Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[F:15][C:16]1[C:21](/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[F:15][C:16]1[C:21]([CH:22]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=3)[NH:12][CH:11]=2)[CH2:23][N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Nc1cccc(/C=C/[N+](=O)[O-])c1F)OCc1ccccc1
Reactant: COCCOc1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(C[N+](=O)[O-])c3cccc(NC(=O)OCc4ccccc4)c3F)c[nH]c2c1
Temperature: 125 °C
Yield: 69.2 %

Procedure:
6-(2-Methoxyethoxy)-1H-indole (1.198 g, 6.26 mmol) and (E)-benzyl 2-fluoro-3-(2-nitrovinyl)phenylcarbamate (1.651 g, 5.22 mmol) were dissolved in THF (50 mL) and concentrated in vacuo, and the mixture was heated at 125° C. overnight. The reaction was cooled to room temperature, and the crude product was purified by flash chromatography (solid loading) using an ISCO 220 g column eluting with 15-75% EtOAc/hexanes to give the desired product (1.888 g, 3.61 mmol, 69.2% yield) as a light orange foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:42])[CH2:13][N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(CCc3ccc(-c4ccccc4)cc3)sc2N1
Solvent: Cc1ccccc1
Product: S=C1CN=C(c2ccccc2Cl)c2cc(CCc3ccc(-c4ccccc4)cc3)sc2N1
Yield: 131.5 %

Procedure:
A suspension of 7.2 g of 5-(2-chlorophenyl)-7-[2-(4-phenylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 187°-189° C. and 3.9 g of Lawesson reagent in 100 ml of toluene is stirred at 58°-60° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 6 g of 5-(2-chlorophenyl)-7-[2-(4-phenylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 190°-191° C. with decomposition.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:11]([S:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)([CH2:14][CH2:15][CH2:16][N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=3)[CH2:18]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1OC.[ClH:39].[CH2:40]([O:42][CH2:43][CH3:44])C>C(O)C>[ClH:39].[CH3:40][O:42][C:43]1[CH:44]=[C:19]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=2[C:11]([S:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)([CH2:14][CH2:15][CH2:16][N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=3)[CH2:18]2)[C:12]#[N:13])[CH:20]=[CH:21][C:22]=1[O:27][CH3:28]
Reactant: COc1ccc(C(C#N)(CCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccccc2C(C#N)(CCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Reaction time: 15 h

Procedure:
To a solution of 1.43 g of α-(3,4-dimethoxyphenyl)-3,4-dihydro-6,7-dimethoxy-α-[(4-methylphenyl)thio]-2(1H)-isoquinolinepentanenitrile in 40 mL of diethyl ether, with stirring, is added 0.617 mL of a 4.71M solution of hydrogen chloride in absolute ethyl alcohol. The reaction mixture is then stirred for 15 hours while sealed. The title product is then collected by filtration, washed with ether, and dried under vacuum to give 1.32 g of the desired product as pink crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=O.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12]>>[CH2:9]([NH:13][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN
Reactant: O=C(O)c1ccco1
Product: CCCCNCc1ccco1

Procedure:
The desired amine was prepared using the method described in Example 1171A starting with 2-furoic acid and butylamine.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:6]2[N:5]=[CH:4][N:3]=1>C(O)(=O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C#CCCO)ccc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Nc1ncnn2c(CCCCO)ccc12
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a dry flask purged with N2 was added platinum(IV) oxide (440 mg, 1.93 mmol) followed by 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)but-3-yn-1-ol (1.30 g, 6.43 mmol) as a solution in acetic acid (50 mL). The mixture was stirred under an H2 atmosphere for 16 h. The mixture was filtered through a pad of Celite®, rinsing with acetic acid and ethanol. The solvent was evaporated under reduced pressure and the residue was taken up in EtOAc (100 mL). The organic was washed with saturated aqueous NaHCO3 (1×100 mL) and the aqueous phase was back extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness to afford the 1.2 g (91%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.77 (s, 1 H), 7.52 (br s, 2 H), 6.78 (d, 1 H), 6.39 (d, 1 H), 4.36 (br s, 1 H), 3.39 (t, 2 H), 2.81 (t, 2H), 1.72-1.61 (m, 2 H), 1.50-1.41 (m, 2 H); ES-MS m/z 207.2 [M+H]+, HPLC RT (min) 1.11.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](N)=[O:22])=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:25].C1(OC)C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:25])=[O:22])=[CH:18][CH:19]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1nnc2ccc(Oc3ccc(CC(N)=O)cc3)cn12
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)c1nnc2ccc(Oc3ccc(CC(=O)O)cc3)cn12

Procedure:
A solution of Example 23 step b (44 mg, 0.12 mmol), TFA (1 mL) and anisole (1 mL) in DCM (1 mL) was stirred at RT for 1 H, then evaporated in vacuo. The resulting residue was suspended in diethyl ether (3 mL), filtered and dried in vacuo to give the title compound (38 mg, quant.). LCMS (Method 5): Rt 3.65 min, m/z 312 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9](=[O:16])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:17][Mg]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([CH3:17])([OH:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[Mg]Cl
Reactant: O=C1CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Solvent: C1CCOC1
Product: CC1(O)CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.3 %

Procedure:
To a solution of 6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.4 mmol) in anhydrous THF (5 mL) cooled to 0° C., MeMgCl (1.3 mL, 3.95 mmol, 3M in THF) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 5 h, cooled to 0° C., and then quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure to give the crude material which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to give the title compound as a pale brown solid (0.01 g, 10%). 1H NMR (500 MHz. DMSO-d6, δ in ppm) 7.75 (s, 1H), 7.60 (s, 1H), 5.96 (s, 1H), 5.15 (s, 1H), 2.19-2.17 (m, 1H), 2.0-1.82 (m, 2H), 1.62-1.59 (m, 1H), 1.45 (s, 3H), 1.43-1.41 (m, 1H), 0.98-1.11 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:22])([O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH3:21])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1ccccc1OC(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): δ 7.14-7.11 (m, 3H), 7.06 (t, 1H, J=7.82 Hz), 6.91 (t, 1H, J=7.82 Hz), 6.79 (d, 1H, J=8.60 Hz), 6.75 (d, 2H, J=8.60 Hz), 4.11 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.18 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.26 Hz), 2.90-2.87 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 2.02-1.99 (m, 2H), 1.81-1.78 (m, 2H), 1.71-1.68 (m, 1H), 1.58-1.52 (m, 2H), 1.47 (s, 3H), 1.38-1.21 (m, 5H). MS [ES+] m/z exact mass calcd for C29H36NO5 478.2593, found 478.2611.
Reaction SMILES: BrC1C=CC=C(Br)C=1O.[C:10]([CH:15]([CH2:19][CH:20]=[CH2:21])[CH2:16]C=C)([O:12][CH2:13][CH3:14])=[O:11]>O(Cl)Cl.[W].C1(C)C=CC=CC=1>[CH:15]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16][CH:21]=[CH:20][CH2:19]1
Reactant: C=CCC(CC=C)C(=O)OCC
Agent: [W]
Agent: ClOCl
Agent: Oc1c(Br)cccc1Br
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=CC1
Temperature: 90 °C
Yield: 71.1 %

Procedure:
A flame-dried 500 mL flask was charged with 2,6-dibromophenol (1.20 g, 4.76 mmol), tungsten oxychloride (0.813 g, 2.38 mmol), and anhydrous toluene (25 mL). The resulting suspension was heated at reflux under nitrogen for 1 h, and then the solvent was evaporated in vacuo. The solid residue was broken up with a spatula and dried in vacuo for 30 min. To the residue were added toluene (160 mL), Et4Pb (1.54 g, 4.76 mL), and 702 (22 g, 131.0 mmol). The mixture was heated at 90° C. under nitrogen for 1.5 h. After being cooled to r.t., the mixture was filtered through a celite, and the celite was rinsed with t-BuOMe. The combined filtrates were washed with 1% NaOH soln, water, and brine, and concentrated by evaporation at reduced pressure. The residue was distilled (37-38° C./1 Torr) to give 13.06 g (71%) of 703 as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.67 (s, 2H, CH═CH), 4.14 (q, 2H, J= 7.2 Hz, OCH2), 3.11 (pentuplet, J=7.6 Hz, 1H, CH), 2.65 (d, J=7.6 Hz, 4H, 2 CH2), 1.27 (t J=7.2 Hz, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:17](Cl)(Cl)=[O:18]>O1CCOCC1>[N:11]1([C:8]2[CH:7]=[C:3]3[C:2](=[CH:10][CH:9]=2)[NH:1][C:17](=[O:18])[NH:6][C:4]3=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)Cl
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1N
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)c2cc(N3CCCCC3)ccc2[nH]1
Yield: 91 %

Procedure:
2-Amino-5-piperidin-1-yl-benzamide (210 mg, 2.33 mmol) in dry dioxane (50 mL) was treated with 2N phosgene solution (1.28 mL in toluene). The resulting orange precipitate was heated to 80 C to give after 3 h, a pale yellow solid. The solution was cooled in an ice bath and the product was collect by filtration to give 6-Piperidin-1-yl-1H-quinazoline-2,4-dione 525 mg (91% yield) HPLC tr=3.6 min (85%), LCMS m/e 246.2 (M+H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([I:28])=[CH:23][N:22]=1>C(#N)C>[Cl:20][C:21]1[N:26]=[C:25]([NH:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:24]([I:28])=[CH:23][N:22]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: NCCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1ncc(I)c(NCCCN2CCOCC2)n1
Temperature: -35 °C
Reaction time: 1 h

Procedure:
In accordance with procedure 2, 3-morpholin-4-yl-propylamine (0.73 ml, 5 mmol) and N-ethyldiisopropylamine (1.71 ml, 10 mmol) are dissolved in 100 ml acetonitrile under argon and cooled to −35° C. The solution of 2,4-dichloro-5-iodo-pyrimidine (1.37, 5.0 mmol) in 50 ml acetonitrile is then added dropwise at −35° C. internal temperature. Stirred 1 hr further at −30 to −20° C., then slowly warmed up to RT and stirred for 3 days at RT.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:28])[C:17]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:21])[CH:18]([CH3:20])[CH3:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:28][CH:16]([C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[Cl:8])[C:17]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:21])[CH:18]([CH3:19])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(O)(c1cccnc1)C(O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1ccc(Cl)cc1Cl)C(O)(c1cccnc1)C(C)C
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
38.2 ml (0.4 mol) of acetic anhydride were added dropwise to a solution of 76 g (0.23 mol) of 1-(2,4-dichlorophenyl)-2-(3-pyridyl)-3-methylbutane-1,2-diol, 197.7 ml (1.318 mol) of triethylamine and about 0.5 g (4 mmol) of 4-N,N-dimethylaminopyridine in 1 1 of methylene chloride while heating at 35° C. After cooling to room temperature, the mixture was stirred for a further 30 minutes and then poured into 500 ml of a saturated sodium bicarbonate solution. The organic phase was separated off and was worked up in a conventional manner to obtain the product. The oily crude product was crystallized by stirring with ethyl acetate. Yield: 56%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]2[C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:4]2=[C:3]1[C:22]#[N:23].IC.[C:26](=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.CN(C)C=O>[CH3:26][N:7]1[C:2](=[O:1])[C:3]([C:22]#[N:23])=[C:4]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14](=[O:21])[C:5]2=[C:6]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1c2c(c(-c3ccccc3)[nH]c1=O)C(=O)c1ccccc1-2
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2ccccc2)c2c(c(C#N)c1=O)-c1ccccc1C2=O

Procedure:
A mixture of 25 parts of 3,9-dihydro-3,9-dioxo-1-phenyl-2H-indeno[2,1-c]pyridine-4-carbonitrile, 114 parts of iodomethane, 115 parts of potassium carbonate, and 475 parts of N,N-dimethylformamide is heated at 85° for 11/4 hours, then diluted with 1500 parts of water, followed by 100 parts of aqueous 5% sodium hydroxide. The deep tan precipitate which forms is filtered off, dried in air, and consecutively recrystallized from a mixture of chloroform and hexane, ethyl acetate, a mixture of ethyl acetate and chloroform, and acetonitrile to give 3,9-dihydro-2-methyl-3,9-dioxo-1-phenyl-2H-indeno-[2,1-c]pyridine-4-carbonitrile melting at approximately 255°-256°. The product has the formula ##STR15##
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[S:13]([NH:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)(=[O:15])=[O:14])=[CH:10][C:9]([Br:27])=[CH:8][CH:7]=2)=[O:3].Cl>CCOC(C)=O>[NH2:19][CH2:18][CH2:17][NH:16][S:13]([C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:27])[CH:10]=2)[NH:5][C:4]=1[C:2]([NH2:1])=[O:3])(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Reaction time: 0.75 h

Procedure:
Through a solution of the product from Example 62, Step B (113 mg, 0.245 mmols) in 20 mL of EtOAc at 0° C. was bubbled HCl gas for 3 minutes. The reaction was sealed, and stirring continued for 45 minutes. The solvent was removed in vacuo to give the titled compound. ESI+ MS: 361 [M+H]+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:14]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:60][O:61][CH3:62])[C:23]([NH:25][CH:26]2[C:58](=[O:59])[N:28]3[C:29]([C:34]([O:36][CH:37]([CH2:48][O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:35])=[CH:30][CH2:31][S:32](=O)[C@H:27]23)=[O:24])[N:21]=1)=[O:15].[I-].[Na+]>CC(C)=O>[CH:14]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:60][O:61][CH3:62])[C:23]([NH:25][CH:26]2[C:58](=[O:59])[N:28]3[C:29]([C:34]([O:36][CH:37]([CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:48][O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:35])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1)=[O:15]
Reactant: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1=CCS(=O)[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
2,2,2-Trifluoroacetic anhydride (2.12 g) was dropwise added to a stirred solution of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer, 2.34 g) and sodium iodide (1.56 g) in dry acetone (40 ml) at 0° to 5° C. over 45 minutes, and stirred at 0° to 5° C. for 2 hours. The resultant mixture was poured into ice water (200 ml), and then extracted with ethyl acetate (110 ml). The extract was washed with an aqueous solution of sodium thiosulfate, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and then dried over anhydrous magnesium sulfate. After evaporating the solution in vacuo, the residue was subjected to column chromatography, on silica gel (100 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder (1.57 g) of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4 -yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.57 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]([OH:12])[CH3:11])=[CH:4][CH:3]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.C(OCC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:10]([O:12][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
1.54 g of (2RS,3RS)-4-(4-bromophenyl)-3-(4-chlorophenyl)-2-butanol (prepared in the same manner as in Reference Example 1) was dissolved in 45 ml of dimethylformamide, and 1.4 g of tert-butyldimethylsilyl chloride and 1.2 g of imidazole were added thereto, followed by stirring at room temperature for one hour. Ethyl ether and water were added to the reaction solution for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to obtain 2.02 g (yield: 99%) of (2RS,3SR)-4-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)-3-(4-chlorophenyl)butane.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:19](/[CH:20]=[CH:21]/[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][CH2:16][C:15]1=[O:29]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH:19]1/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCC(O)/C=C/C1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
Sodium borohydride (42 mg, 1.10 mmol), followed by MeOH (0.38 mL), was added to a solution of 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester (40 mg, 0.11 mmol) in CH2Cl2 (1.13 mL) at 0° C. The mixture was allowed to warm to rt. After 3 h at rt, the reaction was quenched with aqueous HCl (1.0M) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL) then dried (Na2SO4), filtered and concentrated in vacuo to afford 40 mg (99%) of the title compound.
Reaction SMILES: BrC1C=C[C:5]2[N:6]([CH2:16]CCCCC)[C:7]3[C:12]([C:13]=2C=1)=CC(Br)=CC=3.[Br:22][C:23]1[CH:41]=[CH:40][C:26]([N:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>>[CH3:16][N:6]1[CH:7]=[CH:12][CH:13]=[C:5]1[C:37]1[CH:36]=[C:35]2[C:34](=[CH:39][CH:38]=1)[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:26]1[CH:25]=[CH:24][C:23]([Br:22])=[CH:41][C:40]2=1
Reactant: CCCCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCn1c2ccc(Br)cc2c2cc(-c3cccn3C)ccc21

Procedure:
The compound of the present example was synthesized by the same method as described in example 1, except that 4.09 parts of 3,6-dibromo-9-hexyl-9H-carbazole (31) was used to substitute 4-bromo-N,N-diphenyl aniline.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([C:8](OC)=[O:9])[CH2:5][CH:4]1[C:12]([OH:14])=[O:13])[CH3:2].[Li+].[BH4-].O>C1COCC1>[CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH:4]1[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: CCC1CC(C(=O)OC)CC1C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1CC(CO)CC1C(=O)O
Temperature: -20 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of 2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid (8.34 g, 41.7 mmol, Preparation #11, Step A) in THF (208 mL) was added LiBH4 (0.907 g, 41.7 mmol) at about −20° C. The reaction mixture was stirred at about −20° C. for about 1 h. The reaction mixture was allowed to warm to about 25° C. then was stirred at about 25° C. for about 16 h. Additional LiBH4 (0.907 g, 41.7 mmol) was added. The reaction mixture was stirred at about 25° C. for about 4 h. Water (10 mL) was added slowly to quench the reaction. The solid was removed by vacuum filtration. The filtrate was concd under reduced pressure. The resulting residue was partitioned between water (50 mL) and DCM (3×50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid (7.29 g, 100%): LC/MS (Table 1, Method n) Rt=0.44 min; MS m/z: 173 (M−H)+.