Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CO[CH:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.[C:37]([OH:41])(=[O:40])[CH2:38][SH:39].B(F)(F)F.O(CC)CC>C(Cl)Cl>[C:13]1([CH2:12][O:11][CH2:10][CH:9]([S:39][CH2:38][C:37]([OH:41])=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CS
Reactant: c1ccc(COCC(OCc2ccccc2)c2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)CSC(COCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of the ether (151 mg) (Step 2) and thioglycolic acid (31 μL) in CH2Cl2 at 0° C. was added BF3 /OEt2 (117 μL) dropwise. The mixture was stirred at 0° C. for 1 h and poured onto 25% aqueous NH4OAc, extracted with CH2Cl2 and the organic phase was dried and evaporated. Chromatography on silica gel using ethyl acetate/hexane containing 0.1% AcOH afforded the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.O.CC#N.CC#N.Cl[Pd]Cl>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[N:10][CH:9]=[C:8]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: FC(F)(F)c1cncc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 10 %

Procedure:
Charge a sealed tube under a positive pressure of argon with bis(acetonitrile)palladium (II) chloride (18 mg, 0.07 mmol), 2-dicyclohexylphosphino diphenyl (73 mg, 0.21 mmol), cesium carbonate (0.557 g, 1.71 mmol) and 3-chloro-5-trifluoromethylpyridine, (prepared essentially as described in PREPARATION 7), (0.12 g, 0.66 mmol) in acetonitrile and stir at room temperature for 25 min (Angew. Chem. Int. Ed. 42, 5993-5996, (2003)). Add phenylacetylene (0.1 mL, 0.86 mmol) and stir at 100° C. for 16 h. Cool to room temperature, dilute with water, and wash twice with ethyl acetate. Combine the ethyl acetate layers, dry (sodium sulfate), and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 50:50 hexanes:dichloromethane, to obtain the title compound (30 mg, 10%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:18]([Cl:27])=[CH:17][N:16]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[C:30]=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:30](=[O:31])[NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=3)[CH2:23][CH2:22]2)[C:18]([Cl:27])=[CH:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCNCC2)n1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of tert-butyl(2-((5-chloro-4-(piperazin-1-yl)pyrimidin-2-yl)amino)phenyl)carbamate (28 mg, 0.068 mmol) in DCM (0.7 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (0.011 mL, 0.082 mmol) and triethylamine (0.015 mL, 0.1 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was loaded onto silica gel and purified using 0-50% EtOAc/Hexanes gradient to give the title compound (25 mg, 62%). MS (ES+) C27H29ClF3N7O3 requires: 591. found: 592 [M+H]+
Reaction SMILES: [CH2:1]([C@H:5]1[C@@H:14]([NH2:15])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[CH2:1]([C@@H:5]1[C@@H:14]([NH:15][C:23](=[O:24])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H]1CC2(CC[C@@H]1N)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCC[C@H]1CC2(CC[C@@H]1NC(=O)OCc1ccccc1)OCCO2
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
A solution of crude (7R,8S)-7-(butyl)-8-(amino)-1,4-dioxa-spiro[4.5]decane (4.2 g, 0.02 mol) in 100 mL of CH2Cl2 was treated with an aqueous solution of K2CO3 and cooled in a ice bath. The mixture is stirred vigorously while benzyl chloroformate (3.42 g, 0.02 mol) is added slowly. After the addition is complete the mixture is stirred an additional 30 min. The organic layer is separated and washed with water, brine and concentrated. The residue was chromatographed on silica gel to give 3 g of benzyl ((7S,8S)-7-(butyl)-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamate.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:23][C:22]2[C@@:10]([CH3:28])([C@@H:11]3[C@@H:19]([CH2:20][CH:21]=2)[C@H:18]2[C@@:14]([CH3:27])([C@@H:15]([C:24](=[O:26])[CH3:25])[CH2:16][CH2:17]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)([CH3:4])[CH3:3].Br[CH2:32][CH2:33][CH2:34][C:35]([CH3:37])=[CH2:36].[I-].[I-].[Sm+2]>>[CH3:4][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:23][C:22]2[C@@:10]([CH3:28])([C@@H:11]3[C@@H:19]([CH2:20][CH:21]=2)[C@H:18]2[C@@:14]([CH3:27])([C@@H:15]([C@@:24]([OH:26])([CH2:32][CH2:33][CH2:34][C:35]([CH3:37])=[CH2:36])[CH3:25])[CH2:16][CH2:17]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)([CH3:1])[CH3:3]
Reactant: C=C(C)CCCBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [I-]
Agent: [Sm+2]
Product: C=C(C)CCC[C@](C)(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 70.7 %

Procedure:
The coupling reaction of the protected pregnenolone 1 (500.0 mg, 1.16 mmol) with 5-bromo-2-methyl-1-pentene 9 (199.0 mg, 1.22 mmol) in the presence of samarium diiodide was performed under similar condition as described for the preparation of 2 to afford the 20S-hydroxy steroid 10 (419.0 mg, 0.82 mmol, 71%) as a white powder.
Reaction SMILES: [C:1]1(C2CCN(C([O-])=O)CC2)C=CC=CC=1.C[N:17]1[N:21]=[N:20][C:19]([C:22]2[CH:23]=[C:24]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=2)[CH2:25][O:26][CH2:27][C:28]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[N:18]1.N1C(C2C=C(C=C(C(F)(F)F)C=2)COC[C:65]2([C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[CH2:70][CH2:69][N:68]([C:71]([O:73]C(C)(C)C)=[O:72])[CH2:67][CH2:66]2)=NN=N1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:20]1[C:19]([C:22]2[CH:23]=[C:24]([CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=2)[CH2:25][O:26][CH2:27][C:28]2([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[N:18][N:17]=[N:21]1.[C:78]1([CH:65]2[CH2:66][CH2:67][N:68]([C:71]([O-:73])=[O:72])[CH2:69][CH2:70]2)[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3nnn[nH]3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reactant: Cn1nnc(-c2cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)c2)n1
Agent: O=C([O-])N1CCC(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1-c1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 9 %

Procedure:
tert-Butyl 443-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate and tert-Butyl 4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate. tert-Butyl 4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (80 mg, 0.15 mmol) methyl iodide (10.0 μL, 0.15 mmol) and potassium carbonate (21.0 mg, 0.15 mmol) were combined in acetone (1.5 mL) and heated at reflux overnight. After cooling to room temperature, the mixture was filtered and concentrated. Flash chromatography on silica gel (20% ethyl acetate/hexanes) afforded tert-Butyl 4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (7.0 mg, 9%) and tert-Butyl 443-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (48 mg, 60%). Retention time: 4.75 min and 5.20 min. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=6 min., Flow rate=4 mL/min.): Mass spec.: 532.31 (MH)+ and 532.31 (MH)+ respectively.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[OH:17].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To dimethylformamide (200 ml) are added 2-methoxy-4-acetylphenol (20 g), ethyl α-bromoacetate (15 ml) and potassium carbonate (18.3 g), and the mixture is stirred at room temperature overnight. After the reaction is complete, water is added to the mixture, and the mixture is extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting crystals are collected, and washed with n-hexane-diethyl ether to give ethyl α-(2-methoxy-4-acetylphenoxy)acetate (23.86 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[S:3]1(=[O:16])=[O:15].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.CCOCC>[CH2:17]([NH:21][C:22]([NH:14][S:11]([C:10]1[C:4]2[S:3](=[O:16])(=[O:15])[N:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:12])=[O:13])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CN1Cc2cccc(S(N)(=O)=O)c2S1(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cccc2c1S(=O)(=O)N(C)C2
Reaction time: 16 h

Procedure:
A suspension of 13.0 g of 2-methyl-2,3-dihydro-1,2-benzisothiazole-7-sulfonamide-1,1-dioxide, 11.2 ml of butyl isocyanate and 13.8 g of potassium carbonate in 200 ml of dry methyl ethyl ketone was heated at reflux for 2 hours. 13.8 g of potassium carbonate was added and heating was continued for an additional 16 hours. The mixture was cooled, the solvent was decanted from the solids, concentrated in vacuo, the residue dissolved in ethyl acetate and washed with saturated aq. NaHCO3. The aqueous wash was added to the originalsolids diluted with water and acidified to pH ~3 with dilute HCl. Themixture was extracted with methylene chloride, the extract was washed with water and brine, dried and concentrated in vacuo leaving a solid which wasslurried in ether and filtered to give 13.24 g of the title compound as a white powder, m.p. 162°-164° C.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]3[C:30](=[O:40])[C:31]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:32]4[C:33]3=[O:35])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN3C(=O)c4ccccc4C3=O)cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.50 g, 3.53 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (75 ml) were added phthalimide (519 mg, 5.30 mmol), triphenylphosphine (1.39 g, 5.30 mmol) and 40% diethyl azodicarboxylate in toluene solution (2.03 ml, 5.30 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:5) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-phthalimidomethyl-1,3-thiazol-2-yl)azetidine (1.52 mg, yield 78%) as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8]C)=O.Cl.[C:12](=[NH:17])([NH2:16])[CH2:13][CH2:14][CH3:15].C[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:16]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:17][C:6](=[O:8])[CH:5]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1nc(COC)cc(=O)[nH]1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of methyl 4-methoxy-3-oxobutanoate (15.0 g), butanimidamide hydrochloride (15 g) and sodium methoxide (28% in methanol, 51 mL) in methanol (150 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (17 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][OH:35]>CN(C)C=O>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:33][CH2:34][OH:35])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:24]=[O:25])=[CH:6][N:7]=1)[CH3:23]
Reactant: OCCBr
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Temperature: 85 °C
Yield: 51.4 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (90 mg, 0.255 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (234 mg, 2.55 mmol) and 2-bromoethanol (0.090 mL, 1.27 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil (50 mg, 52% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:37]=[CH:36][C:26]2[N:27]([CH3:35])[C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:22][C:23]2[CH:37]=[CH:36][C:26]3[N:27]([CH3:35])[C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N(C)S(C)(=O)=O)n3)ccc21
Yield: 54.4 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (79 mg, 0.22 mmol), 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (49 mg, 0.22 mmol), and 10-Camphorsulfonic acid (80 mg, 0.34 mmol) in Isopropyl alcohol (3 mL) and was heated in a microwave vial for 2 h at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo. Chromatography (ISCO, 2×12 g silica gel, 0-80% EtOAc:Hex) afforded N-{(1R,2R)-2-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide as a white foam (64 mg, 53%). LCMS: 535 (M+H), 1H-NMR (CDCl3): 7.92 (s, 1H), 7.75 (d, 1H, J=8.5 Hz), 7.29 (s, 1H), 7.11 (d, 1H, J=8.5 Hz), 6.85 (s, 1H), 5.65 (d, 1H, J=7.8 Hz), 4.08 (m, 1H), 3.75 (m, 1H), 3.29 (s, 3H), 2.84 (s, 3H), 2.74 (s, 3H), 2.41 (m, 1H), 2.37 (m, 2H), 2.04 (m, 1H), 1.84 (m, 3H), 1.67 (m, 1H), 1.25-1.5 (m, 10H).
Reaction SMILES: [C:1]([CH:3]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15])#[N:2].N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(OCC)C>[C:1]([CH:3]([N:16]1[CH2:21][CH2:20][N:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:18][CH2:17]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15])#[N:2]
Reactant: COc1ccc(C(C#N)N2CCNCC2)c(OC)c1OC
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)N1CCN(C(C#N)c2ccc(OC)c(OC)c2OC)CC1
Temperature: 25 °C

Procedure:
14.5 g. of N-(α-cyano-2,3,4-trimethoxybenzyl)piperazine was dissolved in 50 ml. of anhydrous diethyl ether and to the resultant solution was added 4 g. of pyridine. To the mixture was added dropwise 6 g. of ethyl chloroformate dissolved in 10 ml. of anhydrous diethyl ether over a period of about 30 minutes with ice cooling while the internal temperature was kept at 10° - 15°C. The mixture was further stirred at room temperature and filtered off to separate an insoluble matter. The filtrate was evaporated to give crude N-(α-cyano-2,3,4-trimethoxybenzyl)-N'-ethoxycarbonylpiperazine as an oily substance. This product was dissolved in toluene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from tetrahydrofuran-methanol afforded 14 g. of crystal having a melting point of 137.5° - 139.0°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(O)(=O)C.[N:17]([O-])=[O:18].[Na+]>O>[N:17]([C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:12])=[O:18]
Reactant: O=N[O-]
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(O)ccc2cc(Br)ccc12
Reaction time: 23 h

Procedure:
76.2 g (0.342 mol) of 6-bromo-β-naphthol were suspended in 385 ml of 90%-strength acetic acid and nitrosated for two hours at 4° C. with 28.5 g (0.413 mol) of sodium nitrite in 230 ml of water, and stirring was then continued for 23 h at room temperature. The suspension was then made up to twice its volume by filling up with water and the product formed was filtered off by suction. After drying, 83.8 g (97.3%) of crude 1-nitroso-6-bromo-β-naphthol whose purity is adequate for the further reaction was obtained.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:13]([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C(O)=O>[NH2:8][CH:9]([CH:13]([CH3:16])[CH:14]=[CH2:15])[C:10]([O:12][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11]
Reactant: BrCc1ccccc1
Reactant: C=CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: C=CC(C)C(N)C(=O)OCc1ccccc1

Procedure:
The substrate tripeptide A used in the process, δ-(L-α-aminoadipoyl)-L-cysteinyl-D-γ,δ-didehydroisoleucine, is prepared in the following manner. First, 2-(t-butyloxycarbonylamino)-3-methylpent-4-eneoic acid (prepared according to the method of P. A. Bartlett and J. F. Barstow, J. Org. Chem., 1982, 47, 3933) is esterified with benzyl bromide and sodium bicarbonate. The benzyl ester is treated with formic acid to remove the t-BOC amino-protecting group to provide the amino ester, benzyl 2-amino-3-methylpent-4-eneoate, as the formate salt as shown below. ##STR3##
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@@H:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:39]=[O:40])(C)(C)C.[Pb](=O)=O>C1C=CC=CC=1.ClCCCl>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:40][CH3:39])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNS(C)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=[Pb]=O
Solvent: c1ccccc1
Solvent: ClCCCl
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.18 g (2.4 mmol) of 7β-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.56 g (2.4 mmol) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml of dry benzene is refluxed for 4 hours under a Dean-Stark trap. The solution is evaporated under reduced pressure to leave a residue which is dissolved in 100 ml of 1,2-dichloroethane and cooled to ca. 5° in an ice bath. Three grams of freshly prepared lead dioxide is added in portions over 20 minutes until the starting material is completely consumed. The mixture is filtered through Celite and the filter cake is washed with two 20 ml portions of cold 1,2-dichloroethane. The filtrate is treated with 25 ml of methanol (distilled from magnesium) and the reaction mixture is allowed to stand at room temperature until complete consumption of the oxidized intermediate and formation of a new slower-moving product is shown by thin layer chromatography. The mixture is evaporated and the residue is dissolved in 30 ml of methanol and treated with 2.5 g of Girard reagent T (trimethylaminoacetohydrazide chloride). The reaction mixture is stirred at room temperature for 3 hours, then evaporated to give a residue which is partitioned between ethyl acetate and 20% sodium chloride solution. The organic phase is washed with 10% sodium chloride solution water and a saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.