Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:9]1)=O)(C)(C)C.BrC1C2[O:30][C:29]([F:33])([F:32])[O:28]C=2C=CC=1.C([C@@H]1OC1)Cl.[Cl:39][CH2:40][C@H:41]([OH:54])[CH2:42][C:43]1[C:51]2[O:50][C:49]([F:53])([F:52])[O:48][C:47]=2[CH:46]=[CH:45][CH:44]=1>>[Cl:39][CH2:40][C@H:41]([OH:54])[CH2:42][C:43]1[C:51]2[O:50][C:49]([F:53])([F:52])[O:48][C:47]=2[CH:46]=[CH:45][CH:44]=1.[F:32][C:29]1([F:33])[O:30][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][C@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:16]=2[O:28]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Reactant: FC1(F)Oc2cccc(Br)c2O1
Agent: ClC[C@H]1CO1
Agent: O[C@@H](CCl)Cc1cccc2c1OC(F)(F)O2
Product: FC1(F)Oc2cccc(C[C@@H]3CNCCO3)c2O1

Procedure:
(R)-1-chloro-3-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-propanol was prepared using the same procedure as described for example 2, intermediate (d), but from 4-bromo-2,2-difluoro-benzo[1,3]dioxole and (R)-epichlorohydrin. Example 66 was prepared as described for example 1, intermediate (d), but using (R)-1-chloro-3-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-propanol, to obtain the desired morpholine example 66, as a colorless liquid, (0.214 g, 13.6%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 38.3 %

Procedure:
To a solution (20 ml) of ethyl 1-(3-cyano-4-neopentyloxyphenyl)pyrazole4-carboxylate (2 g) in ethanol was added 2 N aqueous sodium hydroxide solution (3.7 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solution of ethyl alcohol and water to give 0.7 g of 1-(3-cyano-4-neopentyloxyphenyl) pyrazole-4-carboxylic acid, melting point 199-200° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:4][CH:3]=1.[CH3:35][I:36]>CN(C)C=O>[I-:36].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N+:28]5([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:25][CH:26]=4)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CCC3)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CCC3)cc1
Product: [I-]

Procedure:
A solution of 2-(4-methylphenyl)-N-(4-piperidinomethylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (0.26 g) and methyl iodide (0.15 ml) in dimethylformamide (15 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-ethyl acetate to give 1-(N-(2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carbonyl)-4-aminobenzyl)-1-methylpiperidinium iodide (Compound 92) (0.3 g) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]2=[O:26])C1C=CC=CC=1.CO>[Pd].O1CCCC1>[O:19]([C@H:13]1[C@@H:12]([OH:26])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15][CH2:14]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCC1Oc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc2c(c1)[C@H](O)[C@H](Oc1ccccc1)CO2
Reaction time: 24 h
Yield: 65.5 %

Procedure:
A mixture of 10.04 g of the title product of Example 9, 200 ml of methanol, 100 ml of tetrahydrofuran and 1 g 10% Pd/C catalyst was hydrogenated at 44 psig for 24 hours. The catalyst was recovered by filtration and the filtrate was evaporated in vacuo to obtain the crude product, which was triturated with dichloromethane and filtered to give 4.9 g of title product having properties identical to those of the cis-title product of the preceding Example.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33](OC)=O)=[CH:26][C:25]=2[O:24]1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33]3[NH:22][C:20](=[O:21])[C:3]4[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=4[N:1]=3)=[CH:26][C:25]=2[O:24]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 47.7 %

Procedure:
6 mg (0.019 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.103 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4.1 mg (47%) of a solid, Rf=0.68 (dichloromethane/methanol=15:1).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH2:34][C@H:35]([O:48][Si](C(C)(C)C)(C)C)[C:36]4[CH:45]=[CH:44][C:43]([OH:46])=[C:42]5[C:37]=4[CH:38]=[CH:39][C:40](=[O:47])[NH:41]5)=[CH:27][CH:26]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.F.F.C(N(CC)CC)C>C1COCC1.CO>[CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH2:34][C@H:35]([OH:48])[C:36]4[CH:45]=[CH:44][C:43]([OH:46])=[C:42]5[C:37]=4[CH:38]=[CH:39][C:40](=[O:47])[NH:41]5)=[CH:27][CH:26]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c4[nH]c(=O)ccc34)cc2)cc1-c1cccc(CNCc2ccccc2)c1
Agent: F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)cc2)cc1-c1cccc(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine (55 mg, 0.73 mmol) was dissolved in THF/MeOH (5 mL:2 mL). Triethylamine-trihydrofluoride (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 5 h. The solvent was then evaporated, and the residue purified by HPLC to afford N-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine (114). m/z: [M+H+] calcd for C40H41N4O4 641.31. found 641.3
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][OH:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH-].[K+]>CCOCC>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][C:11]#[C:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC#CCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC#CCCOC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.1 %

Procedure:
A solution of alcohol 8 (6.16 g, 33.5 mmol) and p-toluenesulphonyl chloride (7.36 g, 38.5 mmol) in dry ether (80 mL) was cooled to -10°. Powdered KOH (25 g, 446 mmol) was added in 5 g portions over 20 min. The resulting suspension was stirred at 0° for 45 min, poured into ice-water (200 mL) and extracted with ether (3×100 mL). The combined ether solutions were washed with brine, dried (MgSO4), and concentrated in vacuo. Final traces of solvent were removed by pumping for 6 hr at 0.1 mmHg, yielding 11.23 g of 9 (99%). This was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH:7]([C:13]([O-:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[O-][CH2:17][CH3:18].[Na+].[C:20]([O:39]CCCBr)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:21]1C=CC=C[CH:22]=1>CCO>[OH:39][CH2:20][CH2:21][CH2:22][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])([C:13]([O:15][CH2:17][CH3:18])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC[O-]
Reactant: CCOCCOC(C(=O)[O-])C(=O)OCC
Reactant: BrCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCOCCOC(CCCO)(C(=O)OCC)C(=O)OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
6 g of ethyl 2-(2-ethoxyethyl)oxymalonate (24.65 mmoles) are added to a solution of sodium ethoxide in EtOH (15 ml, prepared by dissolution of 0.65 g, 0.028 moles metal Na) under stirring and nitrogen atmosphere. Stirring is continued for 1 h at room temperature, then a solution of 3-trityloxy-1-propyl-bromide (9.4 g, 24.7 mmoles) in EtOH (20 ml) is added dropwise. The reaction mixture is heated at 50° C. and kept at this temperature overnight. When the reaction is completed, the solvent is evaporated off under vacuum and the residue is partitioned between water and AcOEt. The aqueous phase is re-extracted with AcOEt (2×50 ml), the combined organic phases are washed to neutrality with a 5% NaH2PO4 aqueous solution, then with water, and finally dried over sodium sulfate. After evaporation of solvent, the resulting solution of crude ethyl 5-trityloxy-2-ethoxycarbonyl-2-[(2-ethoxy)ethyloxy]-pentanoate in EtOH is treated with 0.3 g of p-toluenesulfonic.H2O acid and kept for 12 h at room temperature. After evaporation of solvent, the residue is dissolved in dichloromethane (15 ml) and the organic phase is washed with 2×5 of 5% aqueous NaHCO3, then with water to neutrality, dried over Na2SO4, the solvent is evaporated off and the residue is purified on a silica gel column (eluent CHCl3 /MeOH 98:1.5), to obtain 6.42 g of ethyl 5-hydroxy-2-[(2-ethoxy)ethyloxy]-2-ethoxycarbonyl-pentanoate.
Reaction SMILES: [Cl:1]Cl.[CH:3]([CH:5]1[O:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH2:7][O:6]1)=C.[C:15]([Cl:19])(Cl)(Cl)Cl>>[Cl:1][CH:3]([CH:5]1[O:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH2:7][O:6]1)[CH2:15][Cl:19]
Reactant: ClCl
Reactant: C=CC1OCC(CCCCO)O1
Reactant: ClC(Cl)(Cl)Cl
Product: OCCCCC1COC(C(Cl)CCl)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Liquid chlorine (228 ml.; 5 moles) was added to a solution of Comonomer B (860 grams; 5 moles), that is, 2-vinyl-4-(4-hydroxybutyl)-1,3-dioxolane, in 3600 ml. of carbon tetrachloride over a period of 4.5 hours while maintaining the temperature at 20°-30° C. by means of intermittent cooling with an ice-bath. When the addition of chlorine was complete, the mixture was stirred at ambient temperature overnight. After removal of solvent by heating the mixture at 51° C. and 1 mm. mercury pressure for one hour, the product was obtained as a colorless viscous material.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.[CH3:22]N(CN(C)C)C.Cl[Si](C)(C)C>CN(C)C=O.O>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11]([CH2:22][N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH3:16])[C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1ncc[nH]1
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Reactant: CN(C)CN(C)C
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Temperature: 90 °C
Reaction time: 10 h
Yield: 66 %

Procedure:
2.0 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2-methyl imidazole and 2 ml of N,N,N′,N′-tetramethyldiaminomethane were suspended in 20 ml of N,N-dimethylformamide, and then 4 ml of chlorotrimethylsilane was slowly added thereto. The reaction mixture was stirred at 90° C. for 10 hours. 100 ml of water was added to the reaction mixture. The resulting solid was filtered and dried, which was then suspended in acetone and stirred for 3 hours, and then filtered and dried under a reduced pressure to give 1.93 g of title compound (yield 66%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][C:15]([CH3:17])([CH3:18])[C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:32]5[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]5)=[O:25])=[CH:21][CH:20]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)O)cc1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (50 mg, 0.137 mmol), 4-hydroxypiperidine (15 mg, 0.15 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (57 mg, 0.15 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in 3 mL of anhydrous DMF was stirred at room temperature. The mixture was poured into 75 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-fluoro-3-[4-{4-[(4-hydroxypiperidin-1-yl)carbonyl]phenyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as orange solid. Yield: 52 mg, 85%.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[N+](C1C=CC([N:43]([CH:47]2[CH2:49][CH2:48]2)[C:44](=O)[O-:45])=CC=1)([O-])=O>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:44]([NH:43][CH:47]3[CH2:49][CH2:48]3)=[O:45])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)C1CC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.58 g, 3.81 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, 4-nitrophenyl-N-cyclopropylcarbamate (0.41 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclopropylamino)carboxamide (0.53 g, 77%) as a white solid: mp 245–247° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.87–7.69 (m, 3H), 6.58 (t, J=5.7 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H)5.19–5.11 (dd, J=5.4 and 12.5 Hz, 1H), 4.65 (d, J=6.1 Hz, 2H), 2.96–2.83 (m, 1H), 2.64–2.40 (m, 3H), 2.08–2.04 (m, 1H), 0.62–0.55 (m, 2H), 0.40–0.34 (m, 2H); 13C NMR (DMSO-d6) δ 172.75, 169.82, 167.63, 167.04, 158.69, 141.11, 134.61, 133.26, 131.49, 126.94, 121.60, 48.83, 30.93, 22.37, 21.97, 6.59; Anal. Calcd. For C18H18N4O5: C, 58.37; H, 4.90; N, 15.13. Found: C, 58.26; H, 4.82; N, 14.85.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](#[N:31])[CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].N12CCCN=C1CCCCC2.C(#N)C>>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][C:23]#[N:31])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CCCCCC=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Yield: 89.89 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (prepared substantially as described in Example 65 of U.S. Pat. App. Pub. No. 2007/0135461 or International App. No. PCT/US2006/047369 (published as WO 2007/070514); 12 g, 0.038 mol), oct-2-enenitrile (6.0 g, 0.049 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.6 mL, 0.030 mol) in acetonitrile (120 mL, 2.3 mol) was stirred at room temperature overnight. After being concentrated in vacuo, the resultant residue was purified on silica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desired product (15 g, 89.89%). The enantiomers (first peak retention time 11.02 min, second peak retention time 14.10 min) were separated on a ChiralCel OD-H column (30×250 mm, 5 μM), eluting with mobile phase of 15% ethanol and 85% hexane at 25 mL/min. MS calculated for C23H35N6OSi(M+H)+: m/z=439.264. Found: 439.4. 1H NMR (300 MHz, CDCl3) δ 8.91 (1H, s), 8.38 (1H, s), 8.37 (1H, s), 7.46 (1H, d, J=3.8 Hz), 6.86 (1H, d, J=3.8 Hz), 5.73 (2H, s), 4.59 (1H, m), 3.60 (2H, t, J=8.3 Hz), 3.06 (2H, td, J=16.8 and 7.5 Hz), 2.21 (1H, m), 2.01 (1H, m), 1.40-1.21 (6H, m), 0.98 (2H, t, J=8.3 Hz), 0.91 (3H, t, J=6.3 Hz), 0.00 (9H, s) ppm.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[OH:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].C1(Br)CCCC1.C1(O)C=CC=CC=1.ClCl>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[O:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(-c2ccc(O)c(OC3CCCC3)c2)c1
Agent: BrC1CCCC1
Agent: ClCl
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc([N+](=O)[O-])c2)cc1OC1CCCC1
Yield: 53.9 %

Procedure:
2-Cyclopentyloxy-4-(3-nitrophenyl)phenol (600 mg, 2.45 mmol) was dissolved in DMF (40 ml) and treated with Cs2CO3 (730 mg, 2.24 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol). After stirring overnight at RT some of the phenol remained (SiO2 :t.l.c, CH2 Cl2). Cs2CO3 (870 mg, 2.67 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol) were added. After stirring at RT for 3 h the phenol had been consumed. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in Et2O (50 ml), filtered, and concentrated in vacuo to give a yellow solid which was recrystallised from dichloromethane/hexane to afford the title compound (378 mg) as yellow needles. δH (CDCl3 ; 80 mHz) 1.5-2.1 (8H, br m, (CH2)4), 3.87 (3H, s, OMe), 4.84 (1H, br m, OCHCH2), 6.91 (1H, d, J9.1 Hz, ArH ortho to OMe), 7.0-7.2 (2H, m, ArH meta to OMe), 7.54 (1H, d, J 7.5 Hz, ArH meta to NO2), 7.80 (1 H, ca. dt, J ca 7.5, 1.5 Hz, ArH para to NO2), 8.09 (1H, ca. dt, J ca.8, 1.5 Hz, ArH para to aryl), 8.33 (1H, ca. t, J ca 2 Hz, ArH ortho to NO2 and aryl); m/z 313 (M+, 7%), 246 (17), 245 (M+ -cyclopentyl, 100), 230 (41), 202 (8), and 139 (9).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][C@@H:23]1[CH3:30])[CH:18]=[CH:17]3.[CH3:32][Cu]C.[Li].[Cl-].[NH4+].C1C=CC=CC=1>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19]([CH2:20][C:21](=[O:31])[CH2:22][C@@H:23]1[CH3:30])=[CH:18][C@H:17]3[CH3:32]
Reactant: C[C@H]1CC(=O)C=C2C=C[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Reactant: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1C=C2CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17β, 19-dihydroxy-1α-methyl-4,6-androstadien-3-one diacetate in anhydrous tetrahydrofuran is slowly added to an ice cold ethereal solution of lithium dimethylcopper prepared as in the preceding Example. Stirring is continued for an additional 30 minutes and the mixture is poured onto a saturated aqueous ammonium chloride solution. Benzene is added and the mixture filtered through a bed of diatomaceous earth. The organic layer is separated, washed with aqueous ammonium chloride, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on a silica gel column and eluted with benzene. The eluant is evaporated and the residue recrystallized from a hexane solution to yield 17β,19-dihydroxy-1α,7α-dimethyl-5-androsten-3-one diacetate.
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[NH2:13])([O-:5])=[O:4]>O1CCOCC1>[BrH:1].[BrH:1].[Br:1][C:10]1[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]([NH2:13])=[CH:8][C:9]=1[NH2:12]
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Reactant: BrBr
Solvent: C1COCCO1
Product: Br
Product: Nc1cc(N)c([N+](=O)[O-])cc1Br
Reaction time: 16 h

Procedure:
The reaction scheme (CCLXIX) illustrates a synthetic process rthat included dropwise adding of 6.4 g bromine (40 mmol) to a solution of 4-nitrobenzene-1,3-diamine (5.56 g, 36.3 mmol), in 50 mL 1,4-dioxane, followed by stirring the solution was room temperature for 16 h. The yellow precipitate was isolated by filtration, washed with 1,4-dioxane (30 mL) and dried in vacuo to give 4-bromo-6-nitro-benzene-1,3-diamine dihydrobromide salt designated on the reaction scheme (CCLXIX) as compound 13 (8 g, 95%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](N1C=CN=C1)=[O:25])[CH2:4][CH3:5])[CH3:2].[CH3:31][Mg]Br.C(OCC)C>C(Cl)Cl>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](=[O:25])[CH3:31])[CH2:4][CH3:5])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)n1ccnc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(C)=O

Procedure:
The title compound was prepared by reacting [4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone with methylmagnesium bromide/ethyl ether in methylene chloride. 1H NMR(CDCl3) d 9.7(d,1H), 6.88(s,2H), 6.10(s,1H), 3.32(m,1H), 2.73(s,3H), 2.31(s,3H), 2.10(s,3H), 2.09(s,6H), 1.5–1.7(m,4H), 0.95(t,6H)ppm.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)C(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)CO
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 65.7 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and isobutanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 9.6 g of p-cyanobenzamide (yield 66%).