Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:31]([CH3:33])([CH2:32][C@@H:13]12)[C@@H:30]1[C@H:19]([C@H:20]2[C@:27]([CH3:35])([CH2:28][C:29]1=[O:34])[C@@H:23]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3.[Cl-].[NH4+]>CCOCC>[CH2:1]([C@H:13]1[CH2:32][C@@:31]2([CH3:33])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:30]2[C:29](=[O:34])[CH2:28][C@@:27]2([CH3:35])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:24](=[O:26])[CH3:25])[CH2:15][C@@H:14]1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A 2 molar solution of n-butyl lithium in hexane (30 ml., 60mmole) was added to a stirred suspension of cuprous iodide (5.7 g., 30 mmole) in dry ether (90 ml.) under nitrogen at -20°. A cold solution of 2α,3α-epoxy-5α-pregnane-11,20-dione (1.65 g., 5 mmole) in dry ether (260 ml.) was then added and the mixture was maintained at 0° for 70 hr. The reaction mixture was then poured into aqueous ammonium chloride solution and extracted into ethyl acetate.
Reaction SMILES: C([Li])CCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[Br:13][C:14]1C=C[C:17]2[O:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[O:21][C:16]=2[CH:15]=1.CI.Cl>O.O1CCCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:18][C:19]([F:24])([F:25])[C:20]([F:22])([F:23])[O:21][C:12]=2[C:10]=1[CH3:11]
Reactant: FC1(F)Oc2ccc(Br)cc2OC1(F)F
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1OC(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
Under nitrogen atmosphere, 11.7 ml of n-butyllithium (1.57 M-n-hexane solution) was dropwise added at −20° C. to a mixture of 1.85 g of diisopropylamine and 50 ml of tetrahydrofuran, and then the mixture was stirred at the same temperature for 30 minutes. 5.0 g of 6-bromo-2,2,3,3,-tetrafluoro-1,4-benzodioxane was dropwise added thereto at a temperature of at most −50° C., followed by stirring at the same temperature for 30 minutes. Then, 5.5 ml of methyl iodide was dropwise added thereto at a temperature of at most −70° C., and then the temperature was raised to room temperature, followed by a reaction for 15 hours. After completion of the reaction, the reaction mixture was put into water and then weakly acidified by an addition of hydrochloric acid. Then, the mixture was extracted with ethyl ether, and the extract was washed with water and dried over magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane) to obtain 3.40 g of oily 6-bromo-2,2,3,3,-tetrafluoro-5-methyl-1,4-benzodioxane. The NMR spectrum data of this product were as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[Si](C=[N+]=[N-])(C)(C)[CH3:13].CCOCC>C1COCC1.CO>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c(Br)c1
Yield: 100 %

Procedure:
3-Bromo-4-fluoro-benzoic acid (2.5 g, 11.42 mmol) was placed in a 100 ml round bottom flask charged with a stir bar, sealed with a septum and placed under a nitrogen atmosphere and dissolved in 9 ml dry THF and 3 ml dry MeOH. A 2.0M solution of TMSdiazomethane in ether (6.28 ml, 12.56 mmol) was added dropwise to the stirring solution of the acid. Conversion of the acid to the ester was complete after twenty minutes according to LC/MS analysis. The solvent was removed under reduced pressure and product was used without further purification. Recovered a light oil (2.66 g, 100% yield) LC/MS (10-99%) M/Z 234, retention time 3.09 minutes.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH:17]1[CH2:22][CH2:21][N:20]([C:23](=O)[CH2:24][C:25]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:26]=2[CH3:32])[CH2:19][CH2:18]1>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:26]=2[CH3:32])[CH2:21][CH2:22]1
Reactant: Cc1ccc(N)cc1CC(=O)N1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1CCN1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
A mixture of (2-methyl-5-nitrophenyl)acetic acid (2.5 g) and 1,1′-carbonyldiimidazole (2.1 g) in dimethyl formamide (50 mL) was stirred at room temperature for 15 min and subsequently added a solution of 7-chloro-3-(piperidin-4-yl)-1H-indole (3.0 g) in dimethyl formamide (50 mL). The resulting mixture was stirred at room temperature for 1 h and poured onto an ice/water mixture. The compound was isolated by filtration and dissolved in tetrahydrofuran. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 7-chloro-3-{1-[2-(2-methyl-5-nitrophenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (4.7 g). A mixture of 7-chloro-3-{1-[2-(2-methyl-5-nitrophenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (16.6 g) and ethanol (500 mL) was heated to reflux temperature and subsequently added concentrated HCl (22 mL) and iron powder (11.3 g) over a period of 30 min. The resulting mixture was boiled under reflux for an additional 90 min, filtered hot and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give give 7-chloro-3-{1-[2-(5-amino-2-methylphenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (14.3 g). A suspension of lithium aluminium hydride (6.4 g) in tetrahydrofuran (250 mL) was cooled (5° C.) and subsequently added a mixture of 7-chloro-3-{1-[2-(5-amino-2-methylphenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (16.0 g) in tetrahydrofuran (250 mL). The resulting mixture was boiled under reflux for 90 min, cooled to 5° C. and quenched by the addition of water. The mixture was dried (MgSO4), stirred for 10 min, filtered and concentrated in vacuo to give 7-chloro-3-{1-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-1H-indole (12.4 g). A solution of 7-chloro-3-{1-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-1H-indole (1.0 g) and N-ethyldiisopropylamine (0.7 g) in tetrahydrofuran (25 mL) was cooled (5° C.) and subsequently added a solution of (4-fluorophenyl)acetyl chloride in tetrahydrofuran (25 mL). The resulting mixture was stirred at room temperature for 1 h and subsequently poured onto brine. The aqueous phase was extracted with tetrahydrofuran, and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/heptane/triethylamine 70:30:5) to give the product (0.81 g). LC/MS (m/z) 504 (MH+), RT=2.45, purity: 62%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:35][CH3:36]>>[NH:2]=[C:1]([N:40]1[CH2:41][CH2:42][N:37]([CH2:34][CH2:35][CH3:36])[CH2:38][CH2:39]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCN1CCNCC1
Product: CCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 30 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of n-propylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]([CH3:30])([CH3:29])[CH2:8][NH:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[C:14]=1[F:28])[CH2:11][CH3:12])C(C)C.[OH-].[Na+]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:10]([NH:9][CH2:8][C:7]([CH3:30])([CH3:29])[C:6]([OH:31])=[O:5])[CH2:11][CH3:12])=[C:14]([F:28])[C:15]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CC[C@@H](NCC(C)(C)C(=O)OCC(C)C)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H](NCC(C)(C)C(=O)O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step 4 A mixture of crude 3-{(R)-1-[4-Chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propylamino}-2,2-dimethyl-propionic acid isobutyl ester (assumed 1.15 mmol), NaOH (aq., 5M, 230 μL. 1.15 mmol) and THF (3 mL) was stirred at room temperature overnight. Only partial reaction. A further 1 eq. of NaOH was added, stirred for 8 h, and then another 2 eq. NaOH added and stirred overnight. LCMS: [MH]+ 393, 73%. Concentrated to give crude 3-{(R)-1-[4-Chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propylamino}-2,2-dimethyl-propionic acid and used directly in next reaction.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[CH:7]=[CH:6][C:5]=1[C:20]1[N:24]([C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[N:23]=[CH:22][C:21]=1[C:30]([O:32]CC)=[O:31]>C(O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[CH:7]=[CH:6][C:5]=1[C:20]1[N:24]([C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[N:23]=[CH:22][C:21]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cnc(OC)c2C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ncc(C)c(-c2ccc(-c3c(C(=O)O)cnn3[C@H]3CCOC3)c(F)c2)c1C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
A 5 N aqueous sodium hydroxide solution (79 mL) was added to a solution of ethyl 5-[2-fluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (43.2 g) in ethanol (574 mL) at mom temperature, and the reaction mixture was stirred at 60° C. for two hours and 10 minutes. The reaction mixture was cooled to room temperature and then concentrated to half volume under reduced pressure. Water (300 mL) was added to the residue, and ethanol was distilled off under reduced pressure. MTBE (130 mL) was added to the resulting residue, and the aqueous layer was separated. The organic layer was extracted with water (30 mL). The combined aqueous layers were made acidic with 5 N hydrochloric acid (78 mL) under ice-cooling and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (39.0 g).
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH2:37][CH3:38])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C>O1CCCC1.CN>[CH2:37]([C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([NH:8][CH3:6])=[O:39])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=1)[CH3:38]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CN
Solvent: C1CCOC1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)NC)CC2)c(C)c1
Yield: 14.1 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 809 and 2 mol/L methylamine tetrahydrofuran solution (220 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (7 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:15])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.S(Cl)(Cl)=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.ClCCCl>CCOC(C)=O.O.[Cl-].[Na+].O.C([O-])(O)=O.[Na+].[Pd].CO>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]([F:1])([F:15])[C:3]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:5])=[CH:7][CH:8]=1
Reactant: O=C(O)C(F)(F)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)C(F)(F)c2ccc(N)cc2)CC1
Temperature: 79 °C
Yield: 86 %

Procedure:
Difluoro-(4-nitro-phenyl)-acetic acid (106 mg, 0.488 mmol) was suspended in Thionyl chloride (1.00 mL, 13.7 mmol) and heated at 79° C. in a vial for 5 h. Conc. and azeotroping with toluene afforded a residue, which was dried in vacuo. 1-Methyl-piperazine (0.100 mL, 0.902 mmol), N,N-Diisopropylethylamine (0.250 mL, 1.44 mmol) and 1,2-Dichloroethane (1.00 mL, 12.7 mmol) were added to the residue. The mixture was diluted with EtOAc (10 mL) and water:brine:NaHCO3 (1:3:2, 6 mL), the layers separated and the aq. extr. with DCM (2×3 mL). The comb. org. were dried, filtered and conc. in vacuo to give an oil which very slowly crystallizes. The crude amide (124 mg) was shaken under an atmosphere of Hydrogen (15 psi) over 10% Palladium on Carbon (50% Wet) (24 mg, 0.011 mmol) in Methanol (10.0 mL) overnight. Filtration and conc. afforded 2-(4-Amino-phenyl)-2,2-difluoro-1-(4-methyl-piperazin-1-yl)-ethanone (0.113 g; Yield=86.0%) as a film.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[NH:16][C:15]=2[CH:20]=1.[H-].[Na+].[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].Cl>CN(C)C=O.O>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[N:16]([CH2:28][CH2:27][O:26][C:23](=[O:25])[CH3:24])[C:15]=2[CH:20]=1
Reactant: Cc1c(-c2ccc3sc(=O)[nH]c3c2)nc2ccccn12
Reactant: CC(=O)OCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCn1c(=O)sc2ccc(-c3nc4ccccn4c3C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
A mixture of 5-(3-methylimidazo[1,2-a]pyridin-2-yl)-2-benzothiazolinone (2.8 g) and sodium hydride (50% suspension in oil, 0.96 g) in dry dimethylformamide (30 ml) was stirred at ambient temperature for 30 minutes. To the resultant mixture was added 2-bromoethyl acetate (3.34 g) at ambient temperature and stirred for 5 hours under the same condition. The reaction mixture was poured into water and adjusted to pH 7.0 with 10% hydrochloric acid. The neutrallized solution was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate and diisopropyl ether (8:2). The fractions containing the desired compound was combined and evaporated in vacuo. The crystalline residue was recrystallized from ethyl acetate to afford 5-(3-methylimidazo[1,2-a]pyridin-2-yl)-3-(2-acetoxyethyl)-2-benzothiazolinone (1.3 g). mp. 113°-115° C.
Reaction SMILES: Cl.[CH2:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22]C)[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:3][CH3:4].CO>O>[CH2:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:3][CH3:4]
Reactant: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: Cl
Solvent: O
Solvent: CO
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Yield: 13.7 %

Procedure:
Add 3N hydrochloric acid (1 cc.) to a solution of 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.61 g.) in boiling methanol (70 cc.) and cool the mixture immediately and allow to stand for 4 1/2 hours. Pour the product into water (300 cc.) and extract the mixture with ether; work up in the usual way to give as residue an amorphous solid (0.6 g.). Crystallize this solid from a mixture of ether and hexane. Take up the resulting solid in benzene (20 cc.) and chromatograph on a column of neutral alumina. Elute the product with ether and recrystallize from a mixture of ether and hexane to obtain 13β-n-propyl-17β-hydroxy-gon-4-en-3-one (0.08 g.), mp. 126°-7°; ultraviolet absorption peak at 240 mμ (ε 15,000); infrared absorption peaks at 2.92, 6.01, 6.20 μ. Evaporation of the mother liquors gives a second, polymorphic, form of the same substance (0.17 g.), m.p. 144°-5°, having ultraviolet and infrared spectra identical with the first material; a mixture of the two forms has m.p. 144°-5°.
Reaction SMILES: [CH3:1][O:2][Si:3]([C:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH:10]=[CH:9]2)([O:6][CH3:7])[O:4][CH3:5].C([SiH]([CH2:20][CH3:21])CC)C.[CH2:22](O)[CH3:23]>ClCCl.C1COCC1.C1(C)C=CC=CC=1>[CH2:22]([C:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH:10]=[CH:9]2)[CH2:23][CH2:20][CH3:21].[CH3:1][O:2][Si:3]([C:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH:10]=[CH:9]2)([O:4][CH3:5])[O:6][CH3:7]
Reactant: CCO
Reactant: CC[SiH](CC)CC
Agent: CO[Si](OC)(OC)C12C=CC(CC1)C2
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCC12C=CC(CC1)C2
Temperature: 80 °C

Procedure:
BuNB (10.97 g, 0.073 mol), Trimethoxysilyl Norbornene (TMSNB, CAS 7538-46-7) (12.95 g, 0.073 mol), triethyl silane (0.34 g, 2.91E-04 mol), ethanol (0.80 g, 1.75E-03 mol) and toluene (170.0 g) were combined in a 500 mL serum bottle and heated to 80° C. in an oil bath to form a solution. To this solution were injected Pd1446 (0.017 g, 1.16E-05 mol) and DANFABA (0.028 g, 3.49E-5 mol), each in the form of a concentrated solution in dichloromethane. After addition, the resulting mixture was maintained at 80° C. for 4 hours. The copolymer was precipitated by adding methanol drop wise into the vigorously stirred reaction mixture. The precipitated copolymer was collected by filtration and dried in an oven at 60° C. under vacuum. After drying, 15.5 g was obtained (65%). The molecular weight of the copolymer was determined by GPC in THF solvent (polystyrene standard) to be Mw=48,000 and Mn=27,000. The composition of the copolymer was determined by 1H-NMR to be (47/53) BuNB/TMSNB copolymer. The refractive indices of this polymer were measured by prism coupling method and determined to be 1.5093 in TE mode and 1.5089 in TM mode at a wavelength of 633 nm. The dried copolymer was dissolved in sufficient toluene to result in a 30 wt % copolymer solution.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2([CH2:11][CH2:10]2)[CH2:8][N:7]([C@@H](C2C=CC=CC=2)C)[CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][CH:5]1[C:9]2([CH2:11][CH2:10]2)[CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CN([C@H](C)c2ccccc2)CC12CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC1CNCC12CC2
Yield: 91.9 %

Procedure:
A suspension of 1.5 g of compound 12 and 500 mg of lithium aluminum hydride in 30 ml of tetrahydrofuran was refluxed for 16 hours. 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added to the mixture in the mentioned order, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated to dryness to yield 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane as a pale yellow oil. 5 ml of acetic anhydride and 5 ml of pyridine were added to 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane which was cooled on an ice-bath. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added thereto and the solution was washed with saturated aqueous sodium bicarbonate and water, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane as a yellow oil. A mixture of 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2.4]heptane and 1.2 g of palladium-on-carbon (50% water wet) in 20 ml of ethanol was shaken under 3.8 atm of pressured hydrogen atmosphere for 5 hours. During the reduction reaction, the reaction vessel was warmed by a tungsten lamp. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 880 mg of title compound 69 as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4](=[CH:9][OH:10])[C:5]([O:7][CH3:8])=[O:6].CO.Cl.[C:15](#N)C>>[CH3:8][O:7][C:5](=[O:6])[C:4](=[CH:9][O:10][CH3:15])[C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)C(=CO)C(=O)OC
Reactant: CC#N
Agent: Cl
Solvent: CO
Product: COC=C(C(=O)OC)C(=O)OC
Reaction time: 24 h
Yield: 79 %

Procedure:
160 g (1.0 mol) of hydroxymethylenemalonic acid dimethyl ester is dissolved in 288 g (9.0 mol) of methanol and 50 g of hydrogen chloride gas is introduced. Then 55.2 g (1.35 mol) of acetonitrile is added and the mixture is let stand for 24 hours at room temperature. Then the low-boiling substances are distilled out, dichloromethane is added to the residue, and ammonium chloride is filtered out. The filtrate is treated with 1.6 g of potassium bisulfate and heated while distilling the volatile components up to 130° C. 138 g (0.79 mol) of methoxymethylenmalonic acid dimethyl ester is obtained, corresponding to 79.3% of the theory.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:9]=[CH:10][C:11]=1[CH3:12]>C(Cl)(Cl)Cl>[CH3:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][C:16]([Cl:3])=[O:18])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CCCC(=O)O)cc1C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CCCC(=O)Cl)cc1C

Procedure:
2.5 mL of thionyl chloride was added at room temperature to a 60 mL chloroform solution of 3.3 g of compound 1-1 obtained in Reference Example 1, and the system was refluxed under heating, for 10 hours. After the reaction, reduced-pressure solvent distillation was performed to obtain 4-(3,4-dimethylphenyl)butanoyl chloride.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([CH:13]=[O:14])[O:10][C:9]=1[CH3:15])=[O:7]>C1COCC1>[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([CH:13]([OH:14])[CH3:1])[O:10][C:9]=1[CH3:15])=[O:7]
Reactant: C[Mg]Br
Reactant: COC(=O)c1cc(C=O)oc1C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)O)oc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (370.5 ml, 1.4M in THF) is added over 30 minutes to a solution of 5-formyl-2-methyl-furan-3-carboxylic acid methyl ester (87.2 g) in THF (1200 ml) under nitrogen at 0° C. After 1 hour at 0° C., the reaction is quenched with a saturated aqueous solution of NH4Cl in water. The mixture is stirred 1 hour at 0° C. and then is extracted three times with ethyl acetate. The organic phases are combined, dried over Na2SO4 and concentrated in verve to yield 5-(1-hydroxy-ethyl)-2-methyl-furan-3-carboxylic acid methyl ester (94.5 g) as a yellow solid. The crude product obtained is used without further purification. MS (HPLC/MS): 185 (MH+).