Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C.[NH2:2][CH:3]([C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)CC(C)C.[C:18]([NH:28][C@H:29]([C:34](O)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:21]([O:20][C:18]([NH:28][C@@H:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:34]([NH:2][CH2:3][C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)=[O:35])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1csc(C(N)CC(C)C)n1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the procedure of Example 13, except substituting 1-(tert-butoxycarbonyl)amino-1-4-carboethoxythiazol-2-yl)methane for (1S)-1-tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][OH:18])[CH:3]=1.C(C1C=C(C=CC=1O)[C:24]#[N:25])=O>>[C:24]([C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH:17]=[O:18])[CH:3]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CO
Reactant: N#Cc1ccc(O)c(C=O)c1
Product: CC(C)(C)OC(=O)COc1ccc(C#N)cc1C=O

Procedure:
Prepared by the method of example 1 part (d) using 3-formyl-4-hydroxy-benzonitrile to give the title compound (1.4 g).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:9]([CH2:17][C:18]#[N:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:18]([NH2:19])=[CH:17][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:2]1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NNc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cc(-c2ccccc2)nn1-c1ccccn1
Yield: 80.5 %

Procedure:
To a solution of 1.09 g 2-hydrazinopyridine in 10 ml 5N hydrochloric acid was added 1.45 g benzoylacetonitrile (from Example 2) under stirring. The mixture was refluxed for 3 hrs. After cooling, the solution was neutralized with Na2CO3. The yellow precipitate was filtrated, washed with H2O, and dried to get 1.9 g 1-pyridyl-3-phenyl-5-aminopyrazole.
Reaction SMILES: BrP(C)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:3]1C=CC=CC=1.CC([O-])(C)C.[K+].[F:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][C:44]=1[F:45])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][C:34]=1[F:41]>>[F:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][C:44]=1[F:45])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH2:3])=[CH:35][C:34]=1[F:41]
Reactant: CP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=Cc1ccc(Oc2ccc(F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D162 starting from bromo(methyl)triphenylphosphorane, potassium 2-methylpropan-2-olate and 4-(3,4-difluorophenoxy)-3-fluorobenzaldehyde.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C@@H:12]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@@H:13]([CH2:29][CH2:30][C@H:31]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:14](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:15])[CH:2]=[CH2:3].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OC)(C)(C)C>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C@H:12]1[N:47]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:14](=[O:15])[C@@H:13]1[CH2:29][CH2:30][C@H:31]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Br)ccc1[C@@H](Nc1ccccc1)[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(F)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: COC(C)(C)C
Product: C=CCOc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
(4S)-3-[(2R,5S)-2-[(S)-[2-(Allyloxy)-4-bromophenyl](anilino)methyl]-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-4-benzyl-1,3-oxazolidin-2-one (1.2 g, 1.5 mmol) was dissolved in anhydrous methyl tert-butyl ether (10 mL) and stirred at room temperature under nitrogen. N,O-bistrimethylsilylacetamide (1.1 mL, 4.5 mmol) was added followed by a catalytic amount (˜5 mg) of tetrabutylammonium fluoride trihydrate. The reaction was stirred at room temperature for 19 h, quenched at room temperature with glacial acetic acid (160 μL) and partitioned between ethyl acetate and water and separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (120 g silica gel, 1% to 85% ethyl acetate-hexane) to afford (3R,4S)-4-[2-(allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (816 mg, 87% yield); Rf 0.56 (1:4 ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:10][C:11]([F:25])([F:26])[C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 2,4-bis(trifluoromethyl)phenylboronic acid (1.38 g, 5.38 mmol), 2M cesium carbonate (8.0 mL, 16 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled to room temperature and concentrated and the residue then partitioned between water and CH2Cl2. The organic layer concentrated and purified by chromatography (20% ethyl acetate:hexanes) to provide the title compound.
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][C:16](=[O:23])/[C:15]/2=[CH:24]\[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:34])[CH:28]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25]/[CH:24]=[C:15]2\[C:16](=[O:23])[NH:17][C:18](=[O:22])[C:19]3[C:14]\2=[CH:13][C:12]([Br:11])=[CH:21][CH:20]=3)=[CH:28][C:29]=1[OH:34])[CH:2]=[CH2:3]
Reactant: C=CCI
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C
Yield: 32.3 %

Procedure:
To a solution of allyl iodide (25.6 μl, 0.28 mmol) and tetrabutylammonium iodide (104 mg, 0.283 mmol) in anhydrous N,N-dimethylformamide (2 ML) is added of potassium carbonate (207 mg, 1.5 mmol). The mixture stirred at room temperature and (4Z)-6-bromo-4-{[(3,4-dihydroxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (100 mg, 0.26 mmol) is added. After the mixture is stirred at 65° C. for 30 min, the resulting mixture is concentrated and the residue is then partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer is then dried and purified by high performance liquid chromatography to give 36 mg of a white solid. MS (ESI) m/z 428.6 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]3[C:44]([Cl:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:40]=3[Cl:47])=[CH:31][CH:30]=2)[CH2:19][NH:20]C(=O)OC(C)(C)C)=[C:14]([CH3:48])[CH:13]=1)(=[O:3])[CH3:2].Cl>CCOCC.CCOC(C)=O>[ClH:45].[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]3[C:40]([Cl:47])=[CH:41][C:42]([CH3:46])=[CH:43][C:44]=3[Cl:45])=[CH:31][CH:30]=2)[CH2:19][NH2:20])=[C:14]([CH3:48])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 2, step 5 using tert-butyl (2-{2′-[(acetylamino)methyl]-3-methylbiphenyl-4-yl}-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from step 1 as starting materials. Following flash chromatography the desired material (colorless oil) was dissolved in CH2Cl2/Et2O (1/1). HCl (4M in dioxane) was added in excess and the resulting suspension was triturated with Et2O to afford after filtration the title compounds as an off-white solid. 1H NMR (500 MHz, CD3OD): δ 7.45 (d, 1H), 7.41-7.33 (m, 3H), 7.24 (d, 2H), 7.21 (s, 2H), 7.07 (s, 1H), 6.99 (d, 2H), 6.83 (d, 2H), 4.35-4.29 (m, 6H), 4.23 (d, 1H), 3.68-3.50 (m, 1H), 3.41-3.34 (m, 1H), 3.02 (dd, 1H), 2.87 (dd, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc2nccc(/C=C/c3ccccc3)c2c1
Agent: [Ti+4]
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: ClCCl
Product: Clc1ccc(C(c2ccc(Cl)cc2)c2ccc3nccc(/C=C/c4ccccc4)c3c2)cc1
Temperature: 0 °C

Procedure:
To a suspension of (E)-bis(4-chlorophenyl)(4-styrylquinolin-6-yl)methanol (18 mg, 0.0373 mmol) and triethylsilane (0.0238 mL, 0.149 mmol) in CH2Cl2 (1 mL) at −78° C. was dropwise added titanium chloride (0.0102 mL, 0.0933 mmol). The resulting mixture was warmed to 0° C. for 20 min. To the reaction was slowly added aq. NaHCO3, ice at 0° C. and CH2Cl2. 1N NaOH was added until the aqueous solution was basic. The aqueous layer was extracted with CH2Cl2 twice. The organics were concentrated and purified by silica column chromatography (20-25% EtOAc/hexanes). The product was found to contain ˜7% cis-isomer based on NMR. The resulting mixture was recrystallized from EtOAc/hexanes to remove the Cis isomer.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[Cl:11][C:12]1[CH:13]=[C:14]([S:43]([NH2:46])(=[O:45])=[O:44])[CH:15]=[CH:16][C:17]=1[CH2:18][S:19][C:20]1[N:21]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:22]([C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)([CH3:27])[CH3:26])=[CH:23][N:24]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([S:43]([NH:46][C:9](=[O:10])[NH:8][CH:5]([CH3:7])[CH3:6])(=[O:45])=[O:44])[CH:15]=[CH:16][C:17]=1[CH2:18][S:19][C:20]1[N:21]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:22]([C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)([CH3:27])[CH3:26])=[CH:23][N:24]=1
Reactant: CC(C)N=C=O
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(S(N)(=O)=O)cc2Cl)n1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)NS(=O)(=O)c1ccc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 43.9 %

Procedure:
To a stirred solution of aluminum trichloride (75 mg, 513 μmol, 3.0 eq) in toluene (1 mL, anhyd) was added isopropylisocyanate (17 μL, 170 μmol, 1.0 eq). After 3 min of stirring at room temperature, 3-chloro-4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)benzenesulfonamide (100 mg, 170 μmol, 1.0 eq) was added neat. The reaction mixture was heated at 80° C. for 16 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×), washed with water, brine, then dried and concentrated. Purification (silica gel chromatography, 20% methanol/ethyl acetate) provided the title compound (50 mg) as an off-white foam. 1H NMR (DMSO-d6, 400 MHz): δ 8.33 (s, 1H), 7.78 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 6.98-6.87 (m, 4H), 6.41-6.35 (m, 2H), 6.05 (br s, 1H), 4.22 (s, 2H), 3.61-3.50 (m, 1H), 1.44 (s, 6H), 0.97 (d, J=6.6 Hz, 6H); MS (EI) m/z 671 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(C[C@@H]2CO2)cc1
Product: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCN(C[C@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 194 was synthesized using 9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=92-93° C., 400 MHz 1H NMR (CDCl3) δ: 8.00-7.97 (d, J=8.21 Hz, 1H), 7.668-7.663 (d, J=1.95 Hz, 1H), 7.46-7.43 (dd, J=1.95, 8.21 Hz, 1H), 7.33-7.23 (m, 5H), 4.09-3.94 (m, 1H), 3.33 (br s, 1H), 2.88-2.82 (m, 4H), 2.75-2.70 (m, 3H), 2.52-2.41 (m, 3H), 2.14-2.11 (d, J=12.9 Hz, 2H), 1.94-1.80 (m, 2H); LCMS: 470 [M+H].
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].N1CCCCC1>C(O)C>[C:17]([C:19]1[C:20](=[O:21])[NH:22][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:9]2)#[N:18]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CC(c2ccccc2)CCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccccc1)CC2
Yield: 73.1 %

Procedure:
1.68 g of 2-acetyl-4-phenylcyclohexanone, 0.73 g of cyanoacetamide and a small amount of piperidine were mixed with 10 ml of ethanol and the obtained reaction mixture was heated under reflux for two hours. After cooling, the precipitated crystals were filtered and purified to give 1.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl- 3-oxo-7-phenylisoquinoline. m.p. >290° C. NMRδTMSDMSO-d6 : 1.90 (3H, m), 2.20 (3H, s), 2.80 (4H, m), 7.28 (5H, s) and 12.14 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:9][C:8]([OH:19])([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[N:17][OH:18])=[CH:12][CH:11]=2)[CH2:7]1)=[O:5])[CH3:2].ClN1C(=O)CCC1=O.C(=O)([O-])O.[K+].[Cl:33][C:34]1[CH:39]=[C:38]([C:40]([C:42]([F:45])([F:44])[F:43])=[CH2:41])[CH:37]=[C:36]([Cl:46])[C:35]=1[Cl:47]>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:9][C:8]([OH:19])([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH2:41][C:40]([C:38]4[CH:37]=[C:36]([Cl:46])[C:35]([Cl:47])=[C:34]([Cl:33])[CH:39]=4)([C:42]([F:45])([F:44])[F:43])[O:18][N:17]=3)=[CH:14][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)C1CC(O)(c2ccc(C=NO)cc2)C1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 50 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a stirred solution of 3-hydroxy-3-[4-(hydroxyimino-methyl)-phenyl]-cyclobutane carboxylic acid ethyl ester (Preparation 2, 4.7 g, 17.87 mmol) in DMF (10 mL) was added N-chloro succinimide (2.61 g, 19.65 mmol) and heated at 50° C. for 1 hour. After complete consumption of starting material, reaction was cooled to 0° C., potassium hydrogen carbonate (2.68 g, 26.88 mmol) was added followed by addition of pre dissolved solution of 1,2,3-trichloro-5-(1-trifluoromethyl-vinyl)-benzene (5.40 g, 19.65 mmol). Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of chloro intermediate, reaction mixture was diluted with EtOAc (50 mL), washed with water (5×30 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. Purification was done by column chromatography (silica gel, 100-200 mesh). Compound was eluted using 15% ethyl acetate in hexane as eluent to afford white sticky solid (4.7 g, 49%). 1H NMR (400 MHz, CDCl3) δ 1.28 (t, J=9.36 Hz, 3H), 2.57-2.62 (m, 2H), 2.83-2.90 (m, 3H), 3.68 (d, J=17.28 Hz, 1H), 4.08 (d, J=17.16 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 7.55-7.57 (m, 2H), 7.64-7.67 (m, 4H). LC-MS (m/z): 536.10 (M−H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:50])/[C:16](/[N:21]2[CH:24]([S:25]S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[CH:23]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:22]2=[O:49])=[C:17](\[O:19][CH3:20])/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(OC(=O)/C=C\C)C2C=CC=CC=2)C=CC=CC=1.N12CCCCC1C=NCCC2>O1CCCC1.C1C=CC=CC=1>[C:8]1([CH:7]([O:14][C:15]([CH:16]2[N:21]3[C:22](=[O:49])[C@@H:23]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@H:24]3[S:25][CH:18]=[C:17]2[O:19][CH3:20])=[O:50])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO/C(C)=C(\C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: C/C=C\C(=O)OC(c1ccccc1)c1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 367 mg (0.5 mM) of a mixture consisting of 2-[4-(p-nitrobenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (1.0 mM) of 1,5-diazabicyclo[5.4.0]undec-5-ene in 10 ml of dry tetrahydrofurane is stirred for 40 minutes at room temperature. The reaction mixture is diluted with benzene, washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution, dried over sodium sulphate and freed from the solvent in vacuo. The residue is chromatographed on acid-washed silica gel, using toluene/ethyl acetate, 7:1, as the running agent, whereby pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester is obtained. Subsequent elution with toluene/ethyl acetate, 2:1, results in the isolation of a mixture which in addition to 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester also contains 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].Cl[CH2:58][O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:58][O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: ClCOCc1ccccc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCOCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 2 ml methylene chloride) was added disopropylethylamine (99.4 μl) followed by benzyl chloromethyl ether (34.2 μl neat) and the mixture stirred at room temperature. After 4 hours, the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (92 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][NH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)(=O)C>[F:18][C:2]([F:1])([F:17])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[N:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1
Reactant: O=C1CNC(c2ccccc2)=NN1CC(F)(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Product: O=c1cnc(-c2ccccc2)nn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A mixture of 0.51 g of 1-(2,2,2-trifluoroethyl)-3-phenyl-4,5-dihydro-1,2,4-triazin-6-one (2.0 mmol) and 0.48 g of DDQ (2.1 mmol) in 20 mL of ethyl acetate was stirred at room temperature overnight, then heated to 70° C. for 2 hours. The reaction mixture was cooled and washed with aqueous potassium carbonate, water (2 times) and brine, dried over magnesium sulfate, filtered and stripped. The product was dissolved in ethyl acetate/methylene chloride and treated with silica gel, then filtered through silica gel over Celite to give 0.40 g of 1-(2,2,2-trifluoroethyl)-3-phenyl-1,2,4-triazin-6-one, melting point 129-131° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].Cl[C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18].CCN(CC)CC.O>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[C:16]([NH:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 0 °C
Yield: 55.7 %

Procedure:
To a suspension of 2-tert-Butyl-5-nitro-phenylamine (4.04 g, 20.80 mmol) in CH2Cl2 (20 mL) at 0° C. was added 1.1 equiv of Methyl chlorooxoacetate (2.10 mL, 22.88 mmol) and followed by dropwise addition of 1.1 equiv of Et3N (3.19 mL, 22.88 mmol). After stirring at 0° C. and allowing to warm up to room temperature over 4 hrs, the reaction mixture was treated with water (20 mL), stirred for 10 min and then partitioned between EtOAc/water. The organic phase was washed with 0.5N HCl (2×25 mL), and saturated NaCl solution (50 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by flask column chromatography on silica gel eluting with EtOAc/Hexane (5–25%) to give the title compound (3.25 g, 56%) as light yellow crystals. TLC (30% EtOAc/Hexane) Rf=0.39; 1HNMR (CDCl3) δ 9.36 (br.s, 1H), 8.97 (d, J=2.4 Hz, 1H), 8.02 (dd, J=9.0, 2.4 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 4.03 (s, 3H), 1.52 (s, 9H).