Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:5]1[CH:4]=[C:3]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:2]([C:38]2[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=2)=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccc(F)cc3F)cc2CN2CCOCC2)cn1
Temperature: 120 °C

Procedure:
To a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)-N-3-pyridinylbenzamide (may be prepared as described in Example 9; 162 mg, 0.31 mmol) in 1,2-dimethoxyethane (5 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.38 mmol), Pd(Ph3P)4 (21.67 mg, 0.02 mmol) and sodium carbonate (0.63 ml, 0.63 mmol). The mixture was heated at 120° C. in the microwave for 35 minutes, cooled and the solvent removed in vacuo. Purification by MDAP yielded the title compound as a brown solid. 75 mg.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1>O1CCCC1.C(OCC)C.[Cl-].[NH4+]>[CH2:3]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)[CH:2]=[CH2:1]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCc1ccc(F)cc1
Reaction time: 16 h

Procedure:
Allyl bromide (4.33 mL, 50 mmol) was added dropwise to a solution of 4-fluorophenyl magnesium bromide (50 mmol) in tetrahydrofuran (25 mL) and diethyl ether (25 mL). After 16 hours, the reaction suspension was diluted with diethyl ether (100 mL) and saturated aqueous ammonium chloride (50 mL). The layers were separated, and the organic layer was washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated to afford 1-allyl-4-fluorobenzene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:5]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A round bottom flask charged with tryptamine (2.0 g, 12.5 mmol) in DCM (20 mL) was added Et3N (3.5 mL, 25 mmol) under an atmosphere of Ar and cooled to 0° C. The solution was then added mesyl chloride (1.5 mL, 18.7 mmol) and the resulting reaction mixture was stir to RT for 2 h. The reaction was quenched with water (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The desired product was purified via automated column chromatography method 2 (2.1 g, 70%) and isolated as a brown oil. 1H NMR (400 MHz, MeOD) δ 7.55 (d, J=7.6 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.08 (m, 2H), 7.01 (td, J=8.0, 0.8 Hz, 1H), 3.35 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.76 (s, 3H). 13C NMR (100 MHz, MeOD) δ 138.28, 128.77, 123.91, 122.54, 119.85, 119.34, 112.93, 112.43, 45.09, 40.02, 27.60.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)CCC.CCOC(C)=O.C(=O)([O-])O.[Na+]>[F:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]2[CH:11]=[CH:10][NH:9][C:4]2=[N:5][CH:6]=1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Fc1cnc2[nH]ccc2c1N1CCCCC1
Temperature: 180 °C
Yield: 25.9 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg) and piperidine (50 mg) in 1-butanol (0.4 mL) was heated in the microwave reactor (120° C., 0.5 hour, 180° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (10 mL) two times and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave 5-fluoro-4-(1-piperidinyl)-1H-pyrrolo[2,3-b]pyridine (10 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1[C:14](=[O:28])[CH2:15][CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]=1[OH:19])(=O)[CH2:9][CH2:10][CH3:11].Cl.[CH2:30]([O:33][NH2:34])[CH:31]=[CH2:32]>C(O)C>[CH2:30]([O:33][N:34]=[C:8]([C:13]1[C:14](=[O:28])[CH2:15][CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]=1[OH:19])[CH2:9][CH2:10][CH3:11])[CH:31]=[CH2:32]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCON=C(CCC)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Reaction time: 8 h
Yield: 66.6 %

Procedure:
Triethylamine (1.2 g) was added to a solution of 2-butyryl-3-hydroxy-4-(4-methoxyphenyl)cyclohex-2-e-n-1-one (2.9 g) and O-allylhydroxylamine hydrochloride (1.2 g) in absolute ethanol (50 ml) at ambient temperature. After stirring overnight at this temperature, the ethanol was evaporated in vacuo, water was added to the residue and the aqueous solution was extracted with methylene chloride. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was chromatographed on a silica gel column using 10% Et2O--CH2Cl2 as eluant to give the title compound (2.3 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.FC(F)(F)C(O)=[O:14].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (1.00 g, 5.00 mmol), trifluoroacetic acid (3.5 mL, 45 mmol), and sulfuric acid (3.5 mL, 66 mmol) was stirred at ambient temperature for 4 hours, at 30° C. for 15 hours, and at 50° C. for 6 hours. After cooling to 0° C., water (20 mL) was added, and the resulting suspension was stirred at 0° C. for 1.5 hours. The solids were collected by vacuum filtration, rinsed with excess water, and dried to afford 4-bromo-2-fluorobenzamide (0.956 g, 88%) as an off-white solid which was carried on without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:54][C:55]([O:57][CH3:58])=[O:56]>C(Cl)Cl>[F:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18]([C:15]1[N:13]2[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:54][C:55]([O:57][CH3:58])=[O:56])[CH2:3][CH2:4]3)[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]2=[N:17][CH:16]=1)=[O:19]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 5C (40 mg, 0.057 mmol) in CH2Cl2 (1 mL) was added DIEA (0.043 mL, 0.248 mmol) and methyl 2-bromoacetate (9.68 mg, 0.063 mmol). The solution was heated to 50° C. overnight. The volatiles were removed via a stream of nitrogen. The resulting dark brown oil was taken up in TFA (0.75 mL) and heated to 65° C. for 2 h, and then cooled to room temperature. The volatiles were removed under a stream of nitrogen and the crude material was diluted with 1 mL of THF and purified via preparatory HPLC using a YMC ODS C-18 30×250 mm column with 10-100% B (Solvent A: 10% aq MeOH with 0.1% TFA; Solvent B: 90% aq. MeOH with 0.1% TFA) and a linear gradient over 60 min at 25 mL/min, monitoring at 220 nm, and a total run time of 70 min. (Rt of desired=46.365 min) Appropriate fractions were concentrated and lyophilized overnight to afford methyl N-(trans-4-((3-((3-fluoro-4-pyridinyl)carbamoyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)glycinate (23 mg, 0.030 mmol, 52.5% yield). HPLC Rt=3.335 minutes. (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA. [M+H]=534.1.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:18](O)([CH3:20])[CH3:19])[CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH3:9].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([C:18]([CH3:20])=[CH2:19])[CH:12]=1)[CH3:9]
Reactant: Cc1cc(CN(C)C/C=C/C#CC(C)(C)C)cc(C(C)(C)O)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)c1cc(C)cc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
Compound 17 (1.08 g; 3.45 mmol) was dissolved in pyridine (50 ml). While the solution was stirred at room temperature, phosphorus oxychloride (5.28 g; 34.5 mmol) was added dropwise. The mixture was heated for 2.5 hours at 100° C. while being stirred, and left to cool to room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml×2) and with saturated brine (×1), and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.53 g of the target compound (yield: 52.0%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=S)[CH2:2][CH3:3].C(O)(=[O:31])C>O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:31])[CH2:2][CH3:3]
Reactant: CC(=O)O
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: CCOC(C)=O
Solvent: O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 0.5 h

Procedure:
Mercuric acetate (0.38 g) is added with stirring to a solution of N-propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (0.6 g) in acetic acid (10 cc), and stirring is continued for 4 hours 30 minutes at a temperature in the region of 20° C. The black reaction mixture is diluted with distilled water (25 cc) and ethyl acetate (50 cc) and then filtered and alkalinized with stirring with 4N aqueous sodium hydroxide solution to pH 13. After settling has taken place, the organic phase is separated and the aqueous phase is extracted with ethyl acetate (20 cc). The combined organic phases are washed successively with saturated aqueous sodium chloride solution (50 cc). After drying over magnesium sulphate, filtration and concentration to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C., N-propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (0.43 g) is obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].CN(C=O)C.[O:43]([C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[S:53])=[CH:47][CH:46]=1)[CH3:44]>CC#N>[CH3:44][O:43][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([N:22]2[CH2:21][CH2:20][N:19]([C:17]3[S:18][C:14](=[CH:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]5[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:3]=5[C:2]([F:36])([F:1])[F:37])=[C:8]([O:26][CH3:27])[CH:9]=4)[C:15](=[O:25])[N:16]=3)[CH2:24][CH2:23]2)=[S:53])=[CH:47][CH:46]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(NC(=S)N2CCN(C3=NC(=O)C(=Cc4ccc(OCc5ccc(C(F)(F)F)cc5C(F)(F)F)c(OC)c4)S3)CC2)cc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
To a N2 purged flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (120 mg, 220 μmol) from Example 23, DMF (8 mL) and MeCN (8 mL). To the reaction solution was added 4-methoxylphenyl isothiocyanate (55 mg, 330 μmol). The reaction was stirred at 55° C. for 20 h and LC analysis should product was formed. The reaction solution was concentrated under reduced pressure and then taken into EtOAc (100 mL), washed with aq. NH4Cl (70 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed using reverse phase preparative HPLC, H2O/MeCN gradient 90:10 to 10:90) to provide the title compound as a white solid (24 mg, 13% yield). 1H NMR (DMSO-d6) δ 8.17 (1H, d, J=8.1 Hz), 8.11 (1H, s), 8.02 (1H, d, J=8.1 Hz), 7.64 (1H, s), 7.15-7.23 (5H, m), 6.88 (2H, d, J=8.9 Hz), 5.42 (2H, s), 4.16 (2H, br s), 4.09 (2H, m), 4.03 (2H, m), 3.86 (3H, s), 3.80 (2H, m), 3.74 (3H, s); MS (ESI) 711 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[O:7]=[CH:8][C:9]([Cl:12])([Cl:11])[Cl:10].O>C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:8]([OH:7])[C:9]([Cl:12])([Cl:11])[Cl:10]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cn1cccc1
Solvent: c1ccccc1
Solvent: O
Product: Cn1cccc1C(O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of N-methylpyrrole (810 mg, 10 mmol) dissolved in benzene (10ml) was added dropwise a solution of chloral (1.47 g, 10 mmol) dissolved in benzene (5 ml) under ice-cooling for 40 minutes. After the mixture was stirred for 1 hour at room temperature, water was added thereto and the mixture was extracted with ether. The extract was dried over sodium sulfate and concentrated to afford 1-methyl-2-(2',2',2'-trichloro-1'-hydroxyethyl)pyrrole (2.04 g) as an oil.
Reaction SMILES: [CH2:1]([N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34]>O1CCCC1>[CH2:1]([N:4]([CH2:5][C:6]([N:32]([O:33][CH3:34])[CH3:31])=[O:8])[C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:2]=[CH2:3]
Reactant: CNOC
Reactant: C=CCN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
2-(Allyl(tert-butoxycarbonyl)amino)acetic acid (49.6 g, 156 mmol) is added to tetrahydrofuran (600 mL) at 0° C. followed by the addition of triethylamine (36.3 g, 359 mmol) and pivaloyl chloride (31 g, 353 mmol). The reaction is stirred at room temperature for 3 hours and then cooled to 0° C. N,O-dimethylhydroxylamine hydrochloride (28 g, 283 mmol), triethylamine (33 mL, 237 mmol) and tetrahydrofuran (400 mL) are then added. The ice bath is removed and the reaction stirred at room temperature for 3 hours and concentrated under reduced pressure. The resulting solid is dissolved in water and extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give a residue. The residue is purified by silica gel column chromatography, eluting with 0-50% gradient of acetone in hexanes to give the title compound (32 g, 54%). 1H NMR (CDCl3) mixture of two rotamers (60:40) δ 1.42, 1.44 (s, 9H), 3.16, 3.17 (s, 3H), 3.66, 3.69 (s, 3H), 3.88-3.98 (m, 2H), 4.01, 4.11 (s, 2H), 5.10-5.18 (m, 2H), 5.73-5.85 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:18](=[O:20])[CH3:19])=[CH:5][S:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:15]2CC[CH2:12][CH2:11][C:10]=2[CH:9]=1.[O:21]1C2C=CC(C3SC=C(C#N)C=3OC)=CC=2CC1>>[O:21]1[C:15]2[CH:16]=[CH:17][C:8]([C:7]3[S:6][CH:5]=[C:4]([C:18](=[O:20])[CH3:19])[C:3]=3[O:2][CH3:1])=[CH:9][C:10]=2[CH2:11][CH2:12]1
Reactant: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCCC2
Reactant: COc1c(C#N)csc1-c1ccc2c(c1)CCO2
Product: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCO2
Yield: 87 %

Procedure:
Synthesis was carried out in the same manner as in Synthesis Method 2 (5) in Reference Synthetic Example 3 by using 2.6 g (0.0101 mol) of 5-(2,3-dihydro-benzofuran-5-yl)-4-methoxythiophene-3-carbonitrile to obtain 2.29 g of the desired product (yield: 87%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([O-:21])=[O:20])=[C:6]([CH2:9][N+:10]3[N:11]([CH3:18])[CH:12]=[C:13]([NH:15][CH:16]=[O:17])[CH:14]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[NH2:32][C:33]1[S:37][N:36]=[C:35](/[C:38](=[N:46]/[O:47][CH2:48][C:49]([OH:51])=[O:50])/[C:39](OS(C)(=O)=O)=[O:40])[N:34]=1.C(OC(C)C)(C)C>O1CCCC1>[NH2:32][C:33]1[S:37][N:36]=[C:35]([C:38](=[N:46][O:47][CH2:48][C:49]([OH:51])=[O:50])[C:39]([NH:1][C@@H:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([O-:21])=[O:20])=[C:6]([CH2:9][N+:10]4[N:11]([CH3:18])[CH:12]=[C:13]([NH:15][CH:16]=[O:17])[CH:14]=4)[CH2:7][S:8][C@H:3]23)=[O:40])[N:34]=1
Reactant: CS(=O)(=O)OC(=O)/C(=N\OCC(=O)O)c1nsc(N)n1
Reactant: Cn1cc(NC=O)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)N[Si](C)(C)C
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: Cn1cc(NC=O)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of di(trifluoroacetic acid) salt of 7β-amino-3-(4-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (4.0 g) and N-(trimethylsilyl)acetamide (9.29 g) in tetrahydrofuran (60 ml) was added methanesulfonyl (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetate (2.07 g) under ice-cooling. The mixture was stirred for 1 hour at ambient temperature and then the resulting mixture was added dropwise to diisopropyl ether. Thus produced precipitate was collected by filtration, dissolved in water and then subjected to column chromatography on macroporous non-ionic adsorption resin, Diaion HP-20 (Trademark: manufactured by Mitsubishi Chemical Industries). The desired product was eluted with 10% aqueous isopropyl alcohol solution, and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3- (4-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer 0.714 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22](O)([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[FH:40].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:40])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 42 °C
Reaction time: 9 h

Procedure:
To a solution of 186 mg (0.368 mmol) of 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile in 3 mL of CH2Cl2 1 mL of hydrogen fluoride-pyridine was added and it was stirred for 9 h at 42° C. Then the reaction mixture was poured to 7 mL of 5N NaOH, 7 mL of ag NaHCO3 and 30 mL of CH2Cl2. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid; 1NMR (CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.24 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=478 (M+1 35Cl, 35Cl) and 480 (+1 35Cl, 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12]Br)=[CH:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([C:21]2([O:29][CH3:30])[CH2:26][CH:25]([CH3:27])[O:24][CH:23]([CH3:28])[CH2:22]2)[CH:18]=[CH:19][CH:20]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:14][C:15]3[CH:16]=[C:17]([C:21]4([O:29][CH3:30])[CH2:26][CH:25]([CH3:27])[O:24][CH:23]([CH3:28])[CH2:22]4)[CH:18]=[CH:19][CH:20]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC1(c2cccc(O)c2)CC(C)OC(C)C1
Reactant: Fc1ccc2ccc(CBr)cc2c1
Product: COC1(c2cccc(OCc3ccc4ccc(F)cc4c3)c2)CC(C)OC(C)C1
Yield: 77 %

Procedure:
Using the procedure described in Example 5, 7-fluoro-2-bromomethylnaphthalene (0.5 g) was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (0.45 g, more polar isomer) to give 4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2,6-dimethyltetrahydropyran (0.74 g, 77%), as an oil which crystallised on standing, m.p. 77° C.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH:16]=[O:17].[CH2:18]([O:20][C:21]([CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)[CH3:19]>CO.C(O)C>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[C:16](=[O:17])[CH:19]=[CH:18][O:20][CH2:21][CH3:23]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC=CC(=O)c1c(Cl)ccc2cc(Cl)cnc12
Reaction time: 3 h

Procedure:
36 ml of a 15% strength solution of sodium methylate in methanol were added dropwise, at 20° C., to a suspension of 22.6 g of 3,7-dichloro-8-formylquinoline and 38.4 g of ethoxycarbonylmethyl-triphenyl-phosphonium chloide in 200 ml of ethanol. The mixture was stirred for 3 hours, after which the precipitate was filtered off under suction, washed with water and dried.