Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[C:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([O:16][CH3:26])=[O:15])=[C:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1
Reactant: O=C(O)c1ccncc1NCc1ccc(Cl)cc1C1CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccncc1NCc1ccc(Cl)cc1C1CC1
Yield: 31 %

Procedure:
To a solution of Example 26 (15 mg, 0.05 mmol) in MeOH (10 mL) was added thionyl chloride (1 mL) at rt. The reaction was stirred at reflux for 2 days. The solution was concentrated and purified by prep-HPLC to give 5 mg (31%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 0.70-0.73 (2H, m), 1.0-1.04 (2H, m), 2.0-2.04 (1H, m), 3.96 (2H, s), 4.74 (3H, s), 7.08 (1H, d, J=1.6 Hz), 7.14 (1H, dd, J=2.0, 8.4 Hz), 7.25 (1H, d, J=8.0 Hz), 7.91 (1H, d, J=4.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.13 (1H, s). [M+H] Calc'd for C17H17ClN2O2, 317; found, 317.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([OH:11])[CH:8]=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([O:11][C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=1)[CH2:8][CH2:7]2
Reactant: OC1C=Cc2cccc(Br)c21
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(OC2CCc3cccc(Br)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
To a mixture of 7-bromoinden-1-ol (1.06 g), triphenylphosphine (1.86 g), 4-chlorophenol (911 mg), and toluene (30 mL) was added dropwise diethyl azodicarboxylate (2.2 M toluene solution, 3.3 mL) at room temperature. After dropwise addition, the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and then the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 7-bromo-1-(4-chlorophenoxy)indane (306 mg).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([N:9]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.CCOC(C)=O>[NH2:3][CH2:2][CH2:1][NH:4][C:12]1[C:13](=[O:14])[N:9]([C:5]([CH3:7])([CH3:6])[CH3:8])[S:10](=[O:23])(=[O:22])[C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(NCCN)=C(c2ccccc2)S1(=O)=O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
Ethylenediamine (0.60 g, 10.0 mmol) was dissolved in dry DMF (50 ml) and heated to 60° C. 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.00 g, 3.34 mmol) dissolved in DMF (10 ml) was added dropwise over 30 mins and stirred at 60° C. for 10 mins. The reaction mixture was diluted with EtOAc (300 ml) and washed with water (400 ml and 2×200 ml), dried (Na2SO4), filtered and evaporated to give the title compound (0.97 g, 90%). 1H-NMR (500 MHz, CDCl3): δ 7.50-7.45 (m, 2H), 7.42-7.37 (m, 3H), 5.83-5.76 (m, 1H), 2.84-2.78 (m, 2H), 2.67-2.62 (m, 2H), 1.71 (s, 9H); 13C-NMR (125 MHz, CDCl3): δ 159.7, 135.4, 131.6, 129.5, 128.6, 125.2, 106.9, 61.5, 46.2, 40.8, 27.7; Mass Spectrum: M+H+ 324.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][Cl:33])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: ClCCCBr
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a suspension of 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-ol (5.59 g), K2CO3 (7.06 g) in DMF (60 mL) was added 1-bromo-3-chloropropane (6.06 mL) at rt, the mixture was stirred at 40° C. for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (5.80 g, 77.00%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.N1C=C[CH:23]=[CH:22][CH:21]=1.C(OCC)(OCC)(OCC)CC>C1(C)C=CC=CC=1.ClC(Cl)C>[CH2:22]([C:23]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:21]
Reactant: Nc1cnc2ccccc2c1NCCOCCO
Reactant: c1ccncc1
Agent: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: CCc1nc2cnc3ccccc3c2n1CCOCCO
Temperature: 25 °C
Yield: 904.4 %

Procedure:
A mixture of 2-{2-[(3-aminoquinolin4-yl)amino]ethoxy}ethanol (43.0 g, 155 mmol) and pyridine hydrochloride (1.79 g, 15.5 mmol) in toluene (200 mL) and dichloroethane (100 mL) was heated at reflux until a solution formed. The solution was allowed to cool to room temperature, then was cooled to 0° C. Triethyl orthopropionate (30.1 g, 171 minol) was added and the mixture was heated at reflux for 3 hours. The solution was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was diluted with chloroform and 4 M NaOH was added to adjust the pH to 9. The mixture was filtered and the isolated solid dissolved when it was washed with water and chloroform. The filtrate was transferred to a separatory fimnel and washed twice with brine. The combined aqueous layers were back-extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to provide 40.0 g of 2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethanol as a tan solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:29])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](O)=[O:16])=[CH:11]2.Cl.C([N:33]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH3:29])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:33])=[O:16])=[CH:11]2
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (1.072 g) in N,N-dimethylformamide (15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.98 g) and 1-hydroxybenzotriazole ammonium salt (0.788 g) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. Water and ethyl acetate were added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed successively with brine and water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate: methanol=100:0 to 95:5, volume ratio) to give the title compound. (910 mg, 85%) as a white amorphous solid. MS 419 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.S(=O)(=O)(O)O.[BrH:17]>>[Br:17][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: Br
Reactant: CC(C)CCCC(C)CCO
Agent: O=S(=O)(O)O
Product: CC(C)CCCC(C)CCBr
Temperature: 100 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
3,7-Dimethyloctan-1-ol (10.0 g, 63.2 mmol) was suspended in 48% aqueous hydrobromic acid solution, concentrated sulfuric acid (0.17 ml) was added dropwise and the mixture was stirred at 100° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, extracted with hexane (200 ml), and washed twice with 5% aqueous sodium hydrogen carbonate solution (100 ml) and once with 20% brine (100 ml). The organic layer was dried over sodium sulfate, and the solvent in the filtrate was evaporated to give the title compound (13.3 g, 95.1%) as a colorless oil.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.CS(C)=O.Br[CH2:14][C:15]1[O:19][N:18]=[C:17]([CH:20]([C:22]#[CH:23])[OH:21])[CH:16]=1.OP([O-])(O)=O.[K+]>C(Cl)Cl>[OH:21][CH:20]([C:17]1[CH:16]=[C:15]([CH:14]=[O:5])[O:19][N:18]=1)[C:22]#[CH:23]
Reactant: C#CC(O)c1cc(CBr)on1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: C#CC(O)c1cc(C=O)on1
Reaction time: 5 h
Yield: 292.3 %

Procedure:
9.8 g of 4-methyl morpholine oxide, 68 cm3 of dimethylsulphoxide and 34 cm3 of methylene chloride are added at 0° C. to a solution containing 4 g of the product prepared in Stage C and 30 cm3 of methylene chloride. The mixture is allowed to return to 20° C. and agitated for 5 hours. It is poured into an aqueous solution of potassium acid phosphate. Extraction is carried out with ethyl acetate, the extracts are dried, filtered and brought to dryness. 8.18 g of product is obtained which is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (1-1). In this way 1.96 g of desired product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[Cl:12])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][C:6]=1[Cl:12])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1Cl
Yield: 86.9 %

Procedure:
16.76 g (83.5 mmol) of 2-chloro-4-hydroxy-benzoic acid ethyl ester and 23.1 g (167 mmol) of potassium carbonate were added to 100 mL of methyl ethyl ketone followed by the addition of 17.1 g (100 mmol) of bromomethylbenzene while stirring. After refluxing for 28 hours, the mixture was cooled and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 21.1 g of a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH2:22]([NH2:25])[CH2:23][CH3:24]>O>[CH3:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[NH:25][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: CCCN
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Solvent: O
Product: CCCNc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
A mixture of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.47 g, 5.00 mmol) and propylamine (2.96 g, 50.0 mmol) was heated and stirred at 100° C. for 6 hours in a sealed stainless tube. The solution was allowed to cool to room temperature and poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1), and the resulting crystals were recrystallized from ethyl acetate/hexane to give the title compound (1.14 g, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([CH3:10])[CH:3]=1.N([O-])=O.[Na+].S(=O)(=O)(O)N.[BrH:20]>O>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([Br:20])=[C:4]([CH3:10])[CH:3]=1
Reactant: Br
Reactant: Cc1cc(Cl)cc(C)c1N
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)cc(C)c1Br
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To an initial charge of 65 ml of 48% aqueous HBr are added, in portions, 15.56 g [0.1 mol] of 4-chloro-2,6-dimethylaniline. The resulting thick suspension is stirred at 80° C. for 15 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 40 minutes at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the suspension of the diazonium salt cooled to −10° C. is metered within about 25 minutes into a solution, heated to 80° C., of 28.6 g [0.103 mol] of FeSO4×7H20 in 65 ml of 62% aqueous HBr. The reaction mixture is then stirred at 80° C. for another 1 hour, allowed to cool to room temperature and admixed with 125 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 17.2 g of an oil which, according to GC, contains 95.6% 4-chloro-2,6-dimethylbromobenzene (75% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:27])[CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]2)=[O:15])[C:11]([CH2:34][OH:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:37]>C1C=CC=CC=1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:27])[CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]([O:26][CH3:37])=[O:25])[CH2:21][CH2:22]2)=[O:15])[C:11]([CH2:34][OH:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CC(=O)O)CC1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)CN1CCC(N(C)C(=O)N2CC(c3cc(F)ccc3F)=CC2(CO)c2ccccc2)CC1
Reaction time: 2 h

Procedure:
To 30 mg (0.06 mmol) of amino acid 17-1 in 1:1 PhH/MeOH was added 120 μL (0.24 mmol) of TMS-diazomethane. After stirring for 2 h, the reaction was concentrated by rotary evaporation and the residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 17-2 as a colorless film. Data for 17-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.45 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.7 (s, 3H), 3.2 (m, 2H), 3.05 (m, 2H), 2.9 (s, 3H), 2.3 (m, 2H), 2.0-1.8 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C27H31F2N3O4: 500.2356. Found: 500.2331.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]([CH3:41])([C:34]([O:36]C(C)(C)C)=[O:35])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>C(Cl)Cl>[CH3:8][C:9]([CH3:41])([C:34]([OH:36])=[O:35])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCC(C)(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCOCCOCCOCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 114.7 %

Procedure:
TFA (1.5 mL, 19.3 mmol) was added dropwise to a stirred solution of tert-butyl 25,25-dimethyl-2,5,8,11,14,17,20,23-octaoxahexacosan-26-oate (58) (0.48 g, 0.97 mmol) in DCM (5 mL), and the reaction was stirred at RT for 4 h. The volatiles were removed in vacuo to afford 25,25-dimethyl-2,5,8,11,14,17,20,23-octaoxahexacosan-26-oic acid (59) (0.49 g, 95%) as a colourless oil: 1H NMR (400 MHz, CDCl3) δ: 3.68-3.60 (m, 26H), 3.55-3.52 (m, 2H), 3.47 (s, 2H), 3.36 (s, 3H), 1.18 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[Cl:10][CH2:11][CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:24][C:18]=3[C:17]([N+:29]([O-:31])=[O:30])=[CH:16][C:15]=2[N:14](C(=O)C(F)(F)F)[CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].CO>O>[Cl:10][CH2:11][CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][C:23]([S:25]([NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:26])=[O:27])=[CH:24][C:18]=3[C:17]([N+:29]([O-:31])=[O:30])=[CH:16][C:15]=2[NH:14][CH2:13]1
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
t-Butyl carbazate (86 mg, 0.65 mmol) was added to a solution of 116 (107 mg, 0.23 mmol) in ThF (5 mL) and the mixture was stirred at room temperature for 16 h. Cs2CO3 (150 mg, 0.46 mmol) and MeOH (2 mL) were added and the mixture was stirred for a further 2 h. The mixture was diluted with water and extracted with CH2Cl2 (×2). The combined extracts were dried and evaporated and the residue was purified by chromatography, eluting with EtOAc/petroleum ether (1:4 then 2:3). The product was recrystallised from EtOAc/petroleum ether to give tert-butyl 2-{[1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}hydrazinecarboxylate (119) (72 mg, 67%) as an orange crystalline solid: mp 179° C. (dec.); 1H NMR [(CD3)2SO] δ 9.60 (br s, 1H), 9.18 (v br s, 1H), 8.54 (d, J=1.4 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.75 (s, 1H), 7.74 (dd, J=8.9, 1.8 Hz, 1H), 6.74 (s, 1H), 4.29-4.22 (m, 1H), 3.94-3.85 (m, 2H), 3.80 (dd, J=11.0, 8.0 Hz, 1H), 3.74 (dd, J=10.5, 3.0 Hz, 1H), 1.10 (br s, 9H). HRMS (FAB) calcd. for C18H2135ClN4O6S (M+) m/z 456.0870, found 456.0877.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CS(C)=O>[CH2:28]([NH:35][CH2:11][CH:12]1[O:26][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:25])[CH2:18]3)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(C)c4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C3)OC(CNCc1ccccc1)CO2
Temperature: 85 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.57 g, 4.04 mmole) and benzylamine (2.18 g, 5.6 mmole) were combined in 10 ml of dry DMSO and heated to 85° C. for 3 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an orange oil. Column chromatography on silica gel using 2% methanol/CH2Cl2 as eluant gave 1.08 g of the free base of the title compound as a light beige solid. This was crystallized from isopropanol with the addition of fumaric acid (0.42 g, 3.7 mmole) to give 0.49 g of the (S) enantiomer of the title compound as a beige solid fumarate, m.p. 219-220° C.
Reaction SMILES: [CH2:1]([CH:3]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8][CH3:9])[CH3:2].[CH2:21](Br)[C:22]#[CH:23]>>[CH2:23]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8][CH3:9])=[CH:13][CH:14]=1)[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: CCC(C)=CCCC(CC)Oc1ccc(C(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OC(CC)CCC=C(C)CC)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1-ethyl-5-methyl-4-heptenyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(1-ethyl-5-methyl-4-heptenyl)oxy]benzoic acid propargyl ester; nD21 = 1.5200.
Reaction SMILES: [C:1]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCCC.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)=[O:42].BrCCCC([O-])=O>>[C:1]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[O:42])[CH:12]=1)(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC/C=C/C(=O)c1c[nH]c2ccccc12
Reactant: COc1ccc(COC(=O)CCCBr)cc1
Agent: CCCCCCC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])CCCBr
Product: CCCCCC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12

Procedure:
The procedure of Ex. 1 was repeated except that (E)-3-(2-nonenoyl) indole obtained in Pre. Ex. 22 was used in place of 3-heptanoylindole, and 4-methoxybenzyl 4-bromobutyrate obtained in Step 5 of Pre. Ex. 19 was used in place of 4-bromobutyrate to give (E)-4-methoxybenzyl 4-[3-(2-nonenoyl)-1-indolyl]butyrate as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:24](=[O:25])[CH:23]3[CH:18]([CH:19]4[CH2:27][CH2:26][CH:22]3[CH2:21][CH2:20]4)[C:17]2=[O:28])=[C:11]([CH3:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:29])[C:12]([C:16]2[C:17](=[O:28])[CH:18]3[CH:23]([CH:22]4[CH2:26][CH2:27][CH:19]3[CH2:20][CH2:21]4)[C:24]=2[O:25][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C2C3CCC(CC3)C2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3CCC(CC3)C2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-benzyloxy-2,6-dimethylphenyl)hexahydro-4,7-ethanoindene-1,3-dione (2.9 g, 0.008 mol), pivaloyl chloride (1.5 ml, 0.012 mol), triethylamine (2 ml, 0.0014 mol) and dichloromethane (100 ml) is stirred at room temperature for 3 hours. The reaction mixture is next evaporated and the crude product is dissolved in dichloromethane, absorbed on to silica then purified by flash column chromatography (20% ethyl acetate in hexanes as eluant) to afford 2,2-dimethylpropionic acid 2-(4-benzyloxy-2,6-dimethylphenyl)-3-oxo-3a,4,5,6,7,7a-hexahydro-3H-4,7-ethanoinden-1-yl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:14](=O)[O:13]C1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:22]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:14]([NH2:22])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Reactant: N
Solvent: C1CCOC1
Product: CC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Reaction time: 5 h
Yield: 82 %

Procedure:
Ten grams of the (S)-3-(benzyloxycarbonyl)-4-(3-oxobutyl)-5-oxazolidinone from Example 4 is dissolved in 480 ml of distilled tetrahydrofuran, followed by 160 ml of ammonia at 0° C. The reaction mixture is stirred at 0° for 5 hours, then at ambient temperature overnight. After stripping under vacuum to dryness, the reaction mixture yields a white solid which is recrystallized from hot ethyl acetate to give 8.8 g of (S)-2-(benzyloxycarbonylamino)-5-oxo-hexanamide as a white solid (82% yield), mp 142°-144°; [α]D25 =-4.0° (c 0.4, CH3OH).