Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=O)[O:6][CH:5]2O.[NH2:13][NH2:14]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:6])[NH:14][N:13]=[CH:5]2
Reactant: NN
Reactant: O=C1OC(O)c2cc(Br)ccc21
Solvent: CC(C)O
Product: O=c1[nH]ncc2cc(Br)ccc12

Procedure:
5-Bromo-3-hydroxyphthalide (49 gm) was slurred in 200 ml isopropanol. Hydrazine (20 ml) was added and the mixture refluxed for 2 hours. The reaction mixture was allowed to cool and the product filtered off, washed with isopropanol and dried. The product weighed 46.8 gm and melted at 280°-283° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH:17]([CH3:19])[CH3:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH:17]([CH3:19])[CH3:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)C1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC(C)[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a mixture of 2-chloro-4-[3-hydroxy-2-(1-methylethyl)-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]benzonitrile (300 mg) and acetic acid (0.68 mL) in acetonitrile (10 mL) was added sodium borohydride (103 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→-ethyl acetate), and recrystallized from hexane-ethyl acetate to give the title compound as colorless crystals (yield: 76 mg, 25%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][C:26]1[C:27]([N:32]([CH3:34])[NH2:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl.CO>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:33][N:32]([CH3:34])[C:27]3[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: Cc1cccnc1N(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cccnc1N(C)NC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -70 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) in EtOAc (20 mL). The solution was cooled to −70° C. and was treated consecutively with 3-methyl-2-(1-methylhydrazinyl)pyridine (0.135 g, 1.0 eq.), T3P (50% in EtOAc; 1.4 mL, 4 eq.) and DIPEA (0.6 mL, 6 eq.). The clear reaction mixture was stirred at −60° C. for 4 hr. The progress of the reaction was followed by TLC analysis using 2.5% MeOH in CH2Cl2 as mobile phase and visualizing under UV. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford a crude compound that was purified by column chromatography (60/120 mesh SiO2 and eluting with a MeOH:CH2Cl2 gradient). The desired compound started eluting with 0.3-0.4% MeOH in dichloromethane. Fractions containing the desired material were combined to obtain 0.21 g (yield: 40%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-methyl-N′-(3-methylpyridin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ=10.73 (s, 1H), 9.32 (s, 1H), 8.52 (s, 2H), 8.45-8.46 (d, J=4.4 Hz, 1H), 8.29 (s, 1H), 7.97-7.99 (d, J=8 Hz, 1H), 7.48-7.50 (d, J=10 Hz, 1H), 7.01-7.05 (m, 1H), 5.86-5.88 (d, J=10 Hz, 1H), 3.26 (s, 3H); LCMS for C20H14F9N6O [M+H]+ 525.35. found 525.19 (RT 3.31 min, purity 99.40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1.[C:17](O)([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:9][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:8]
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC(C)(C)C)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A mixture of 5-nitro-isophthalic acid monomethyl ester (D77) (5.0 g, 22.2 mmol, 1 equiv), tert-BuOH (8.2 g, 111 mmol, 5 equiv), EDAC.HCl (4.8 g, 25 mmol, 1.1 equiv) and DMAP (205 mg, 1.68 mmol, 0.07 equiv) dissolved in CH2Cl2 (50 ml) was stirred for 1 h at room temperature The mixture was then diluted with CH2Cl2 (50 ml), washed with 2N aqueous HCl solution (50 ml) and saturated aqueous NaHCO3 solution (50 ml), dried over MgSO4 and concentrated in vacuo to give of 5-nitro-isophthalic acid 1-tert-butyl ester 3-methyl ester (D78) (5.3 g, 85%) as a pale yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18]
Reactant: O=C1Nc2cccc3c2[C@@]1(CCCCO)CCC3
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1Nc2cccc3c2[C@@]1(CCCCBr)CCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
(S)-2a-(4-hydroxybutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (1.96 g, 8.0 mmol) was dissolved in acetonitrile (50 ml). Then, carbon tetrabromide (3.31 g, 10.0 mmol) and triphenylphosphine (2.72 g, 9.6 mmol) were added to the resulting solution and stirred at room temperature for four hours. The solvent was evaporated from the reaction mixture, and ethyl acetate, water and hydrochloric acid (1N) were added to the resulting residue. The reaction product was extracted with ethyl acetate, and the extracted product was washed with saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent. The resulting product was separated and purified by means of silica gel column chromatography, whereby 2.40 g (yield 97%) of the above-described object compound could be obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14]>>[F:10][C:7]1[CH:8]=[CH:9][C:2]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(F)ccc1F
Product: N#Cc1cc(F)ccc1OCC(F)(F)F

Procedure:
2,5-difluoro-benzonitrile was reacted with 2,2,2-trifluoro-ethanol according to the method of Example 84A to provide the title compound. MS (DCI/NH3) m/z 220 (M+1)+.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:21][CH:20]2[C@:15]([CH3:23])([CH2:16][CH2:17][C:18](=[O:22])[CH2:19]2)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:24])[CH2:8][CH2:7]1)([OH:3])=[O:2].CO.[CH3:27]CN=C=NCCCN(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:2][C:1]([C@@H:4]1[CH2:21][CH:20]2[C@:15]([CH3:23])([CH2:16][CH2:17][C:18](=[O:22])[CH2:19]2)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:24])[CH2:8][CH2:7]1)=[O:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@]12CCC(=O)CC1C[C@@H](C(=O)O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7α-carboxyandrostane-3,17-dione (680 mg) in CH2Cl2 (30 mL) at 0° C., MeOH (160 μL), DMAP (20 mg) and EDAC (800 mg) were added. After stirring overnight at room temperature, H2O was added and the mixture was extracted with CH2Cl2 (2×). The combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc 60/40) to give the title compound II-bc (500 mg, 70%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.63 (3H, s), 2.85 (1H, m), 2.50-0.75 (20H, m), 1.12 (3H, s), 0.86 (3H, s).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>C(OCC)(=O)C.C(OCC)C>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2ccccc2)C(=O)O)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Yield: 100 %

Procedure:
In a mixture of 50 ml of ethyl acetate and 50 ml of diethylether were dissolved under heating 7.4 g of 2,4-cis-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine and 4.0 g of N-p-toluenesulfonyl-D-phenylalanine. The solvent was concentrated by heating, 30 ml of diisopropyl ether was added thereto and the mixture was stirred. Precipitated crystals were removed and mother liquor was washed with a concentrated aqueous ammonia solution, dried and concentrated under reduced pressure. To the residue was added 4.0 g of N-p-toluenesulfonyl-L-phenylalanine, and 50 ml of ethyl acetate and 30 ml of diisopropyl ether were added thereto and dissolved by heating, the mixture was stirred at room temperature for 16 hours. Precipitated crystals were collected by filtration, washed with diisopropyl ether, and dried, to give 4.0 g of N-p-toluenesulfonyl-L-phenylalanine salt of (2R,4S)-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidine.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:15])[CH:8]=[CH:7]1)(C)(C)C.Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:6][CH:7]=[C:8]2[C:23]1[CH:24]=[CH:19][N:20]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:22]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cccc(Cl)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-7-chloro-1H-indole (prepared by TBDMS protection of 7-chloro-1H-indole using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 280 mg (34%).
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CC#N.O>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])[C:10]([CH2:9][NH2:8])=[CH:19]2
Reactant: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2ccccc2C(F)(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc2cc(CN)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure G using N-(4-methoxybenzyl)(8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine (1.1427 g, 2.62 mmol, 1 eq) and ammonium cerium(iv) nitrate (3.59 g, 6.55 mmol, 2.5 eq) in CH3CN—H2O (2:1, 12 mL). After purification, (8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine was obtained as brown syrup. 1H NMR (DMSO-d6) δ ppm 8.47 (1H, s), 7.91 (1H, d, J=7.4 Hz), 7.84 (1H, d, J=7.4 Hz), 7.67-7.81 (2H, m), 7.47-7.62 (3H, m), 3.46-3.70 (2H, m), 2.61 (3H, s), 1.86 (2H, br. s.). Mass Spectrum (ESI) m/e=317.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21](O)=[O:22])[CH:14]=[N:13]2)[CH2:8][C@@H:7]1[CH3:24])=[O:5])[CH3:2].C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl.CN(C=O)C>[Cl:28][C:21]([C:15]1[CH:14]=[N:13][N:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C@@H:7]([CH3:24])[CH2:8]2)[C:16]=1[C:17]([F:20])([F:19])[F:18])=[O:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@@H]1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)Cl)c2C(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a light-yellow clear solution of 1-((1S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid with its (1R,3R,4R)-isomer (0.3128 g, 0.898 mmol) in DCM (8.98 ml) was added oxalyl chloride (0.095 ml, 1.123 mmol) followed by DMF (1 drop) and the light-yellow clear reaction mixture was stirred at room temperature. After 2 h. The mixture was concentrated in vacuo to give (1S,2S,4S)-ethyl 4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexane carboxylate with its (1R,2R,4R)-isomer as brown syrupy solid. To the residue was added a solution of N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-1-amine (0.352 g, 0.898 mmol) in THF (8.98 ml) followed by DIPEA (0.626 ml, 3.59 mmol). The brown heterogeneous mixture was stirred at room temperature. After 3 h, LC-MS (ESI) showed that the intermediate (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexanecarboxylate with its (1R,2R,4R)-isomer was formed: LCMS (ESI) m/z 721.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>>[OH:4][C@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][NH:1][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)c1cccnc1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4cccnc4)CC3)cc2)S1

Procedure:
The title compound was prepared from (1R)-2-amino-1-(3-pyridinyl)-1-ethanol (which was obtained in Example 135) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp 87° C. (decomposed); 1H NMR (400 MHz, DMSO-d6) δ 1.38–1.43 (m, 2 H), 1.89–1.91 (m, 2 H), 2.62–2.71 (t, 2), 2.71–2.91 (m, 4 H), 3.23–3.27 (m, 1 H), 3.60–3.63 (m, 2 H), 4.58–4.61 (m, 1 H), 4.72–4.75 (m, 1 H), 6.38–6.85 (d, 2 H), 7.02–7.05 (d, 2 H), 7.34–7.37 (m, 1 H), 7.75–7.78 (m, 1 H), 8.45–8.46 (m, 1 H), 8.56–8.57 (m, 1 H); MS (ES) m/z: 427 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]([CH3:26])=[N:14][O:15][C:16]=2[C@@H:17]([NH:19][S@](C(C)(C)C)=O)[CH3:18])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].Cl.C([Mg]Cl)(C)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3[C:13]([CH3:26])=[N:14][O:15][C:16]=3[C@H:17]([CH3:18])[NH:19][C:7](=[O:8])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(Cl)ccc1-c1c(C)noc1[C@H](C)N[S@@](=O)C(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CO
Product: Cc1noc2c1-c1ccc(Cl)cc1C(=O)N[C@H]2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a round bottomed flask was added methyl 5-chloro-2-(5-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-3-methylisoxazol-4-yl)benzoate (3.37 g, 8.45 mmol), MeOH (48 mL), and HCl [2M in ether] (8.45 mL, 16.90 mmol). The reaction was stirred at room temperature for 30 min before concentrating. The crude residue was concentrated from toluene (2×) and hexane (1×) before being placed on a high vacuum line overnight. The crude residue (as an off-white foam) was dissolved in THF (100 mL) before cooling to −78° C. and addition of isopropylmagnesium chloride (15 mL, 30.0 mmol). The solution was stirred at −78° C. for 5 min before removal of the cold bath and warming the reaction to room temperature. The solution was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford a white solid. This material was purified via chiral SFC to afford the titled compound (1.9 g, 7.23 mmol); LC/MS m/z 263 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[S:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1.CO>[OH-].[K+].CCO.C(Cl)Cl>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[C:21](=[CH:32][C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH2:20][CH2:19]3)[N:10]=[CH:9]1
Reactant: O=Cc1ccsc1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: O=C1C(=Cc2ccsc2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 62.7 %

Procedure:
According to the method of Example 32, Step 2, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.270 g, 0.76 mmol) was reacted with thiophene-3-carboxaldehyde (0.128 g, 1.14 mmol) in 5 mL of 4% KOH in EtOH for 22 hours to afford, after chromatography (silica gel, 50 g; 8% MeOH in DCM), 0.167 g (59%) of the title compound as a dull yellow powder, mp 94-96° C.: CI-MS m/e 351 (M+ +1).
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.N([O-])=[O:23].[Na+]>C(O)(=O)C.O>[C@@H:12]1([N:8]2[C:6]3[NH:7][C:2](=[O:23])[NH:3][C:4](=[O:21])[C:5]=3[S:10][C:9]2=[O:11])[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14]
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Reaction time: 0.5 h

Procedure:
To a suspension of 7 (0.76 g, 2.4 mmol) in glacial acetic acid (150 mL) was added dropwise a solution of sodium nitrite (1.5 g, 21.7 mmol) in water (15 mL) with stirring. After 30 min the suspension became clear and stirring was continued at room temperature overnight. The white solid which had separated was filtered, washed with cold water and dried. Recrystallization from hot water gave fine colorless crystals of 8: yield 0.3 g, 40%: mp 250° C. dec.: UV λmax (pH 1) 293 nm (ε5500): UV λmax (pH 7) 212 nm (ε14200), 301 (6100): UV λmax (pH 11) 204 nm (ε21900), 301 (5600). Anal. Calcd. for C10H11N3O7S: C, 37.86: H, 3.49: N, 13.24: S, 10.10. Found: C, 37.81: H, 3.42: N, 13.01: S, 10.01.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:6][C:5]([CH:11]=[CH2:12])([C:7](OC)=[O:8])[CH2:4]1.CC(C[AlH]CC(C)C)C.CO>C1COCC1>[CH3:14][O:13][C:3]1([O:2][CH3:1])[CH2:4][C:5]([CH2:7][OH:8])([CH:11]=[CH2:12])[CH2:6]1
Reactant: C=CC1(C(=O)OC)CC(OC)(OC)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1(CO)CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of methyl 3,3-dimethoxy-1-vinylcyclobutanecarboxylate (2.02 g, 10.09 mmol) in THF (20 mL) was added DIBAL-H (1.04M in toluene, 29 mL, 30.16 mmol) at 0° C. under argon, and the mixture was stirred for 30 minutes at 0° C. To the mixture was carefully added MeOH (29 mL) and Na2SO4.10H2O (29 g), and the mixture was stirred overnight. The mixture was filtered and evaporated under reduced pressure. And the residue was diluted with hexane/EtOAc=1:1 and filtrated through the pad of silica gel and concentrated in vacuo to give (3,3-dimethoxy-1-vinylcyclobutyl)methanol (1.42 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[C:25]1([CH:31](N)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N(OC(C)C)=O>C(#N)C>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CC(C)ON=O
Solvent: CC#N
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
3-Methyl-7β-phenoxyacetamido ceph-3-em-4-carboxylic acid (3.48 g., 10 m. moles), diphenylmethylamine (3.20 g., 17.5 m. moles) and isopropyl nitrite (3.12 g., 35 m. moles) were heated at 35° over 2 hours in acetonitrile (50 ml). The solvent was removed in vacuo, replaced by ethyl acetate (50 ml) and washed as described in example 7. The organic residue was crystallised from hot isopropanol (30 ml) to yield the title ester (4.25 g., 82.6% based on the input acid) m.pt. 155°, pure by t.l.c.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:18].[Na+].Cl>CO>[NH2:18][CH:9]([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.2 %

Procedure:
To a solution of 4-hydroxyphenylacetone (0.5 g, Avocado, U.K.) and ammonium acetate (2.54 g, Aldrich, U.S.A.) in 10 mL methanol was added 0.17 g of sodium cyanoborohydride (Aldrich, U.S.A.). After stirring for 72 h at rt, concentrated hydrochloric acid was added dropwise until the solution reached pH 2. The solvent was evaporated and the resulting residue was dissolved in water, then extracted 3 times with diethyl ether. The aqueous layer was neutralized to pH 8 by the addition of potassium hydroxide and extracted with diethyl ether. The basic ether layer was dried over sodium sulfate and the solvent was removed in vacuo to give 0.23 g of 4-(2-amino-propyl)-phenol.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[CH:14]([C:16]1[N:17]=[CH:18][S:19][CH:20]=1)[OH:15]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]([C:16]1[N:17]=[CH:18][S:19][CH:20]=1)=[O:15]
Reactant: CN(C)CCc1sc2ccccc2c1C(O)c1cscn1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CN(C)CCc1sc2ccccc2c1C(=O)c1cscn1
Reaction time: 8 h
Yield: 85 %

Procedure:
[2-(2-Dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-thiazol-4-yl-methanol (200 mg, 0.42 mmol) was dissolved in CHCl3 (10 mL) and MnO2 (0.54 g, 3.1 mmol) was added. The reaction mixture was stirred overnight, filtered over celite and washed with dichloromethane and MeOH. Purification by preparative HPLC afforded [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-thiazol-4-yl-methanone (Compound 14-2) (113 mg) as a TFA salt. MH+=316.7