphorus pentoxide to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylic acid (syn isomer) (390 mg). mp 178° -182° C. (dec.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:16]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[O:17])[C:11](=[O:36])[CH:10]=1.[OH-].[Li+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:16]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])[C:11](=[O:36])[CH:10]=1
Reactant: COC(=O)c1ccc(NC(=O)C(Cc2cccnc2)n2ccc(-c3cc(Cl)ccc3Br)cc2=O)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(NC(=O)C(Cc2cccnc2)n2ccc(-c3cc(Cl)ccc3Br)cc2=O)cc1

Procedure:
65 mg (purity 85%, 0.10 mmol) of methyl 4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoyl}amino)benzoate (racemate) (Example 9.2E) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 14 mg (26% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[CH2:9][NH:10][C:11]([C@@:13]2([CH3:27])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[F:33][C:34]([F:48])([F:47])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O)=[CH:37][CH:36]=1>C(#N)C.O>[CH3:18][C:15]1([CH3:19])[N:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@@:13]([CH3:27])([C:11](=[O:12])[NH:10][CH2:9][C:8](=[O:28])[C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][C:38]3[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:47])[F:48])=[CH:40][CH:39]=3)=[C:3]([C:29]([F:31])([F:32])[F:30])[CH:4]=2)[CH2:17][O:16]1
Reactant: OCCCCCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(O)c(C(F)(F)F)c1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(OCCCCCc2ccc(C(F)(F)F)cc2)c(C(F)(F)F)c1
Yield: 31 %

Procedure:
The title compound was prepared from (R)-tert-butyl 4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate (0.25 mmol, 1.0 equiv) and 5-(4-(trifluoromethyl)phenyl)pentan-1-ol (0.25 mmol, 1.0 equiv) according to the general procedure in 31% yield. HPLC retention time on a C18 column (30×4.6 mm, 3.5 V) was 3.26 min with gradient 50-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=675.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]1[CH2:20][CH2:19][C@@:18]([CH3:22])([OH:21])[C:17]1([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:20][CH2:19][C@:18]([OH:21])([CH3:22])[C:17]3([CH3:24])[CH3:23])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC1(C)[C@H](N)CC[C@@]1(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@@]1(C)O
Temperature: 120 °C
Yield: 88.1 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 38.3 mg, 0.140 mmol) and (1R,3R)-3-amino-1,2,2-trimethylcyclopentanol (from Step 2 of Intermediate 20, 20 mg, 0.140 mmol) in MeCN (1 mL) was added DIPEA (0.050 mL, 0.279 mmol). The reaction was sealed and heated to at 120° C. for 60 min. The reaction was cooled and concentrated then purified by flash chromatography on silica gel using 30-70% ethyl acetate/hexanes as the eluent to afford the title compound (47 mg, 86% yield). HPLC (Conditions L): retention time=7.21 min., (condition P): retention time=8.31 min.; LCMS: 382.97 (M+2); 1H NMR (CDCl3, 400 MHz) δ 10.51 (br d, J=9.4 Hz, 1H), 7.84 (s, 1H), 7.57 (d, J=1.7 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 5.45 (br s, 2H), 4.69 (q, J=9.5 Hz, 1H), 2.38 (m, 1H), 1.99 (m, 1H), 1.79 (m, 1H), 1.56 (m, 1H), 1.27 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6](=[O:8])[CH3:7])[CH2:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:40][N:41]1[CH2:46][CH2:45][C:44]2([CH2:55][C:54]3[C:49](=[N:50][CH:51]=[C:52](/[CH:56]=[CH:57]/[C:58](O)=[O:59])[CH:53]=3)[NH:48][C:47]2=[O:61])[CH2:43][CH2:42]1>CN(C)C=O>[C:6]([CH:4]1[CH2:5][N:2]([C:58](=[O:59])/[CH:57]=[CH:56]/[C:52]2[CH:53]=[C:54]3[C:49](=[N:50][CH:51]=2)[NH:48][C:47](=[O:61])[C:44]2([CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]2)[CH2:55]3)[CH2:3]1)(=[O:8])[CH3:7]
Reactant: CC(=O)C1CNC1
Reactant: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reaction time: 8 h

Procedure:
1-(Azetidin-3-yl)ethanone hydrochloride (110 mg, 0.8 mmol), EDCI (153 mg, 0.8 mmol), HOBt (108 mg, 0.8 mmol) and diisopropylethylamine (700 μL, 4.0 mmol) were successively added to a solution of (E)-3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid hydrochloride (136 mg, 0.4 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (9:1:0.1) as eluent. Precipitation in a mixture DCM/pentane allowed isolation of the title product as a yellow solid (44.6 mg, 29%).