Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][CH:7]1[CH:11]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9][C:8]1=O)([O:3][CH2:4][CH3:5])=[O:2].[CH2:21]([OH:24])[CH2:22]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]([CH2:6][CH:7]1[O:24][CH:21]2[CH2:22][CH2:8][CH2:9][CH:10]2[CH:11]1/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: OCCO
Reactant: CCCCCCC=CC1CCC(=O)C1CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC/C=C/C1C(CC(=O)OCC)OC2CCCC21

Procedure:
A mixture of 10.142 g. (0.0362 mole) of 2-(carbethoxymethyl)-3-(1-octenyl)cyclopentanone (ethyl 9-oxo-3,4,5,6,7-pentanor-13-trans-prostenoate, Example 213), 3.49 g. (0.0562 mole) of ethylene glycol, 0.344 g. of p-toluenesulfonic acid monohydrate, and 30 ml. of benzene is refluxed for 4.5 hours with azeotropic removal of water. The mixture is cooled, placed onto a column of 130 g. of Florisil in benzene and the ketal is eluted off with benzene. The filtrate is evaporated to yield 9.53 g. of a colorless oil.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:5][CH2:6][N:7]([C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:35])[CH2:8][CH2:9]1)#[N:3]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)N2CCOCC2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and 4-morpholine carbonyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [S:1]([C:4]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:13])=[CH:6][CH:5]=1)[C:2]#[N:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(#N)C>[CH3:25][O:24][C:22](=[O:23])[CH2:21][O:13][C:7]1[CH:6]=[CH:5][C:4]([S:1][C:2]#[N:3])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2
Reactant: COC(=O)CBr
Reactant: N#CSc1ccc(O)c2c1CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc(SC#N)c2c1CCC2

Procedure:
7-Thiocyanato-indan-4-ol (Example 1B) (3.23 g, 16.89 mmol), cesium carbonate (11 g, 33.8 mmol) and methyl bromoacetate (2.58 g, 16.89 mmol) were stirred in 20 ml acetonitrile at ambient temperature for 4 h. The reaction was filtered and concentrated. The crude product was recrystallized from ethyl acetate/heaxanes to afford the title product. MS m/z 239 (M+1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([Br:11])=[CH:6][N:5]=1.Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15].O>CN(C)C=O>[Br:11][C:7]1[CH:6]=[N:5][C:4]2[NH:3][C:14](=[O:15])[C:13]([CH3:20])([CH3:19])[O:10][C:9]=2[CH:8]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ncc(Br)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.68 g) in N,N-dimethylformamide (15 mL) was added dropwise a solution of 2-amino-5-bromopyridin-3-ol (3.22 g) in N,N-dimethylformamide (25 mL) at room temperature over a period of 10 minutes, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added dropwise ethyl α-bromoisobutyrate (3.32 g) over a period of 20 minutes, and the reaction mixture was stirred at room temperature for 1 hour and at 80° C. for 2 hours. After cooling, to the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively water and brine, dried over magnesium sulfate and concentrated in vacuo by a half volume. The precipitates were collected by filtration to give 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (0.90 g) was obtained as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C(N(CC)CC)C.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:18][CH:19]([CH3:23])[C:20]([NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])=[O:21]
Reactant: CC(Br)C(=O)Br
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cc(C)c1NC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 4-bromo-2,6-dimethylaniline (100.0 g) in tetrahydrofuran (400 mL) was added triethylamine (60.7 g) and 2-bromopropionyl bromide (129.5 g) under ice-cooling. The mixture was stirred at room temperature for 1 hour and cooled in an ice-cooling bath. To the reaction mixture was added a sodium hydrogencarbonate aqueous solution and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water and diethyl ether, and dried to give 2-bromo-N-(4-bromo-2,6-dimethylphenyl)propionamide (151.2 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[CH2:21]([NH:23][CH2:24][CH2:25][OH:26])[CH3:22]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][OH:26])=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CCNCCO
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CCN(CCO)CCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 2-(ethylamino)ethanol were converted to yield 2-[[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-ethyl-amino]-ethanol, MS: 422 (MH+, 1Br).
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][OH:12].N1C=CC=CC=1>C(O)C>[C:1]1(=[N:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCCCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CCCCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution containing cyclooctanone (12.6 g, 0.1 mol) and hydroxylamine hydrochloride (14.0 g, 0.2 mole) in a mixture of pyridine (40 mL, 0.5 mole) and ethanol (50 mL) was stirred at ambient temperature for about 15 hours. The solvent was then removed by rotary evaporation. The residue was dissolved in diethyl ether (300 mL) then washed with hydrochloric acid (2×100 mL). The aqueous layer was extracted with diethyl ether (2×150 mL). The ether extracts were combined, dried over magnesium sulfate then concentrated to provide cyclooctanone oxime as a white solid.
Reaction SMILES: Br[C:2]1[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH3:13]>C(O)C>[NH2:13][C:2]1[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: CC(C)c1ccc(C#N)c(Br)n1
Solvent: CCO
Product: CC(C)c1ccc(C#N)c(N)n1
Yield: 93 %

Procedure:
To a solution of the product of Example 36C (21 g, 0.093 mol) and liquid ammonia (250 mL) in 500 mL of ethanol were reacted in a sealed high-pressure vessel at 130° C. for 20 hours. The reaction mixture was concentrated under vacuum and the residue ground to a fine powder then washed with water (2×50 mL) and dried in a vacuum oven for 24 hours to provide the title compound as a beige solid (14 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:26][CH2:25][O:24][CH3:23])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Oc3ccc(Cl)cc3F)c2cc1OC
Temperature: 180 °C
Yield: 68.6 %

Procedure:
A mixture of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), 2-bromoethyl methyl ether (83 mg, 0.6 mmol) and potassium carbonate (207 mg. 1.5 mmol) in DMF (3 ml) was heated at 180° C. for 45 minutes. The reaction mixture was allowed to cool, diluted with water and acidified to pH3.5. This aqueous mixture was extracted with ethyl acetate and the organic extract was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/ether (7/3) to give 4-(4-chloro-2-fluorophenoxy)-7-(2-methoxyethoxy)-6-methoxyquinazoline (130 mg, 68%).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:26]=[O:27])C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:26]=[O:27])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12.7 g of t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane and 7.5 g of N,N,N′N′-tetramethylethylenediamine in 250 ml of THF was cooled to −75° C. under a nitrogen atmosphere, and then 55.6 ml of s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After adding 7.74 ml of DMF and stirring at −75° C. for 1 hour, the temperature was raised to room temperature. Next, 500 ml of diethyl ether and 500 ml of a 5% aqueous ammonium chloride were added to the reaction mixture, the organic layer was washed twice with 500 ml of water and once with 500 ml of saturated aqueous sodium chloride in that order, and the aqueous layer was extracted with 100 ml of diethyl ether. The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.6 g) as a white solid.
Reaction SMILES: C(OP([CH:9]([CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:25]=O>>[S:21]1[CH:22]=[C:18]([CH2:17][C:9](=[CH2:25])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[N:19]=[CH:20]1
Reactant: CCOP(=O)(OCC)C(Cc1cscn1)C(=O)OC(C)(C)C
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Product: C=C(Cc1cscn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a stirred solution of tert-butyl 2-(diethoxyphosphoryl)-3-(1,3-thiazol-4-yl)propanoate (step 1, 7.17 g, 20.5 mmol) in tetrahydrofran (100 mL) was added sodiumhydride (60% dispersion in mineral oil, 820 mg, 20.5 mmol) at 0° C. under nitrogen. After 10 min, to the mixture was added paraformaldehyde (1.85 g, 61.5 mmol) and the mixture was stirred at room temperature for 45 min. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1) to afford 4.25 g (92%) of the title compound as a colorless oil:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9]2[N+:18]([O-:19])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N+:11]([O-:20])[C:10]=2[C:21]([O:23][CH3:24])=[O:22])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:8][C:9]2[N+:18]([O-:19])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N+:11]([O-:20])[C:10]=2[C:21]([O:23][CH3:24])=[O:22])=[O:33])=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(CSc2ccncc2)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(CS(=O)c2ccncc2)[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
Methyl 3-[(4-pyridyl)-thiomethyl]-2-quinoxalinecarboxylate-1,4-dioxide (0.03 moles) in 120 ml of chloroform was treated dropwise with m-chloroperbenzoic acid (0.03 moles) in 80 ml of chloroform at 0°-5° C. The solution after 2 hours was washed with 5% NaHCO3 solution (3 × 200 ml), water (1 × 60 ml) and then dried over sodium sulfate. The chloroform solution was concentrated to a small volume and added with stirring to 300 ml of ether to precipitate the desired product. Yield, 10.1 grams (94%); m.p. 137°-39° C. (dec.).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[CH2:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[O:17][C:16]=1[C:27]([F:30])([F:29])[F:28]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[O:17][C:16]([C:27]([F:28])([F:29])[F:30])=[C:15]([CH2:14][CH2:13][OH:12])[CH:19]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)Cc1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCc1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.5 M Diisobutylaluminium hydride in toluene (0.8 ml) was added to a solution of methyl[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]acetate (intermediate 86, 0.10 g) in tetrahydrofuran (5 ml) at 0° C. under nitrogen. The solution was allowed to stir thus for 2.5 hours then was quenched with methanol and allowed to warm to room temperature. Silica was added and the solvent was removed in vacuo. The crude product was purified using SPE (silica cartridge): the product was eluted using cyclohexane:ethyl acetate (5:1) and concentrated to form a colourless oil.
Reaction SMILES: [OH-].[Na+].[C:3]1(CC(=O)C(O)=O)C=CC=CC=1.CI.Cl.[O:18]=[C:19]([CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]>C(O)(C)(C)C>[O:18]=[C:19]([C:23]([CH3:3])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)(C)O
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57 %

Procedure:
A 3N aqueous solution of sodium hydroxide (3.0 ml, 9.0 mmoles) and 6 ml of t-butyl alcohol were added to 0.492 g (3.0 mmoles) of phenylpyruvic acid to form a solution. Then, 0.6 ml of methyl iodide was added, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was acidified with 20 ml of 1N hydrochloric acid, and extracted with ether. The organic layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated under reduced pressure to give a pale while oil. The NMR spectral analysis of the product led to the determination that 2-oxo-3-phenylbutanoic acid was formed in a yield of 57 %, and 2-oxo-3-methyl-3phenylbutanoic acid, in a yield of 30 %.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-].[K+]>C(O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:14]1[O:16][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccccc1OCC1CO1

Procedure:
To a solution of 40 parts of o-t-butylphenol, 75 parts of epichlorhydrin, and 40 parts of ethanol boiling under reflux with stirring was added dropwise over 10 minutes a solution of 17.6 parts of potassium hydroxide dissolved in 66 parts of ethanol and the minimum amount of water. The mixture was stirred and refluxed for 105 minutes, cooled, diluted with water, and well extracted with ether, which was then washed with water, dried over magnesium sulphate, and evaporated to an oil. Distillation at 144° /8 mm afforded 43 parts of 3-(2-t-butylphenoxy)-1,2-epoxypropane as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[CH2:6][CH2:5]2.Cl[CH2:16][C:17]([CH3:19])=[CH2:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][C:10]1[C:9]([CH3:12])=[C:8]2[C:4]([CH2:5][CH2:6][N:7]2[CH:13]=[O:14])=[CH:3][C:2]=1[O:1][CH2:18][C:17]([CH3:19])=[CH2:16]
Reactant: Cc1c(O)cc2c(c1C)N(C=O)CC2
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cc2c(c(C)c1C)N(C=O)CC2
Temperature: 60 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
A suspension of 2,3-dihydro-5-hydroxy-6,7-dimethyl-1H-indole-1-carbaldehyde (21.8 g, 0.11 mol), 3-chloro-2-methyl-1-propene (15 mL, 0.15 mol) and potassium carbonate (23.6 g, 0.17 mol) in DMF (200 mL) was stirred at 60° C. for 15 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate four times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, treated with active carbon, filtered, and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to obtain 20.6 g of title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([OH:24])[CH2:22][CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:24][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=2)[CH2:22][CH3:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Yield: 73 %

Procedure:
To a solution of (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-propan-1-ol (described herein above) (21.0 mg, 0.0576 mmol) and 6-chloro-nicotinonitrile (9.6 mg, 0.069 mmol) in 1 mL of DMF was added sodium hydride (60%, 10 mg, 0.25 mmol) at room temperature. The mixture was stirred over night and quenched by an addition of aq. ammonium chloride solution. The mixture was extracted with ethyl acetate and the separated organic layer was washed with water two times and brine subsequently. The organic phase was dried over anhydrous sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (heptane/ethyl acetate 2:1) yielding the titled compound(19.6 mg, 73% yield) as a light yellow oil. ES-MS m/e: 466.1 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](/[CH:15]=[CH:16]/[CH3:17])=[CH:12][N:11]1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[CH:22][C:21]=1[N+:39]([O-])=O)=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Zn].C(O)=O.C(O)C>[NH2:39][C:21]1[CH:22]=[C:23]([O:28][Si:29]([CH:33]([CH3:34])[CH3:35])([CH:36]([CH3:38])[CH3:37])[CH:30]([CH3:32])[CH3:31])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[C:18]([N:11]1[CH:12]=[C:13](/[CH:15]=[CH:16]/[CH3:17])[CH2:14][C@H:10]1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[O:19]
Reactant: C/C=C/C1=CN(C(=O)c2cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc2[N+](=O)[O-])[C@H](CO[Si](C)(C)C(C)(C)C)C1
Agent: [Zn]
Solvent: CCO
Solvent: O=CO
Product: C/C=C/C1=CN(C(=O)c2cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc2N)[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Zinc dust (22.0 g, 0.33 mol, 37 eq) was added, in portions over 20 mins, to a solution of the propenyl intermediate 6 (5.5 g, 9.1 mmol, 1.0 eq) in 5% v/v formic acid/ethanol (55 mL), using an ice bath to maintain the temperature between 25-30° C. After 30 mins, the reaction mixture was filtered through a short bed of Celite®. The Celite® was washed with ethyl acetate (65 mL) and the combined organics were washed successively with water (35 mL), saturated sodium bicarbonate (35 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 90/10 v/v n-hexane/EtOAc) to afford the product as a pale yellow oil (3.6 g, 69.0%). LC/MS (4.439 min (ES+)), m/z: 575.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 6.75 (m, 1H), 6.40 (br s, 1H), 6.28 (m, 1H), 6.11 (d, 1H, J=15.4 Hz), 5.53 (m, 1H), 4.67 (m, 1H), 4.36 (m, 2H), 3.93 (br s, 1H), 3.84 (br s, 1H), 3.73 (s, 3H), 2.86 (dd, 1H, J=15.7, 10.4 Hz), 2.73 (dd, 1H, J=15.9, 4.5 Hz), 1.80 (dd, 3H, J=6.8, 1.3 Hz), 1.35-1.23 (m, 3H), 1.12 (d, 18H, J=7.3 Hz), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: C([C:4]1[C:5]([O:16][CH2:17][C:18]([Cl:20])=[CH2:19])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[CH3:15])(=O)C.ClC(=C)[CH2:23][O:24]C1C(O)=C2C(C(C)=CC(=O)O2)=CC=1>>[Cl:20][C:18](=[CH2:19])[CH2:17][O:16][C:5]1[C:4]([O:24][CH3:23])=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][C:11](=[O:14])[O:12]2)=[CH:7][CH:6]=1
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1O
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1C(C)=O
Product: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1OC

Procedure:
As shown in FIG. 24, the synthesis pathway for the compounds of the present invention involves starting with the following compound, Compound 1: ##STR5## This starting compound in the synthesis of Compound 2 is 4,5'-dimethyl-8-methoxypsoralen. The synthesis of this precursor compound has been described previously in the literature. See Bender, et al., J. Org. Chem. 44:2176 (1979). Alternatively, the starting compound may be synthesized by the following method: 8-acetyl-7-(2-chloroallyl)oxy-4-methylcoumarin, described in Bender, et al., J. Org. Chem. 48:2709 (1983), is initially oxidized to a phenolic compound, 7-(2-chloro-2-propenyl)oxy-8-hydroxy-4-methylcoumarin, and then methylated, providing 7-(2-chloro-2-propenyl)oxy-8-methoxy-4-methylcoumarin. Claisen rearrangement provides 6-(2-chloro-2-propenyl)-7-hydroxy-8-methoxy-4-methylcoumarin, which is then converted to 4,5'-dimethyl-8-methoxypsoralen.