Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.OO.C([O-])([O-])=[O:38].[K+].[K+]>CS(C)=O>[OH:1][C:2]([CH3:33])([CH3:34])[CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]([NH2:24])=[O:38])=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](c1ccc(-c2ccc(C(N)=O)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile (120 mg, 0.26 mmol) in DMSO (8 mL) were added H2O2 (0.5 mL, 30%) and K2CO3 (35 mg, 0.26 mmol), and the mixture was stirred at rt for 3 h. The reaction was quenched with H2O (10 mL) and the mixture was extracted with EtOAc (4×20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to give 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide (55.46 mg, 45%). LC-MS Method 2 tR=1.12 min, m/z=474, 416. 1H NMR (CDCl3): 1.03 (s, 3H), 1.09 (s, 3H), 1.46 (d, 3H), 2.13-2.26 (m, 5H), 2.30 (m, 1H), 2.44 (s, 1H), 2.79 (d, 1H), 5.61 (m, 1H), 6.15-6.38 (s, 1H), 6.97 (d, 2H), 7.13-7.29 (m, 5H), 7.60 (d, 2H), 7.70 (d, 2H), 8.15 (d, 1H), 9.05 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)OCC(=O)N2
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A suspension of 10% palladium on carbon (0.24 g) and 2b (2.39 g, 12.3 mmol) in methanol (65 ml) was shaken under 25 lbs H2 in a Parr hydrogenation apparatus. After 3 h, the catalyst was filtered and the filtrate evaporated to afford 1.63 g (81%) of compound 2c. An analytical sample was recrystallization from MeOH/hexane. Mp 216°-7° C.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S(O[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:23][CH:22]=2)=[C:18]([CH3:35])[N:17]=[C:16]([NH2:36])[N:15]=1)(=O)=O.[CH2:37]([NH2:42])[CH2:38][CH2:39][CH2:40][CH3:41]>C(O)CCC>[CH3:35][C:18]1[N:17]=[C:16]([NH2:36])[N:15]=[C:14]([NH:42][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:19]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:25][CH:26]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(COC3CCCCO3)cc2)c(C)c1
Reactant: CCCCCN
Solvent: CCCCO
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(COC2CCCCO2)cc1

Procedure:
A mixture of the product from step (iii) (6.49 g) and n-pentylamine (7.34 ml) in 1-butanol was heated under reflux for 24 h. The solvent was evaporated and the residue partitioned between EtOAc and water. The organics were separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 8% MeOH/DCM to afford the subtitle compound, 3.4 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3=[C:20]([C:39]([O:41][CH3:42])=[O:40])[C:21]([C:35]([O:37][CH3:38])=[O:36])=[C:22]4[CH:23]=[CH:24][C:25]([CH2:26][O:27][Si](C(C)(C)C)(C)C)=[C:17]([N:18]34)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.S(=O)(=O)(O)O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3=[C:20]([C:39]([O:41][CH3:42])=[O:40])[C:21]([C:35]([O:37][CH3:38])=[O:36])=[C:22]4[CH:23]=[CH:24][C:25]([CH2:26][OH:27])=[C:17]([N:18]34)[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C(=O)OC)c2c(-c3ccc(OCc4ccccc4)cc3)cc3c(CO[Si](C)(C)C(C)(C)C)ccc1n32
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c2c(-c3ccc(OCc4ccccc4)cc3)cc3c(CO)ccc1n32
Temperature: 25 °C
Yield: 89 %

Procedure:
The general synthetic pathway outlined in example 89, step 5, and example 91 have been applied to proper starting material in the preparation of dimethyl 3-(4-benzyloxyphenyl)-5-(tert-butyldimethylsilanyloxymethyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate. Dimethyl 3-(4-benzyloxyphenyl)-5-(tert-butyldimethylsilanyloxymethyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate (4.5 g, 7.7 mmol) was dissolved in 100 ml of methanol and 4 drops of sulfuric acid. The mixture was refluxed for 2 minutes, and cooled to room temperature. The yellow precipitate was filtered off to afford 3.24 g (89%) of dimethyl 3-(4benzyloxyphenyl)-5-hydroxymethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate as yellow crystals. 1H-NMR (CDCl3, 300 MHz) δ: 3.93 (s, 3H); 3.97 (s, 3H); 5.12 (s, 2H); 5.20 (s, 2H); 7.03 (d, 2H); 7.31-7.50 (m, 6H); 7.62 (m, 2H); 7.72 (m, 1H); 8.07 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18]C(=O)OC)[CH2:13]1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH3:1])[CH2:13]1
Reactant: COC(=O)N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@@H]1CCC[C@H](N)C1
Reaction time: 8 h

Procedure:
Methyl N-[(1R,3S)-3-benzyloxycarbonylaminocyclohexyl]carbamate, 19a, (1.09 g, 3.56 mmol) was dissolved in ethanol (100 mL) and treated with 10% Pd/C (0.38 g, 0.36 mmol). The flask was capped, degassed and fitted with a hydrogen balloon and allowed to stir overnight. The reaction mixture was filtered under nitrogen and concentrated in vacuo to provide the product, 19b, as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([N:15]([CH3:35])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([CH3:36])=[CH:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].O.[Li+].[OH-].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([N:15]([CH3:35])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]4)[C:12]([CH3:36])=[CH:11][N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ncc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(-c2ncc(C)c(N(C)CCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)n2)cc1
Reaction time: 24 h
Yield: 88.5 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[[2-(4-ethylphenyl)-5-methyl-4-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 343, 140 mg, 0.290 mmol) in a mixture of THF (5 mL), water (5 mL), and EtOH (2.5 mL) was added LiOH (27.5 mg, 1.15 mmol). After vigorously stirring for 24 h, the reaction mixture was acidified to pH ˜5 using HCl (1 N aqueous solution) and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and then concentrated under reduced pressure to give the product (118 mg, 89%) as a white foam. 1H NMR (400 MHz, acetone-d6) δ 1.26 (t, 3H), 1.70-1.76 (m, 1H), 2.18-2.21 (m, 2H), 2.37 (s, 3H), 2.33-2.42 (m, 2H), 2.67-2.85 (m, 5H), 3.28 (s, 3H), 3.44-3.45 (m, 1H), 3.86 (t, 2H), 4.07 (t, 2H), 6.71 (d, 1H), 6.78 (s, 1H), 7.12 (d, 1H), 7.27 (d, 2H), 8.08 (s, 1H), 8.35 (d, 2H); LC-MS: RT=2.53 min, (M+H)+ 460.4.
Reaction SMILES: C([O:8][C:9](=[O:48])[CH2:10][CH2:11][NH:12][C:13](=[O:47])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([NH:22][C:23](=[O:46])[C@H:24]([CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:45])[NH:41][N+]([O-])=O)[NH:25]C(OCC2C=CC=CC=2)=O)[CH:15]=1)C1C=CC=CC=1>C(O)=O.[Pd]>[CH:9]([OH:48])=[O:8].[NH2:25][C@H:24]([C:23]([NH:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:48])=[O:8])=[O:47])=[O:46])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:45]
Reactant: COc1ccc(C(=O)NCCC(=O)OCc2ccccc2)cc1NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Product: COc1ccc(C(=O)NCCC(=O)O)cc1NC(=O)[C@@H](N)CCCNC(=N)N
Yield: 150.7 %

Procedure:
390 mg of N-[3-[[N2 -(benzyloxycarbonyl)-N5 -(N-nitroamidino)-L-ornithyl]amino]-p-anisoyl]-β-alanine benzyl ester and 160 mg of Pd/C (5%) are stirred in 8 ml of formic acid for 5 hours under hydrogen. The filtered solution is evaporated and the residue is purified on silica gel with methanol-formic acid (99:1). There are obtained 195 mg of N-[3-(L-arginylamino)-p-anisoyl]-β-alanine formate (1:2), [α]D20 =+46.6° (H2O, c=0.5%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH:14]([N:17]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:15]#[N:16])[CH2:2][CH:3]=[CH2:4].Cl>C1COCC1.O>[NH2:17][CH:14]([CH2:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:1][CH2:2][CH:3]=[CH2:4])[C:15]#[N:16]
Reactant: C=CCCOc1ccc(F)cc1CC(C#N)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CCCOc1ccc(F)cc1CC(N)C#N
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of 3-(2-(but-3-en-1-yloxy)-5-fluorophenyl)-2-((diphenylmethylene)amino)propanenitrile (1.39 g, 3.49 mmol, 1 equiv) in THF (14 mL) was added 1 N HCl (3.84 mL, 3.84 mmol, 1.1 equiv). After 3 h, the reaction was diluted with water and washed with ether. The aqueous layer was then neutralized with 1 N NaOH and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to provide the product (0.60 g, 73%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.00-6.92 (m, 2H), 6.85-6.77 (m, 1H), 5.90 (ddt, J=17.1, 10.2, 6.8 Hz, 1H), 5.20 (dd, J=17.1, 1.5 Hz, 1H), 5.15 (d, J=11.0 Hz, 1H), 4.12 (t, J=7.3 Hz, 1H), 4.03 (t, J=6.3 Hz, 2H), 3.05 (d, J=7.3 Hz, 2H), 2.57 (q, J=6.5 Hz, 2H), 2.19 (br. s., 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:12](S(C(F)(F)F)(=O)=O)[S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14]>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2ncccc2c1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
Quinolin-6-ol (2.9 g, 20 mmol) was dissolved in pyridine (30 mL). The mixture was cooled to 0° C. in an ice bath under nitrogen and Tf2O (4 mL, 24 mmol) was added to the reaction mixture slowly. The reaction mixture was stirred at room temperature for 5 hours, before partitioning between dichloromethane (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was separated and washed with brine (5×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 3.9 g of trifluoromethanesulfonic acid quinolin-6-yl ester as a brown oil (70% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[OH:15].CC1C=CC(S(O[CH2:27][CH2:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[O:35][CH2:34][CH2:33][C:32]3=[O:39])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:27][CH2:28][C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[O:35][CH2:34][CH2:33][C:32]4=[O:39])[CH2:13][CH2:14]2)=[CH:4][C:3]=1[OH:15]
Reactant: Oc1cc(CC2CCNCC2)ccc1Br
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)C(=O)CCO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCOc2ccc(CCN3CCC(Cc4ccc(Br)c(O)c4)CC3)cc21
Temperature: 57.5 °C
Reaction time: 6 h

Procedure:
A suspension of 2-bromo-5-(piperidin-4-ylmethyl)phenol (RE4) (500 mg, 1.9 mmol), 2-(4-oxo-3,4-dihydro-2H-chromen-6-yl)ethyl 4-methylbenzenesulfonate (RE6) (612 mg, 1.8 mmol) and potassium carbonate (489 mg, 3.5 mmol) in acetonitrile (50 mL) and dimethylformamide (20 mL) was stirred at 55-60° C. for 6 hours. The reaction mixture was cooled to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→chloroform:methanol=20:1) to obtain a semi-purified product of the title compound. A small amount of ethyl acetate was added thereto, and the resulting precipitate was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain the title compound (5-8) of interest (37 mg, 5%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(-c2ccccc2)c2ccccc2n1
Agent: O=S(=O)(O)O
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)c2ccccc2n1

Procedure:
2-methyl 4-(3-nitro phenyl) quinoline is prepared by nitration at 0° C. of 2-methyl 4-phenyl quinoline (1.36 10-1 mole) with sulfonitric mixture (90 ml nitric acid 60% and 90 ml concentrated sulfuric acid) and separation of isomers. It has a melting point of 157° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]([OH:6])[CH:12]=[CH2:13])[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1c(F)ccc(Cl)c1F
Solvent: C1CCOC1
Product: C=CC(O)c1c(F)ccc(Cl)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
3-Chloro-2,6-difluorobenzaldehyde (1.0 g, 5.66 mmol) was dissolved in THF (28.3 mL) under an atmosphere of argon, and the solution was cooled to −78° C. To the cold solution was then added vinyl magnesium bromide, 1.0 M in THF (8.50 mL, 8.50 mmol) dropwise over 10-15 min. Stirring was continued at −78° C. for 1 h. The reaction was warmed to rt, then cooled to 0° C. and carefully quenched with saturated NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The organic extracts were combined and washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated to yield the desired product as a light yellow oil (1.19 g, 98%). MS (ESI) m/z: 187.0 (M−H2O)+. 1H NMR (500 MHz, CDCl3) δ 7.36-7.30 (m, 1H), 6.88 (td, J=9.2, 1.9 Hz, 1H), 6.21 (dddt, J=17.1, 10.3, 5.8, 1.1 Hz, 1H), 5.59 (dd, J=7.4, 6.6 Hz, 1H), 5.33 (dd, J=17.1, 0.8 Hz, 1H), 5.26 (dt, J=10.3, 1.2 Hz, 1H), 2.35 (dt, J=8.5, 1.8 Hz, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[Br:7][C:8]1[N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(Br)c(Br)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
Potassium t-butoxide (0.75 g, 6.7 mmol) is added in portions at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (2.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (20 mL). After 30 minutes, ethyl bromoacetate (1.12 g, 6.7 mmol) is added dropwise and the mixture stirred for 4-5 hours at room temperature. Work-up as described in Example 15 gives the product as white solid (0.42 g); m; 140°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)(O)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:10](=[O:37])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:40])=O>ClCCl>[Cl:40][C:18]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:33][CH:34]1[CH2:36][CH2:35]1)[C:10](=[O:37])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cn1cncc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(3-Chloro-phenyl)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (2.3 g, 4.35 mmol) in dichloromethane (60 mL) at 0° C. was treated with thionyl chloride (15 mL). The reaction mixture was warmed to room temperature, stirred for 1 hour, heated to 45° C., and stirred for an additional hour. The mixture was cooled to ambient temperature and concentrated in vacuo to give 6-[Chloro-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one; hydrochloride (2.15 g, 85%) as a bright yellow powder.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.C=O.CC1(C)O[C:18](=O)[CH2:17][C:16](=[O:21])[O:15]1.O>C(#N)C>[N:1]1[CH:2]=[C:3]([CH2:18][CH2:17][C:16]([OH:21])=[O:15])[N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: c1cn2c(n1)CCCCC2
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C=O
Solvent: CC#N
Solvent: O
Product: O=C(O)CCc1cnc2n1CCCCC2

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine in acetonitrile are added aqueous formaldehyde solution and 2,2-dimethyl-1,3-dioxane-4,6-dione with stirring and the mixture is heated for 4 hours. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the resulting 2,2-dimethyl-5-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-ylmethyl)-1,3-dioxane-4,6-dione is dissolved in pyridine with sting. Water and copper powder are added and the mixture is refluxed under heating for 3 hours. After the completion of the reaction, the reaction mixture is filtered while it is hot and the solvent is evaporated under reduced pressure to give 3-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)propionic acid. To a solution of this compound in dimethylformamide are added 4-(4-chlorophenyl)piperidine, triethylamine and cyanophosphonic acid diester and the mixture is stirred at room temperature. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the resulting 1-(4-(4-chlorophenyl)piperidin-1-yl)-3-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)propan-1-one is dissolved in tetrahydrofuran and lithium aluminum hydride is added under ice-cooling with stirring and the mixture is stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the obtained residue is subjected to silica gel column chromatography to give 3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C@H:14]([CH3:17])[C@H:13]([OH:18])[C@@H:12]([CH3:19])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:24]O)(C)(C)C>C1C=CC=CC=1.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[C:1]1([S:7]([C:10]2[C@H:16]3[C@H:15]([O:24]3)[C@H:14]([CH3:17])[C@H:13]([OH:18])[C@@H:12]([CH3:19])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H]1C=CC(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O
Reactant: CC(C)(C)OO
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: c1ccccc1
Product: C[C@@H]1[C@H](O)[C@@H](C)C=C(S(=O)(=O)c2ccccc2)[C@@H]2O[C@H]12
Temperature: 80 °C
Yield: 88 %

Procedure:
A suspension of dienyl sulfone 32 (67 mg, 0.24 mmol), molybdenum hexacarbonyl (3 mg, 0.01 mmol), and tert-butylhydroperoxide (74 μL of 5M solution in decane) in benzene (3 mL) was heated at 80° C. for 10 h. The reaction mixture was concentrated via rotary evaporation, purified by flash column chromatography (ethyl acetate/hexanes; 50:50) to afford 62 mg (88% yield) of epoxide α36 as a light yellow solid. mp 137.0-139.0° C.; [α]20D=+59.3 (c=0.51, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.93-7.96 (m, 2H), 7.58-7.70 (m, 3H), 7.39 (d, J=7.2 Hz, 1H), 3.90 (dd, J=4.5 Hz, 1.5 Hz, 1H), 3.64 (br s, 1H), 3.42 (m, 1H), 3.05-3.15 (m, 2H), 2.55 (tq, J=2.1 Hz, 7.2 Hz, 1H), 1.39 (d J=7.2 Hz, 3H), 1.18 (d, J=7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 147.9, 139.7, 136.5, 133.9, 129.7, 128.2, 78.3, 65.5, 52.5, 41.5, 32.2, 17.4, 17.2; Analytical. Calculated for C15H18O4S: C, 61.20; H, 6.16. Found: C, 60.95; H, 6.07.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH:15]1[CH2:21][CH2:20][C:19]2([O:25][CH2:24][CH2:23][O:22]2)[CH2:18][O:17][C:16]1([CH3:33])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][OH:31])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH2:7]([O:14][CH:15]1[CH2:21][CH2:20][C:19]2([O:22][CH2:23][CH2:24][O:25]2)[CH2:18][O:17][C:16]1([CH3:33])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:32])[CH:30]=[O:31])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(CO)CCCC1(C)OCC2(CCC1OCc1ccccc1)OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C=O)CCCC1(C)OCC2(CCC1OCc1ccccc1)OCCO2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
A solution of pyridine (3.6 g, 0.0444 mol) and chromium trioxide (2.2 g, 0.0222 mol) in methylene chloride (450 ml) at 23° C. in a nitrogen atmosphere is stirred for 45 minutes. The mixture is cooled to -10° C. and celite (13 g) is added followed by (2S*, 3R*)-3-benzyloxy-6,6-ethylenedioxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-oxepane (1.4 g, 0.0037 mol) in methylene chloride (150 ml). The mixture is stirred for 1 hour at -10° C. and 30 minutes at 0° C. The mixture is then filtered and the celite cake is washed with methylene chloride (10×50 ml). The filtrate and washings are combined and washed with saturated sodium bicarbonate (2×150 ml). The methylene chloride phase is separated, dried (MgSO4) and the solvents are removed at reduced pressure. The crude product (1.3 g) is chromatographed on SilicAR CC-7 (25 g, Mallinckrodt) in hexane. Elution with 7-10% ethyl acetate/hexane gives (2S*, 3R*)-3-benzyloxy-6,6-ethylenedioxy-2-methyl-2-(4'-methyl-5'-oxopentyl)-oxepane as a clear colorless oil (1.157 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.CN1CC[O:19][CH2:18]C1.C(O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:18]([NH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=CO
Product: CC(C)(C)OC(=O)c1ccc(NC=O)cc1
Reaction time: 18 h

Procedure:
Combined tert-butyl 4-aminobenzoate (15.3 g, 79 mmol), DMAP (1.935 g, 15.84 mmol), N-methylmorpholine (15.67 mL, 143 mmol) in DCM (120 mL) and, after cooling to 0° C., slowly added formic acid (9.11 mL, 238 mmol). After stirring for 18 h, the reaction was concentrated and then partitioned with 1N HCl (100 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layer was washed with brine (50 mL) and dried (MgSO4). The desired product was collected as yellow syrup (16 g).