Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:9]([C:15](=[O:18])[CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].[BH4-].[Na+]>CCO.O>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([C@H:15]([OH:18])[CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)[C@H](C(=O)CC)N(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H]([C@H](O)CC)N(Cc1ccccc1)Cc1ccccc1
Yield: 54.9 %

Procedure:
To a stirred solution of ethyl (2S*)-2-(dibenzylamino)-3-oxo-pentanoate [prepared as for example 47, step 1] (0.6 g, 1.76 mmol) in EtOH (30 mL), at rt, a solution of NH4Cl (1.89 g, 35.29 mmol) in H2O (8.0 mL) was added. NaBH4 (0.667 g, 17.6 mmol) was then added in small portions. After 1 h from the last addition, the reaction was quenched with H2O and the solvent evaporated. The crude mixture was taken up with H2O and CH2Cl2 and pH corrected to 9 with 20% NH4OH aqueous solution. After extraction, the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (90:10), gave the title compound (0.33 g, 55% over 2 steps), as a pure syn diastereoisomer, as a colorless oil. MS (ESI) m/z: 342 [M−H]+. 1H NMR (DMSO-d6) δ 0.75 (t, J=7.38 Hz, 3H), 1.26 (t, J=7.11 Hz, 3H), 1.30-1.52 (m, 2H), 3.14 (d, J=6.88 Hz, 1H), 3.67 (d, J=14.07 Hz, 2H), 3.85 (tt, J=4.61, 7.61 Hz, 1H), 4.08 (d, J=14.02 Hz, 2H), 4.11-4.25 (m, 2H), 4.66 (d, J=4.59 Hz, 1H), 7.20-7.27 (m, 2H), 7.28-7.41 (m, 8H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1.[Cl:14][C:15]1[C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[N:19][CH:18]=[CH:17][N:16]=1>C(O)(C)C>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:20]2[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][N:19]=2)=[CH:6][CH:7]=1)(=[O:10])[NH2:11]
Reactant: Clc1nccnc1OCC1CO1
Reactant: NCCOc1ccc(C(N)=O)cc1
Solvent: CC(C)O
Product: NC(=O)c1ccc(OCCNCC(O)COc2nccnc2Cl)cc1

Procedure:
A solution of 9.0 g of 4-(2-aminoethoxy)-benzamide in 120 ml of isopropanol is heated to the reflux temperature and a solution of 9.3 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine in 120 ml of isopropanol is added dropwise; duration of the addition: 5 hours. Thereafter the reaction mixture is heated to the reflux temperature for a further 7 hours. After completion of the reaction, the mixture is evaporated under a waterpump vacuum. The residue crystallises from ethyl acetate and gives 1-[2-(4-carbamoylphenyloxy)-ethyl-amino]-3-(2-chloro-3-pyrazinyloxy)-2-propanol, melting point 134°-135° C. after recrystallisation from isopropanol. The hydrochloride prepared therefrom using the calculated amount of methanolic hydrochloric acid melts at 223°-225° C. after crystallisation from a mixture of methanol and acetone.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH:6]2[CH2:8][CH2:9][N:3]1[CH2:4][CH2:5]2.[CH2:10](O)[CH3:11]>[Ni]>[N:3]1[CH:2]=[CH:7][CH:6]=[C:10]([CH:11]=[C:2]2[CH2:7][CH:6]3[CH2:8][CH2:9][N:3]2[CH2:4][CH2:5]3)[CH:4]=1
Reactant: ClC1CC2CCN1CC2
Reactant: CCO
Agent: [Ni]
Product: C(=C1CC2CCN1CC2)c1cccnc1
Reaction time: 6 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 m water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (3 g, 14.0 mmol) was dissolved in 200 ml methanol and sodium borohydride (3 g, 79.6 mmol) was added in portions (exothermic reaction) with vigorous stirring. After 1 hr of continued stirring, acetone (100 ml) was slowly added to neutralize the remaining borohydride reagent. The mixture was evaporated to dryness and the resulting residue suspended in water (200 ml) and extracted three times with 200 ml portions of chloroform. The chloroform phases were combined, dried over MgSO4, and rotary evaporated to give a clear oil; crystallization of the free base gave a quantitative yield of 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as a white precipitate. 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7 mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol) under a nitrogen atmosphere at 0° C., the reaction was than brought to room temperature and stirred for one additional hour. Rotary evaporation at 60° C. produced a viscous oil which, when suspended in ether, afforded 3-chloro-2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). This chloroquinuclidine (0.3 g, 15 mmol) was dissolved in ethanol (50 ml) and wet Rainey nickel (0.5 g) was carefully added under nitrogen. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 6 hrs followed by filtration through a pad of Celite filter aid and additional washing of the pad with methanol. Rotary evaporation of the pooled solvents gave 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane as a clear oil that solidified upon cooling (0.2 g, 70%). This material (120 mg) was dissolved in 50 ml methanol followed by the careful addition of 0.1 g 10% palladium on charcoal. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 28 hrs followed by filtration through a pad of Celite filter aid and additional washing of the pad with methanol. Evaporation of the solvents afforded a white residue which was crystallized from ethanol-ether to give the desired material, 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane, as a white solid (99 mg, 81%).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CN
Reactant: COc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Product: CNc1ncc2c(=O)[nH]c(-c3ccccc3OC)nc2n1

Procedure:
In a similar manner to Example 33 reaction of 7-methylthio-2-(2-methoxyphenyl)-4-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine (0.75 g) and 33% methylamine in industrial methylated spirit (25 ml) for 18 hours yielded the title compound, 0.38 g, m.p. 265-267° C. (recrystallized twice from methanol).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:22][OH:23])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:23][CH2:22][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:21])[F:20])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 92 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.46 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(4-trifluoromethoxy-phenyl)cyclopropane (Example 11) (0.25 g), benzene (12 ml) and pyridine (0.09 ml) to yield the title compound (0.27 g, 92%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2C(OCC2C=CC=CC=2)=O)=[CH:5][CH:4]=1>CO.[Pd]>[F:30][C:2]([F:1])([F:29])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1ccc(C2NCCc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of benzyl 1-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (90 mg, 218 μmol) in MeOH (3 mL) at RT under N2 was added 10% palladium on carbon (46 mg, 44 μmol) and suspension was sparged with H2 15 min. The reaction was stirred under H2 at RT 3.5 h. The reaction was filtered through a pad of Celite® (2×5 mL EtOAc wash) and concentrated to give 1-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline which was carried on to the next step without purification.
Reaction SMILES: [CH3:1][C:2]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=1)([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3].[H-].[Na+].I[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C=O>[CH3:3][C:2]([C:4]1[N:5]([CH2:9][CH2:7][CH2:6][CH2:12][CH3:11])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([C:13]1[N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:1]
Reactant: CC(C)(c1nc2ccccc2[nH]1)c1nc2ccccc2[nH]1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1c(C(C)(C)c2nc3ccccc3n2CCCCC)nc2ccccc21
Reaction time: 4 h
Yield: 163.9 %

Procedure:
2.8 g 2,2′-Propane-2,2-diylbis(1H-benzimidazole) was added to 60 ml of N,N-dimethylformamide. 1.21 g Of a 60% sodium hydride dispersion in mineral oil was added in portions. 6.0 g Of 1-iodopentane was added and the mixture was stirred under nitrogen. After 4 hours, the reaction was quenched with 160 ml of water and then extracted with two 75 ml portions of ethyl acetate/methanol (˜99:1, v/v). The combined organic layers were washed twice with 75 ml of water. The cloudy organic layer was filtered. Following solvent removal to give a brown oil, the product was purified by silica gel chromatography increasing from 25% to 50% ethyl acetate in hexane by volume over the course of the elution. 3.46 g Of a yellow oil was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: NC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCC(N)=O)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromopropanamide (47 mg, 0.31 mmol, TCI-EP, Cat. No. B1410), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 hours. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 45 mg of the product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=266.2
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[N:6]=1)=[O:4].[F:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2B(O)O)=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:25]2[CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]2[CH:37]=[CH:38][C:18]([F:17])=[CH:19][CH:20]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(C2=C(Br)CCC2)n1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Product: COC(=O)c1cccc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)n1

Procedure:
Prepared by general procedure 3 but using 6-(2-bromocyclopent-1-enyl)-pyridine-2-carboxylic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl) -benzoic acid ethyl ester and 2-(4-fluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: C(Cl)(=O)C.[N+:5]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([O-:7])=[O:6].NC1C=C2C(=CC=1)CN(C(N[C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:39])NCCC)=[CH:30][CH:29]=1)=O)C2>>[CH:30]1([CH2:31][C:34]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:39])[CH2:29][CH2:28][CH2:33][CH2:32]1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(CC1CCCC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared as described in Example 278, substituting 2-cyclopentylacetyl chloride for acetyl chloride and 4-nitroaniline for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:31])([CH3:34])[CH3:33]
Reactant: Cn1c(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Product: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2cccc(Cl)c2)n1C
Yield: 55.46 %

Procedure:
3-Benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-05) (363.0 mg, 55.46%) was synthesized as a gummy liquid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-05) (600.0 mg, 1.29 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:27]O>>[CH3:27][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CO
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)NC1=O
Reaction time: 4 h

Procedure:
In 300 ml of methanol was suspended 10 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and, under cooling at -20° C. or below, 10 g of thionyl chloride was added dropwise. The mixture was stirred at 0°-5° C. for 4 hours and then at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-acetone (4:1). The eluate was concentrated under reduced pressure and to the residue was added ethyl ether to give crystals. Yield 5.8 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Cl)[C:10]=2[Cl:16])=[C:4]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[N:3]=1.[Cl:24]C1C=C(Cl)C=CC=1CC#N>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[N:3]=1
Reactant: CCOC(OCC)c1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Reactant: N#CCc1ccc(Cl)cc1Cl
Product: CCOC(OCC)c1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared in a manner analogous to 2,4-diamino-5-(2, 3-dichlorophenyl)-6-(diethoxymethyl)pyrimidine (Example 18.1) from 2,4-dichlorophenylacetonitrile, mp. 225° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:22]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(C(=O)OC)c1C(=O)OC
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
3-Hydroxyphthalic anhydride (1.0 g, 6.6 mmol) was dissolved in methanol (20 ml), and a catalytic amount of p-toluene sulfonic acid was added to this solution. The mixture was stirred with refluxing under heating for 5 hours, and concentrated under reduced pressure to give a crude product of dimethyl 3-hydroxyphthalate. The crude product of dimethyl 3-hydroxyphthalate was dissolved in DMF (20 ml), and potassium carbonate (6 g, 43 mmol) and n-amyl bromide (3 ml, 24 mmol) were added to this solution. The mixture was stirred at 90° C. for 1.5 hours, and solids were removed by filtration through Celite. The filtrate was concentrated under reduced pressure to give a crude product of dimethyl 3-pentyloxyphthalate. The crude product of dimethyl 3-pentyloxyphthalate was dissolved in methanol (10 ml), and a 1N aqueous sodium hydroxide solution (20 ml) was added to this solution. The mixture was stirred at 90° C. for 2 hours, and a 3N aqueous hydrochloric acid solution (15 ml) was added to the reaction nixture. The mixture was extracted with ethyl acetate (30 ml×3), and washed with saturated brine (20 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 3-pentyloxyphthalic acid. The crude product of 3-pentyloxyphthalic acid was dissolved in acetic acid (20 ml), and a mine hydrochloride (1.0 g, 7.3 mmol) was added. The mixture was stirred at 90° C. for 2 hours and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give N-2-(4-hydroxyphenyl)ethyl-3-pentyloxyphthalimide (0.8 g, 2.3 mmol, 35%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12].BrC1C=CC=CC=1N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1ccccc1Br
Reactant: NN
Agent: Nc1ccccc1Br
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccccc1Br
Temperature: 25 °C
Yield: 73 %

Procedure:
This compound was prepared using 125 mg (0.5 mmol) of 2-[(2-bromophenyl)-hydrazono]malononitrile, which was derived from 2-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Very little solid had formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 102 mg (73%) of the title compound as an orange solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1.[Mg].II.[Br-].[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17]Br>C1COCC1.II>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1
Reactant: BrCCC1OCCCO1
Reactant: COc1ccc(Br)c(CBr)c1
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CCCC2OCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.5 %

Procedure:
A solution of 2-(2-bromoethyl)-1,3-dioxane (3.41 ml, 4.88 g, 25.0 mmol) in dry THF (15 ml) was slowly added to dry magnesium turnings (0.67 g, 27.5 mmol) and ~10 mg iodine at room temperature under N2. After heat evolved and the iodine color vanished, the contents were heated to reflux and the remainder of the bromide solution was added dropwise over 10 min. After 2 h reflux, the alkylmagnesium-bromide solution was cooled to room temperature and transferred via syringe to a solution of 2-bromo-5-methoxybenzyl bromide (3.50 g, 12.5 mmol) in 20 ml dry THF. The contents were cooled to -10° with ice-salt, treated with Li2 CuCl4 in THF (0.45 ml of 0.1M solution), and allowed to stir at room temperature overnight for convenience. After 19 h, the solvent was evaporated and the residue partitioned between ether and 5% NH4Cl. The ether layer was washed with 5% NH4Cl, water, and brine, then dried over MgSO4, filtered, and evaporated to yield 4.59 g of a pale yellow oil. The crude material was purified by column chromatography (140 g silica gel, 50% ether/petroleum ether as eluent) under "flash" conditions to yield 2.31 gm (58%) of the dioxane as a colorless oil; tlc (silica gel, 50% ether/petroleum ether) Rf 0.48. A dimeric by-product, 1,2-bis(2-bromo-5-methoxyphenyl)ethane, was obtained as a white solid (1.02 g, 41%); mp 98°-101°. TLC (silica gel, 50% ether/petroleum ether) Rf 0.63.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[N:23]([CH3:31])[C:22]2=[O:32]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[N:23]([CH3:31])[C:22]2=[O:32]
Reactant: CN1C(=O)c2cccc(Cl)c2C12CCNCC2
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Product: CN1C(=O)c2cccc(Cl)c2C12CCN(C(=O)CCc1ccccc1C(F)(F)F)CC2

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 7-chloro-2-methylspiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1 tR=1.77, min, m/z=453, 451
Reaction SMILES: C([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][CH2:29][O:30][CH3:31])[CH2:6]1)(=O)C.C[O-].[Na+]>CO>[OH:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][CH2:29][O:30][CH3:31])[CH2:6]1
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Reaction time: 2 h
Yield: 88.7 %

Procedure:
In 10 ml of methanol was dissolved 100 mg of 1α-acetoxy-3β-(methoxymethyl)oxypregna-5,7-diene-20carbaldehyde, followed by addition of 50 mg of sodium methoxide. The mixture was stirred in an atmosphere of argon gas for 2 hours. The reaction mixture was then worked up in the same manner as Example 164 to give 80 mg of 1α-hydroxy-3β-(methoxymethyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([N+:17]([O-])=O)[CH:11]=1.CC1C=CC(O)=C([N+]([O-])=O)C=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:12]([NH2:17])[CH:11]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: Cc1ccc(O)c([N+](=O)[O-])c1
Product: Nc1cc(Br)ccc1Sc1ccccc1

Procedure:
5-bromo-2-(phenylthio)benzenamine was prepared according to procedures similar to those described in Examples 6a, 6b, and 6c substituting benzenethiol for 4-mercaptophenol and 4-bromo-2-nitrophenol for 4-methyl-2-nitro phenol.