Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C[CH2:11][N:12]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN>CN(C=O)C>[CH3:11][NH:12][C:7]([C:5]1[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=1)=[O:9]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nc(C(=O)O)c[nH]1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c[nH]c(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
2-Methyl-1H-imidazole-4-carboxylic acid (378 mg, 3 mmol), EDCI (745 mg, 3.9 mmol), HOBt (253 mg, 1.5 mmol), DIEA (1.6 mL, 9 mmol) and methyl amine (2M in THF) (3.6 mL, 7.2 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 16 hours. After removal of DMF, the residue was dry loaded and purified by flash chromatography (SiO2, 0-10% methanol in DCM and 1% NH4OH) to give 280 mg (67%) of the title compound. m/z (ES+) 140 (M+H)+.
Reaction SMILES: [N:1]1([C@@H:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][CH2:9][CH2:8][C@H:7]2O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(Cl)(=O)=O.[CH3:23][NH2:24].[OH-].[Na+]>O1CCCC1.C(O)C.O.C(N(CC)CC)C>[CH3:23][NH:24][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7][C@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O[C@@H]1CCCc2ccccc2[C@H]1N1CCCC1
Reactant: CN
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN[C@@H]1c2ccccc2CCC[C@H]1N1CCCC1
Reaction time: 23 h

Procedure:
8.2 g of the product of Step A were dissolved in 82 ml of tetrahydrofuran and 7 ml of triethylamine and after the mixture was cooled in a bath to -20° C., 3.9 ml of methane sulfonyl chloride in solution in 8 ml of tetrahydrofuran were added. After returning to ambient temperature, 35 ml of methylamine at 33% in ethanol were added and the mixture was stirred for 23 hours. The solvents were eliminated under reduced pressure and 150 ml of water and 10 ml of a solution of sodium hydroxide were added. Extraction was effected with methylene chloride and the extracts were washed with salted water, dried, filtered and concentrated to dryness under reduced pressure to obtain 8.7 g of the expected products as an orange-colored oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:27]([Cl:28])[C:21]=2[N:20]=1>>[Cl:28][C:27]1[C:21]2[N:20]=[C:19]([N:15]3[CH2:16][CH2:17][N:12]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=4)[CH2:13][CH2:14]3)[NH:23][C:22]=2[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:26]=1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Product: FC(F)(F)c1cnc(N2CCN(c3nc4c(Cl)cc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1

Procedure:
The reaction of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine (186 mg, 0.7 mmol, ABCR) and 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole (127 mg, 0.5 mmol, Example 5b) under the conditions of Example 3c afforded the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 484 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:29][CH:30]([CH3:33])[C:31]#[CH:32]>C1COCC1.[Pd].[Cu]I>[Cl:27][C:23]1[N:24]=[CH:25][NH:26][C:22]=1[C:20]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:4]2[CH:3]=[C:2]([C:32]#[C:31][CH:30]([CH3:33])[CH3:29])[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[C:12]=1[F:28])=[O:21]
Reactant: C#CC(C)C
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Agent: [Cu]I
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 53.1 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (95 mg, 0.196 mmol), Palladium dichloropistriphenylphosphine (103 mg, 0.196 mmol), 3-methyl-1-butyne (26.7 mg, 0.392 mmol) and copper(I) iodide (1.869 mg, 9.81 μmol) in THF (4 ml) was added TEA (0.141 ml, 1.012 mmol) and the reaction mixture was irradiated in a personal microwave reactor for 10 minutes at 120° C. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(3-methyl-1-butyn-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (49 mg, 0.104 mmol, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (d, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.41-7.50 (m, 2H), 7.32 (t, 1H), 7.11 (s, 1H), 4.49 (d, 2H), 2.76 (dt, 1H), 1.15 (d, 6H). LC-MS (ES+) m/z 471.13, [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH2:35][CH3:36])[CH3:34].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH:33]([CH2:35][CH3:36])[CH3:34])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:22])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CCC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
To a suspension of 500 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 352 mg of potassium carbonate in 1.3 ml of N,N-dimethylformamide, 704 mg of 2-iodobutane was added, and the mixture was stirred at room temperature for 12 hours. After completion the reaction, the reaction mixture was mixed with 3 ml of water and extracted with ethyl acetate (3 ml×2), the resulting organic layers were combined, washed with water (3 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 522 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[O:14][CH:13]=[N:12][C:11]=1[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[N:23]=[C:22]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O>[CH3:15][C:11]1[N:12]=[CH:13][O:14][C:10]=1[C:3](=[N:2][O:1][CH2:17][C:18]1[N:23]=[C:22]([N:24]2[C:25](=[O:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]2=[O:33])[CH:21]=[CH:20][CH:19]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ncoc1C(=NO)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: Cc1ncoc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Yield: 92.5 %

Procedure:
To a solution of N-hydroxy-1-(4-methyl-1,3-oxazol-5-yl)-1-phenylmethanimine (0.15 g, 0.74 mmol) dissolved in acetonitrile (3 mL) were added 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (259 mg, 0.82 mmol), cesium carbonate (507 mg, 1.56 mmol) and potassium iodide (12.3 mg, 0.074 mmol). After stirring for 8 hours at room temperature water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford 2-{6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (0.3 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[C:5](/[C:13]#[N:14])=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[N+]([CH:19]([CH3:21])[CH3:20])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[Na+].[Cl-]>CCO>[CH2:1]([O:3][C:4]([C:5]1([C:13]#[N:14])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:19]1([CH3:21])[CH3:20])=[O:15])[CH3:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Temperature: 50 °C
Yield: 63.6 %

Procedure:
A mixture of (E)-2-cyano-3-phenyl-acrylic acid ethyl ester (83.6 g, 415 mmol), 2-nitropropane (37 g, 415 mmol) and potassium carbonate (57.4 g, 415 mmol) in EtOH (325 mL) was heated at reflux for 4 hours, then heated to 50° C. for 18 hours. The reaction mixture was then poured into an aqueous solution of NaCl (15%, 2 L) and extracted with DCM. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by distillation under vacuum to give 1-cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid ethyl ester (64.26 g, 64% yield, pale yellow oil) which distilled at 118° C. (oil bath temperature 157° C.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:9][C:8]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O.[C:28]([C@:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C)C=O>[CH2:19]([C:8]1[CH:9]=[C:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:11]=[CH:12][C:7]=1[C:29]#[C:28][C@:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCN1c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCCN1c1ccc(C#C[C@@]2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
To a mixture of 200 mg of 2-benzyl-4-[2-pyrrolidinon-1-yl]phenyl trifluoromethanesulfonate (Production Example 5), 80 mg of (3R)-3-ethynyl-3-quinuclidinol (Production Example 22), 30 mg of tetrakis(triphenylphosphine)palladium (0), 5 mg of copper (I) iodide and 0.2 ml of triethylamine was added 1 ml of N,N-dimethylformamide, followed by heating under stirring under nitrogen atmosphere in an oil bath at 80° C. for 3 hours. After standing to cool, aqueous ammonia was added to the reaction mixture, which then was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by NH-silica gel column chromatography with ethyl acetate, to give 66 mg of the title compound.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:22])([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[N:15]2)=[CH:10][CH:9]=1>CCOCC>[Br:2][CH2:19][C:16]1[CH:17]=[CH:18][N:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]([F:22])([F:21])[F:5])=[CH:9][CH:10]=2)[N:15]=1
Reactant: OCc1ccn(-c2ccc(OC(F)(F)F)cc2)n1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-n2ccc(CBr)n2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
PBr3 (0.312 mL, 3.32 mmol) was added to a solution of alcohol 67 (0.858 g, 3.32 mmol) in ether (15 mL) at 0° C. The mixture was stirred at room temperature for 17 h, then cooled to 0° C., quenched with ice, and partitioned between CH2Cl2 and water. Column chromatography of the organic portion on silica gel (eluting with CH2Cl2) gave 3-(bromomethyl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole (68) (0.952 g, 89%) as a white solid: mp 71-73° C.; 1H NMR (CDCl3) δ 7.84 (d, J=2.5 Hz, 1H), 7.69 (d, J=9.1 Hz, 2H), 7.31 (d, J=9.1 Hz, 2H), 6.54 (d, J=2.5 Hz, 1H), 4.56 (s, 2H). APCI MS m/z 321, 323 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:35])([CH3:34])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH:56]1[O:61][CH2:62][CH2:63]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:30]([Si:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:16][CH2:15][C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:63][CH2:62][O:61][CH:56]3[CH2:57][CH2:58][CH2:59][CH2:60][O:55]3)[CH:8]=2)[N:5]=1)([CH3:35])[CH3:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(O)c2)n1
Reactant: OCCOC1CCCCO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
A mixture of Intermediate 153d (0.53 g, 1.09 mmol) in dry THF (8 mL) was treated with triphenylphosphine (0.57 g, 2.18 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.22 mL, 1.64 mmol). The mixture was cooled to 0° C. then diisopropylazodicarboxylate (0.43 mL, 2.18 mmol) was added dropwise. After stirring at ambient temperature for 20 h the mixture was treated with water (0.1 mL) and concentrated in vacuo to a yellow oil. The oil was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound as an orange oil (0.41 g, 61%). LCMS (Method 3): Rt 5.25 min, m/z 614.6 [MH+].
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Mg]>O1CCCC1.Cl[Ni]Cl>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:19][CH:20]=1
Reactant: CCCc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: COc1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(-c3ccc(OC)cc3)nn2)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
3-Chloro-6-(4'-propylphenyl)-pyridazine prepared according to a method disclosed in a known literature (m.p.: 127.6°-129.6° C.) (60.0 g) was dissolved in tetrahydrofuran (THF) (700 ml), followed by adding NiCl2 (dppp) (2.5 g) as a catalyst, agitating the mixture at -10° C. for 15 minutes, dropwise adding therto a Grignard reagent obtained by reacting p-bromoanisole (96.5 g) with magnesium in THF, agitating the mixture in an ice bath for one hour, removing the ice bath, agitating it at room temperature for 3 hours, allowing it to stand overnight, adding toluene (500 ml), further adding 6N-hydrochloric acid, separating the resulting organic layer, washing it with water, then with an alkali and further with water till the washing water became neutral, drying with MgSO4, distilling off toluene, purifying the residue according to column chromatography using activated alumina (300 g) and toluene as an eluent, concentrating, and recrystallizing from ethyl acetate (700 ml) to obtain 3-(4'-methoxyphenyl)-6-(4'-propylphenyl)-pyridazine (70 g). This product had a m.p. of 155.9° C., exhibited nematic phase and formed an isotropic liquid at 254° C.
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22](=[O:36])([O:27][CH:28]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[O:23][CH:24](Cl)[CH3:25]>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH:24]([O:23][C:22]([O:27][CH:28]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:36])[CH3:25])=[O:19]
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: CC(Cl)OC(=O)OC1CCCCCCC1
Product: CC(OC(=O)OC1CCCCCCC1)OC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)O)[C@@H]21
Yield: 18.2 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 380 mg) and 1-chloroethyl cyclooctyl carbonate (A-11-1, 745 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-11, 93 mg) as a colorless solid.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19](Br)=[CH:20][N:21]=2)[N:18]=1)=[O:5])=C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CC#N.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>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:19]1[N:17]2[N:18]=[C:13]([N:12]3[CH2:11][C@@H:7]4[CH2:8][CH2:9][CH2:10][N:6]4[C:4]3=[O:5])[CH:14]=[CH:15][C:16]2=[N:21][CH:20]=1
Reactant: COc1ccccc1B(O)O
Reactant: C=COC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1cnc2ccc(N3C[C@@H]4CCCN4C3=O)nn12
Temperature: 150 °C
Yield: 64.4 %

Procedure:
A mixture of (S)-2-[(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-methyl]-pyrrolidine-1-carboxylic acid vinyl ester (125 mg, 0.34 mmol), (2-methoxyphenyl)boronic acid (67.2 mg, 0.44 mmol), K2CO3 (141 mg, 1.02 mmol) and dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.017 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The reaction was repeated at 140° C. After removal of the water the reaction mixtures was combined and diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (S)-2-[3-(2-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (76.5 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.51 (m, 1H) 1.89-2.02 (m, 1H) 2.05-2.18 (m, 2H) 3.18-3.26 (m, 1H) 3.72-3.96 (m, 6H) 4.09-4.16 (m, 1H) 7.04-7.13 (m, 2H) 7.35-7.42 (m, 1H) 7.90-7.96 (m, 1H) 8.03-8.10 (m, 2H) 8.40 (dd, J=9.85, 2.78 Hz, 1H). LRMS (ESI) m/z 350.2 [(M+H)]+, calc'd for C19H19N5O2: 349.4.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([F:19])=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[F:12])(=O)C.[OH-].[Na+].CO>C(O)(=O)C>[F:19][C:7]1[C:6]([CH2:5][OH:4])=[C:11]([F:12])[CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OCc1c(F)ccc(-c2ccccc2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: OCc1c(F)ccc(-c2ccccc2)c1F
Yield: 87 %

Procedure:
A solution of 3.1 g (0.012 mole) of (2,4-difluoro[1,1'-biphenyl]-3-yl)methyl acetate in 25 ml of a 2% aqueous solution of sodium hydroxide and 75 ml of methanol was stirred at ambient temperature until the reaction was complete as indicated by thin layer chromatography. The reaction mixture was neutralized with glacial acetic acid and concentrated under reduced pressure to give a residual solid. The solid was partitioned between diethyl ether and water. The phases were separated and the aqueous phase was extracted with two portions of diethyl ether. The ether layers were combined and washed with one portion of 150 ml of 2% aqueous hydrochloric acid, one portion of 150 ml of water, one portion of 150 ml of a 10% aqueous solution of sodium carbonate, one portion of 150 ml of water, and finally, one portion of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 2.3 g of 2,4-difluoro[1,1'-biphenyl]-3-methanol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: FC1C=C(C=C(F)C=1)N.[Cl:10][C:11]1[C:12]([F:25])=[C:13](C(O)=O)[C:14]([F:21])=[C:15]([C:19]=1[F:20])C(O)=O>>[Cl:10][C:11]1[C:12]([F:25])=[CH:13][C:14]([F:21])=[CH:15][C:19]=1[F:20]
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(C(=O)O)c1F
Agent: Nc1cc(F)cc(F)c1
Product: Fc1cc(F)c(Cl)c(F)c1

Procedure:
EP 460 639 describes a three-stage preparation of 3,5-difluoroaniline. Starting from 5-chloro-2,4,6-trifluoroisophthalic acid, this is decarboxylated to give 2-chloro-1,3,5-trifluorobenzene. By reaction of the 2-chloro-1,3,5-trifluorobenzene with copper and water at 300° C., 1,3,5-trifluorobenzene can be prepared. According to Example 6 of EP 460 639, 1,3,5-tri-fluorobenzene is reacted with methanol saturated with ammonia at 200° C. for 60 hours and 3,5-difluoroaniline is obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([O-:11])(=O)=[O:9])[N:6]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([Cl:14])(=[O:11])=[O:9])[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nc(CS(=O)(=O)[O-])cs1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(CS(=O)(=O)Cl)cs1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium (2-methylthiazol-4-yl)methanesulfonate, 40, (357 mg, 1.66 mmol) is dissolved in phosphorous oxychloride (6 mL) and is treated with phosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture is stirred at 50° C. for 3 hours, then allowed to cool to room temperature. The solvent is removed under reduced pressure and the residue is re-dissolved in CH2Cl2 (40 mL) and is washed with sat. NaHCO3 and brine. The organic layer is dried over MgSO4, filtered, and the solvent removed in vacuo to afford 0.095 g of the desired product as a brown oil. LC/MS ESI+ 211 (M+1). Intermediates are obtained in sufficient purity to be carried forward according to Scheme IX without the need for further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:31])/[C:19](=[N:28]\[O:29][CH3:30])/[C:20](=[O:27])[CH2:21][O:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:15](=[O:32])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C(=O)([O-])O.[Na+].[Cl-].[Ca+2].[Cl-].Cl>CO>[CH3:26][S:23]([O:22][CH2:21][C:20](=[O:27])/[C:19](=[N:28]/[O:29][CH3:30])/[C:18]([NH:17][CH:16]1[C:15](=[O:32])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][CH3:1])[CH2:7][S:8][C@H:9]12)=[O:31])(=[O:24])=[O:25]
Reactant: CO/N=C(/C(=O)COS(C)(=O)=O)C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Ca+2]
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)C(=O)COS(C)(=O)=O)[C@H]2SC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
510 mg of 3-acetoxymethyl-7-[4-methanesulphonyloxy-3-oxo-(Z)-2-methoxyiminobutyrylamino]-3-cephem-4-carboxylic acid and 130 mg of sodium hydrogen carbonate were dissolved in 5.1 ml of 67% v/v aqueous methanol, and 5.1 g of anhydrous calcium chloride were added. The mixture was stirred for 1 hour at a bath temperature of 70° C., after which 50 ml of ice-water were added and the mixture was acidified to a pH value of 1.0 by the addition of hydrochloric acid. The mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate, after which the solvent was distilled off, giving 352 mg of the title compound in the form of a pale brown, foamy substance.