Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8].C1C[O:22][CH2:21]C1.[H-].C([Al+]CC(C)C)C(C)C.ClC(OC)=O.CC(C)([O-])C.[K+]>>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:10]([CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[C:21](=[O:22])[N:8]=[CH:7]2
Reactant: N#Cc1cc(Br)ccc1NCCN1CCOCC1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: COC(=O)Cl
Product: O=c1ncc2cc(Br)ccc2n1CCN1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-bromo-2-(2-morpholinoethylamino)benzonitrile (0.5521 g, 1.8 mmol) in THF (0.13 g, 1.8 mmol) was added bis(iso-butyl)aluminum hydride (2.4 ml, 3.6 mmol) at 0° C. and the resulting bright yellow-orange solution was stirred at 0° C. for 1 h. Methyl chloroformate (0.17 ml, 2.1 mmol) was added to the reaction at 0° C. The mixture was stirred at RT for 2 h, then treated with potassium tert-butoxide 1M THF (3.6 ml, 3.6 mmol) and heated to 60° C. for 5 h. After cooling, the reaction was quenched with NH4Cl(aq) and water (10 mL each) and the separated aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated to give a crude residue. Flash column chromatographic purification (eluting with 100% DCM to 3% MeOH in DCM gradient) provided 6-bromo-1-(2-morpholinoethyl)quinazolin-2(1H)-one as a sticky colorless oil. MS m/e 338 (M+H)+.
Reaction SMILES: [CH2:1]([O:3]C(C1C=CC=CC=1)C=O)C.[CH2:13]([O:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:18]=[O:19])[CH2:14][CH3:15]>>[CH2:13]([O:16][C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:1][OH:3])[CH2:18][OH:19])[CH2:14][CH3:15]
Reactant: CCOC(C=O)c1ccccc1
Reactant: CCCOC(C=O)c1ccccc1
Product: CCCOC(CO)(CO)c1ccccc1

Procedure:
The procedure in Example 6 was repeated except that 2-ethoxy-2-phenylethanal was replaced with 2-propoxy-2-phenylethanal, to obtain 2-propoxy-2-phenyl-1,3-propanediol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])[CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Temperature: 100 °C
Yield: 77.9 %

Procedure:
A mixture of 2.42 g of 2,6-dimethylaniline, 7.35 g of hexafluoroacetone hydrate, and 0.04 g of p-toluenesulfonic acid monohydrate was stirred under heating at 100° C. for 5 hours. After the temperature was returned to room temperature, the mixture was diluted with ethyl acetate and washed with a 1N sodium hydroxide aqueous solution. Then, the solvent was distilled off under reduced pressure, and the precipitated crude crystals were washed with a n-hexane-ethyl acetate mixed solvent to obtain 4.47 g (yield 78%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH2:10]([NH:13][OH:14])[CH2:11][CH3:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:3]2[O:2][C:11]([CH:10]=[N+:13]([CH2:5][CH2:6][CH3:7])[O-:14])=[CH:12][CH:4]=2)=[CH:5][CH:4]=1
Reactant: CCCNO
Reactant: COc1ccc(S)cc1
Product: CCC[N+]([O-])=Cc1ccc(Sc2ccc(OC)cc2)o1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 4-methoxybenzenethiol and N-n-propylhydroxylamine. The title compound was isolated in 76.6% yield as slightly yellowish crystals, m.p. 63.0° C. (Rf =0.17 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:14]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]3([CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22]3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].ClC1C=CC(Cl)=CC=1Cl.[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>CC(C)=O>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]3[CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22][C:12]3=[C:13]([S:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C2=NC3(C=CC(=O)C=C3)C(Sc3ccccc3)=C2)CC1
Agent: O=C(O)C(=O)O
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Product: C=CCN1CCN(c2cc(Sc3ccccc3)c3ccc(=O)ccn23)CC1
Yield: 41.6 %

Procedure:
By working as in Example 5, but starting with 2-(4-allyl-1-piperazinyl)-4-phenylthio-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (15.2 g) and 1,2,4-trichlorobenzene (150 cc), a residue is obtained which is redissolved in chlorofrom (300 cc). The solution obtained is poured into silica (300 g) contained in a column 4.2 cm in diameter. Elution is first performed with chloroform (1 liter) and this eluate is rejected. Elution is then performed with a mixture of chloroform and methanol (90:10 by volume) (3 liters) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in acetone (15 cc). Oxalic acid (1.9 g), dissolved in acetone (15 cc), is added to the solution obtained. The precipitate formed is separated by filtration and washed with ethyl ether (10 cc). 3-(4-Allyl-1-piperazinyl)-1-phenylthio-7H-pyrrolo[1,2-a]azepin-7 -one dioxalate (2.45 g), m.p. 225° C., is thereby obtained.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+].[F-].[Cs+]>COCCOC.O>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=3)[S:10][C:9]=12
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CO)cc4)sc23)c(F)c1
Yield: 81.9 %

Procedure:
To a solution of 42 (1.0 g, 2.71 mmol) in dry DME (20 ml) was added 4-(hydroxymethyl)phenylboronic acid (823 mg, 5.4 mmol), NaHCO3 (682 mg, 8.13 mmol), CsF (820 mg, 5.4 mmol) and water (10 mL) and the reaction mixture was refluxed under nitrogen for 2 hrs. After cooling to room temperature the DME was removed under reduced pressure, the residue was dissolved in EtOAc and the organic solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The resultant solid residue was triturated with Et2O to afford the title compound 51 as a white solid (880 mg, 82% yield). MS (m/z): 397.1 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][OH:23])[CH2:17]1.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:23][CH2:22][CH:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:17]1
Reactant: O=Cc1ccccc1F
Reactant: OCC1CCCNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1N1CCCC(CO)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
2-Fluorobenzaldehyde (3.26 mL, 30.0 mmol), potassium carbonate (5.64 g, 40.0 mmol) and tetrabutylammonium iodide (739 mg, 2.00 mmol) were added to 3-piperidylmethanol (2.30 g, 20.0 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at 130° C. for 8 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=5:1->1:1) gave 1.56 g (36%) of the desired compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35](OSC1C=CC=CC=1[N+]([O-])=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH2:35]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=[N+]([O-])c1ccccc1SOCc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
A mixture of 2.09 g. of N-benzyloxycarbonylglycine, 2.62 g. of triphenyl phosphine, 2.61 g. of 2-nitrobenzenesulfenic acid benzyl ester, 2.20 g. of 2,2'-dipyridyl disulfide and 50 ml. of methylene chloride is stirred at room temperature for 3 hours. The reaction mixture is washed successively with water, saturated aqueous sodium bicarbonate, water, 0.1 N hydrochloric acid and water and then dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is dissolved in methylene chloride. The solution is subjected to column chromatography using silica gel and eluted with methylene chloride. Distillation of the solvent from the eluate gives 2.51 g. of the desired product melting at 72°C.
Reaction SMILES: C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)C=1CCC(OCC)=O)C.[CH2:49]([O:51][C:52](=[O:93])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:75]=[C:74]([C:76]([N:78]3[CH2:82][CH2:81][C:80]([F:84])([F:83])[CH2:79]3)=[O:77])[CH:73]=[C:72](Br)[CH:71]=2)[C:58]=1[CH2:86][CH2:87][C:88]([O:90][CH2:91][CH3:92])=[O:89])[CH3:50].[S:94]1[CH:98]=[CH:97][C:96](B(O)O)=[CH:95]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.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]>[CH2:49]([O:51][C:52](=[O:93])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:71]=[C:72]([C:96]3[CH:97]=[CH:98][S:94][CH:95]=3)[CH:73]=[C:74]([C:76]([N:78]3[CH2:82][CH2:81][C:80]([F:84])([F:83])[CH2:79]3)=[O:77])[CH:75]=2)[C:58]=1[CH2:86][CH2:87][C:88]([O:90][CH2:91][CH3:92])=[O:89])[CH3:50]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N3CCC(F)(F)C3)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 78.9 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 4-[3-{6-[3-bromo-5-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (114 mg, 0.163 mmol), thiophen-3-ylboronic acid (42.57 mg, 0.326 mmol), PdCl2(dppf) (17.94 mg, 0.025 mmol) and cesium carbonate (107.5 mg, 0.326 mmol) in dimethoxyethane (3.7 mL) to obtain 4-[3-{6-[3-(3,3-difluoro-pyrrolidine-1-carbonyl)-5-thiophen-3-yl-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (90 mg, 79%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=O.[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH2:27])[S:25][CH:26]=1>>[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH:27][C:18](=[O:20])[CH2:17][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([O:12][C:13]([F:16])([F:15])[F:14])[CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:26]=1
Reactant: O=C(O)Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid (79 mg, 0.275 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (35 mg, 0.137 mmol) according to protocol A. Retention time (min)=6.037, method [7], MS(ESI) 514.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.15 (s, 1H), 8.11 (d, J=9.9 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.41 (s, 1H), 7.26 (m, 1H), 7.10 (s, 1H), 6.81 (d, J=9.9 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: II.[Mg].Br[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[N:10]1([C:14]2(C#N)[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11]1>C(OCC)C.C1COCC1.CCOC(C)=O.CCCCCC>[S:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:14]1([N:10]2[CH2:11][CH2:12][CH2:13]2)[CH2:23][CH2:22][C:17]2([O:18][CH2:19][CH2:20][O:21]2)[CH2:16][CH2:15]1
Reactant: N#CC1(N2CCC2)CCC2(CC1)OCCO2
Reactant: Brc1cccs1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1csc(C2(N3CCC3)CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A catalytic amount of iodine was added to magnesium (5.1 g) in 50 ml diethyl ether. After 10 minutes a solution of 2-bromothiophene (5.7 g) in 10 ml THF was added to this reaction mixture. Once the Grignard reaction had started, 2-bromothiophene (15 ml) dissolved in 50 ml THF was added dropwise and on completion of the addition the mixture was stirred for two hours at room temperature. 8-Azetidin-1-yl-1,4-dioxaspiro[4,5]decane-8-carbonitrile (12 g) dissolved in 60 ml THF was added dropwise to this reaction mixture at 60-70° C. under a nitrogen atmosphere. Then the reaction mixture was stirred for 1 hour at room temperature and the reaction progress was monitored by thin-layer chromatography (50% EtOAc/hexane). Once the conversion was complete the reaction mixture was cooled to 0° C., quenched with saturated ammonium chloride solution (50 ml) and then extracted with ethyl acetate (2×100 ml). The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica, 5-10% EtOAc/hexane). The desired product was obtained as a brown solid (10.2 g, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[O:11][C:10]([C:13](Cl)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[NH2:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:12]2[O:11][C:10]([C:13]([NH:16][C:17]3[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=3[C:22]([NH2:24])=[O:23])=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CCOc1cccc2cc(C(=O)Cl)oc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1cc2cccc(OCC)c2o1

Procedure:
From 7-ethoxybenzofuran-2-carbonyl chloride (4.124 g, 20 mmol), 1 (1.82 g, 10 mmol), DMAP (32.5 mg, 0.27 mmol) and Et3N (2.02 g, 20 mmol) in anhydrous CH2Cl2 (65 mL) using the same procedure as for 3 the title compound was obtained as?a white solid; mp: 219-221° C.; 1H NMR (DMSO-d6) δ 0.86 (t, J=7 Hz, 3 H), 1.43 (t, J=7 Hz, 3 H), 1.56 (sxt, J=7 Hz, 2 H), 2.42 (t, J=7 Hz, 2 H), 3.91 (s, 3 H), 4.28 (q, J=7 Hz,2 H), 7.10 (d, J=6 Hz, 1 H), 7.26 (t, J=6 Hz, 1 H), 7.35 (d, J=6 Hz, 1 H), 7.50 (s, br. 1 H), 7.71 (s, 1 H), 7.76 (s, br. 1 H); MS (m/z): 371 (MH+).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([C:9]1[CH2:13][CH2:12][C:11](=O)[CH:10]=1)([CH3:8])([CH3:7])[CH3:6].Cl>C(OCC)C>[CH2:1]([C:12]1[CH2:11][CH:10]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH:13]=1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)C1=CC(=O)CC1
Agent: Cl
Solvent: CCOCC
Product: CCC1=CC(C(C)(C)C)=CC1
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, a 300 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock was charged with 200 ml of dehydrated diethyl ether and 52 ml (154 mmol) of diethyl ether solution of 3.0M ethyl magnesium bromide. In an ice-water bath, 17.8 g (129 mmol) of 3-tert-butylcyclopentenone was added dropwise over 1 hour and the resultant solution was further stirred at room temperature for 20 hours. Then, the reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was subjected to extraction with 50 ml of ether twice. The organic layers obtained were combined with the organic layer previously obtained, and the liquid was washed two times with a saturated aqueous solution of sodium hydrogencarbonate, two times with water, and once with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and then the residue was purified by column chromatography to obtain 20.2 g of a pale yellowy clear solution (75% GC purity). The yield was 78%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][C:16](C(O)=O)([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:32]=[N+]=[N-])=O)=CC=1.C(N(CC)CC)C.[Si](O[K])(C)(C)C>C1(C)C=CC=CC=1.C1COCC1>[NH2:32][C:16]12[CH2:19][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: O=C(NC12CCCC(C(=O)O)(CC1)C2)OCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)O[K]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC12CCCC(NC(=O)OCc3ccccc3)(CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid (8.5 g, 28.0 mmol), diphenylphosphonic azide (9.3 g, 33.8 mmol) and triethylamine (5 mL, 68 mmol) in toluene (150 mL) was stirred at room temperature for one hour, and then refluxed for three hours. After cooled to 0° C., a solution of TMSOK (10.7 g, 83.6 mmol) in THF (85 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 h, and then quenched with 5% citric acid (20 mL) and concentrated under reduced pressure. The residue was treated with aq. HCl (2 N, 200 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×100 mL). The aqueous phase was adjusted to pH 9˜10 with Na2CO3 and extracted with dichloromethane/methanol (10/1, 3×150 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford 5.13 g (42%) of benzyl 5-aminobicyclo[3.2.1]octan-1-ylcarbamate as a yellow solid. ESI-MS m/z: 275 (M++1).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:35]([NH:37][C:38]1[S:39][C:40]([Br:50])=[C:41]([C:43](=[N:47][O:48][CH3:49])[C:44](O)=[O:45])[N:42]=1)=[O:36]>C(OCC)(=O)C.CN(C)C=O>[CH:35]([NH:37][C:38]1[S:39][C:40]([Br:50])=[C:41]([C:43](=[N:47][O:48][CH3:49])[C:44]([NH:1][CH:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]4[NH:13][N:14]=[N:15][N:16]=4)[CH3:10])[CH2:7][S:8][C@H:3]23)=[O:45])[N:42]=1)=[O:36]
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nc(NC=O)sc1Br
Yield: 41.8 %

Procedure:
A solution of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (660 mg.) and trimethylsilylacetamide (1.3 g.) in dry ethyl acetate (23 ml.) and a mixture of dimethylformamide (0.2 ml.), phosphoryl chloride (0.24 ml.), dry ethyl acetate (10 ml.) and 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 740 mg.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 520 mg.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)[CH3:2].[Mg].II.[CH2:15]([O:22][C:23]1[CH:36]=[CH:35][C:26]([CH:27]=[N:28][CH2:29][CH:30]([O:33][CH3:34])[O:31][CH3:32])=[CH:25][C:24]=1[O:37][CH3:38])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C.O>[CH2:15]([O:22][C:23]1[CH:36]=[CH:35][C:26]([CH:27]([NH:28][CH2:29][CH:30]([O:31][CH3:32])[O:33][CH3:34])[CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[CH:25][C:24]=1[O:37][CH3:38])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOc1cccc(CCl)c1
Reactant: COc1cc(C=NCC(OC)OC)ccc1OCc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CCOc1cccc(CC(NCC(OC)OC)c2ccc(OCc3ccccc3)c(OC)c2)c1
Reaction time: 1 h

Procedure:
3-Ethoxybenzylchloride (13.6 g, 80 mmol) was dissolved in diethyl ether (100 mL) and magnesium metal (2.04 g, 84 mmol) was added without stirring. Several crystals of iodine were added to the magnesium “pile”. When the reaction begins, stirring is started and external cooling is applied as necessary to maintain gentle refluxing. Once the initial reaction was complete, the mixture was refluxed for 1 h to complete the reaction. The resulting gray/green mixture was cooled in an ice-bath and (4-benzyloxy-3-methoxy-benzylidene)-(2,2-dimethoxy-ethyl)-amine (13.2 g, 40 mmol) in diethyl ether (60 mL) was added dropwise (a precipitate forms with each drop). After addition was complete, the resulting suspension was heated at reflux for 2 hours. The mixture was cooled in an ice-bath and saturated aqueous ammonium chloride solution (100 mL) was carefully added dropwise. The mixture was stirred at 0° C. for 15 minutes and then room temperature for 1 h. Water (80 mL) was added, and the mixture was filtered. The organic layer was separated, washed with water (50 mL), saturated aqueous sodium chloride solution (40 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford [1-(4-benzyloxy-3-methoxy-phenyl)-2-(3-ethoxy-phenyl)-ethyl]-(2,2-dimethoxy-ethyl)-amine as a light tan solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH3:21])=[N:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.[Cl-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH3:21])[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN=C2C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CCNC2C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
To a solution of 249 (949 mg, 3.4 mmol) in EtOH (15 ml) at 0° C. was added sodium borohydride (256 mg, 6.8 mmol) portionwise. The reaction mixture was stirred at rt for 1.5 h. Water (100 ml) was added and the aqueous layer was neutralised. The aqueous layer was saturated with sodium chloride and extracted with EtOAc (3×100 ml). The combined organic layers were washed with sat. aq. sodium hydrogen C(Ar)bonate (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (600 mg, 63%) a yellow oil. 1H NMR (400 MHz; DMSO-d6) 1.58 (3H, d, J=6.4 Hz, CH3CH), 2.50 (2H, s, CH2), 2.82-2.95 (2H, m, CH2), 3.76 (3H, s, OCH3), 4.42 (1H, q, J=6.4 Hz, CH3CH), 5.06 (2H, s, CH2Ph), 6.86 (1H, s, CH), 6.88 (1H, s, CH), 7.31-7.44 (5H, m, 5×CH, phenyl), 9.40 (1H, brs, NH). LC/MS (ES+) tr=0.73 min, m/z 284.13 (M++H).