Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]2[NH2:30].C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:30][CH:24]4[CH2:25][CH:26]5[CH2:29][CH:23]4[CH2:28][CH2:27]5)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CC2CCC1C2
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CC2CCC1C2
Temperature: 110 °C
Yield: 98.8 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.92 g, 2.7 mmol), bicyclo[2.2.1]hept-2-ylamine (0.36 ml, 3.0 mmol), diisopropylethylamine (0.62 ml, 3.5 mmol) in propan-2-ol (12 ml) was heated at 110° C. in a microwave reactor for 20 min. The mixture was then cooled to 25° C. and was partitioned between water (200 ml) and EtOAc (2×200 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the resulting yellow oil by column chromatography on silica gel (gradient: 0 to 60% EtOAc in heptanes) afforded (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-bicyclo[2.2.1]hept-2-yl-amine (1.1 g, 98%) as a yellow solid. TLC: 50% EtOAc in heptanes; Rf=0.66). This material was used in the next step below without additional characterization.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCC1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC1CCNC1

Procedure:
3.1 g (0.01 mol) (3RS)-1-benzyl-3-(N-tert-butyloxycarbonylaminoethyl) pyrrolidine was hydrogenated at 0.28 MPa over 0.6 g of Pearlman's catalyst (Pd(OH)2) in 40 ml ethanol (95%) over night. After filtration of the catalyst through cellite and evaporation of the solvent 1H-NMR showed that the reaction was not completed. Therefore 0.6 g of Pearlman's catalyst was added in 40 ml ethanol (95%) once more and the mixture was treated under H2 -atmosphere at 0.28 MPa over night. Filtration through cellite and evaporation of the solvent gave the product in a quantitative yield (2.18 g).
Reaction SMILES: [Na].O.S(O)(O)(=O)=O.[OH:8][NH:9][C:10]([NH2:12])=[NH:11].O[NH:14]C(N)=N.O.C(NC(=O)/C=C(\[O:28][C:29]([C:31]1[C:36](N)=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=1)=O)/C)(C)(C)C>CC(O)C>[NH2:14][NH:11][C:10](=[NH:12])[NH:9][O:8][C:29]([C:31]1[CH:36]=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=1)=[O:28]
Reactant: N=C(N)NO
Reactant: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: N=C(NN)NOC(=O)c1cnc(N)c(Cl)n1

Procedure:
Sodium metal (3.1 g., 0.135 g.at.) is dissolved in 2-propanol (500 ml.) and hydroxyguanidine hemisulfate hydrate (20.0 g., 0.075 mole) is added. The reaction mixture is heated at reflux for 1 hour then treated with N-t-butyl-3-(3,5-diamino-6-chloropyrazinecarbonyloxy)-crotonamide (20.5 g., 0.06 mole) heated at reflux for an additional hour to give product which is filtered, washed with water and dried. 3,5-Diamino-6-chloropyrazinecarbonyloxyguanidine melts at 192°-3° C. after purification by precipitation from dilute aqueous methanesulfonic acid with aqueous ammonia.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[C:13]([O:25][CH3:26])[C:12]([CH3:27])=[C:11]2[C:7]=1[C:8](=[O:28])[O:9][CH2:10]2)=[O:4].O[Li].O.C(O)(=O)CCC=CC>>[CH3:1][O:2][C:3]([NH:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:13]([O:25][CH3:26])[C:12]([CH3:27])=[C:11]2[C:7]=1[C:8](=[O:28])[O:9][CH2:10]2)=[O:4]
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)OC)c2c(c(C)c1OC)COC2=O
Agent: CC=CCCC(=O)O
Agent: [Li]O
Solvent: O
Product: COC(=O)Nc1c(C/C=C(\C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (1.0 g) in 10 ml methanol was heated to reflux for 4 hours and then evaporated to dryness. The residue was recrystallized from acetone/hexane to give 0.41 g of methyl (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. The ester (0.35g) and 0.05 g of LiOH-H2O in 9 ml 2:1 MeoH-H2O was heated at reflux for 4hours. The mixture was acidified, extracted with ethyl acetate, and the organic layer was dried over MgSO4. The organic layer was concentrated and the residue was further purified by silica gel chromatography (eluant 60:40:2 hexaneethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4- methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl. 4-hexenoic acid, mp 155°-158° C.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:13])(=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>C(O)C>[O:16]=[C:17]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:13]=[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:12]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a mixture of sodium methoxide (16.5 g) and anhydrous ethanol (200 ml) is added benzamidine hydrochloride (16 g) at 0-5° C. The mixture is stirred at 0° C. for 30 minutes, and thereto is added dropwise a solution of diethyl ethoxymethylenemalonate (20 g) in anhydrous ethanol (50 ml) at the same temperature. After the addition, the mixture is stirred at room temperature for 30 minutes, and refluxed for 6 hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in water. To the mixture is added with stirring and drowpise hydrochloric acid at 0-5° C. until the pH value of the mixture is adjusted to pH 4. The precipitates are collected by filtration, washed with water, washed with diethyl ether, and washed with ethanol to give the desired compound (17.5 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].O[Li].O>O>[C:18]([O:17][C:15]([NH:14][CH2:13][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC12CCCCC2
Agent: [Li]O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCCC2
Reaction time: 48 h
Yield: 62.4 %

Procedure:
To a solution of crude 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid methyl ester (35.0 g, ˜96.2 mmol) was added LiOH—H2O (12.3 g, 294 mmol) followed by the addition of water (75 mL). The mixture was heated to reflux. After 48 hours, an additional portion of LiOH—H2O (6.15 g, 146 mmol) was added and refluxed for an additional 24 hours. The solvent was removed under reduced vacuum. The residue was partitioned between water and ether. The aqueous layer was acidified to pH 2–3 with aqueous HCl with ice bath cooling with a layer of CH2Cl2 present. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 times). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 17.0 g (63%, 2 steps) of 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid an off-white solid.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].Br[C:19]1[CH:32]=[CH:31][C:22]2[CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:25][C:21]=2[CH:20]=1.[NH4+].[Cl-]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:29]([O:28][C:26]([C:24]1[S:25][C:21]2[CH:20]=[C:19]([CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:32]=[CH:31][C:22]=2[CH:23]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)c1cc2ccc(Br)cc2s1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
Di-tert-butyl malonate (1.5 g, 6.93 mmol) was dissolved in THF (6 mL) and sodium hydride (60% dispersion in mineral oil, 0.28 g, 7.00 mmol) was added. The mixture was stirred for 10 minutes before adding Pd(PtBu3)2 (0.1 g, 0.196 mmol) and a solution of ethyl 6-bromo-1-benzothiophene-2-carboxylate (1.8 g, 6.31 mmol) in THF (12 mL). The resulting mixture was heated to reflux under N2 for 18 hours. Room temperature was attained, saturated NH4Cl (150 mL) was added and the products extracted into EtOAc (2×125 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave 1.27 g of desired product (pale yellow solid, 48%). 1H NMR (DMSO-d6) δ 8.17 (s, 1H), 8.01 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.4, 1.8 Hz, 1H), 4.83 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.40 (s, 18H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1(=[O:35])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:7]2=[O:29])[C:4](=[O:30])[C:3]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:2]12.[H][H]>O1CCCC1.[Pd]>[C:4]1(=[O:30])[N:5]([C@H:6]2[C@@H:9]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:7]2=[O:29])[C:1](=[O:35])[C:2]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:3]12
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2/C=C/c2ccccc2)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2CCc2ccccc2)c(OC)c1
Yield: 95.6 %

Procedure:
In 150 ml of tetrahydrofuran is dissolved 5 g of cis-3-phthalimido-4-(E)-styryl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, followed by addition of 2.5 g of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere for 30 minutes. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is crystallized from ether and recovered by filtration to give 4.8 g of cis-3-phthalimido-4-(2-phenylethyl)-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, m.p. 148°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:22])[C:14]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (7.28 g, 20.0 mmol, Intermediate 5: step a) in tetrahydrofuran (215 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 118.7 mL, 59.37 mmol) over 7 minutes. The mixture was stirred at −78° C. for 5 minutes and 0° C. for 1.5 hours. The resulting cold solution was quenched with water. The white solid formed was completely dissolved by addition of excess water. The aqueous phase was washed once with EtOAc and then acidified by slow addition of 2 N aqueous HCl solution (kept pH above 2). The off-white precipitate formed was filtered and dried in the air overnight and at 40° C. for 1 hour to provide the title compound.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][C@H:10]([C:19]([O:21][CH3:22])=[O:20])[C@H:9]1[C:23]([O:25]CC1C=CC=CC=1)=[O:24])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:15]([O:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:23]([OH:25])=[O:24])[C@@H:10]([C:19]([O:21][CH3:22])=[O:20])[CH2:11]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate (80.0 mg, 0.000182 mol) in 5 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, overnight. After filter off the catalyst, the filtration was concentrated to dry and used directly in next step (43 mg, 91.1%). MS (ESI): (M+H)+=260.1.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: c1c[nH]cn1
Reactant: C=CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=CCCCn1ccnc1
Reaction time: 50 h

Procedure:
Pent-4-enyl bromide (10 g, 0.067 mole) was added dropwise to a stirred refluxing mixture of imidazole (9 g; 0.132 mole) and sodium bicarbonate (11 g; 0.13 mole) in methanol (50 ml). After addition the mixture was stirred for a further 50 hours under reflux. The reaction mixture was filtered to remove the insoluble matter and the filtrate evaporated to a yellow oil. This oil was taken up in 2M HCl (150 ml) and washed with ether (50 ml). The acid solution was then basified with 10M NaOH (about 30 ml) and extracted with chloroform (3×50 ml). The combined extracts were dried over anhydrous MgSO4 and the solvent removed under vacuum to leave a yellow oil as crude product, which was purified on silica gel column using 10% MeOH/EtOAc as eluent. 1.0 g distilled in vacuo b.p. 132°/12 mm, yield 0.9 g. Micro analysis: C8H12N2 requires C,70.59, H,8.82, N,20.59. Found: C,69.24, H,8.56, N,20.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:19][CH2:20][CH3:21])[C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][C:13]([OH:18])=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:19][CH2:20][CH3:21])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:16]2[CH3:17])([CH3:28])[CH3:27])[CH3:23]
Reactant: CCCn1c(-c2ccc(Cl)cc2)c(C)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(-c2ccc(Cl)cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-(4-chloro-phenyl)-3-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:19])[C:17]#[CH:18])[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:19])[C:17]#[C:18][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(O)c1ccc(N2CCCC2)c(C(C)(C)C)c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC(C)(C)c1cc(C(O)C#Cc2ccc(C(=O)O)cc2)ccc1N1CCCC1
Yield: 45.4 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 640 mg (2.5 mmol) of 1-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)prop-2-yn-1-ol with 520 mg (2.1 mmol) of 4-iodobenzoic acid, 20 mg (0.1 mmol) of copper iodide and 37 mg (0.05 mmol) of bis(triphenylphosphine)palladium chloride. 360 mg of 4-[3-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a beige solid (Mp=150° C., yield=46%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1([F:33])[CH2:28][CH2:27][CH:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:30](=[O:31])[CH2:29][CH:26]2[CH2:27][CH2:28][C:23]([F:33])([F:22])[CH2:24][CH2:25]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Reactant: O=C(O)CC1CCC(F)(F)CC1
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)CC2CCC(F)(F)CC2)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-(4,4-difluorocyclohexyl)acetic acid were treated using a method similar to that described in Example 56 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.32 (dd, J=7.8, 1.4, 1H), 8.11 (d, J=8.0, 1H), 8.04-7.95 (m, 1H), 7.95-7.86 (m, 1H), 7.48-7.37 (m, 1H), 4.48-4.42 (m, 2H), 2.32-2.22 (m, 3H), 2.05-1.70 (m, 6H), 1.39 (s, 9H), 1.35-1.20 (m, 2H); MS (ESI−) M/Z 449 (M−H)−.
Reaction SMILES: O[C:2]1([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[BH3-]C#N.[Na+]>ClCCCl.[Zn+2].[I-].[I-]>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccs2)CC1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cccs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(thiophen-2-yl)piperidine-1-carboxylate (6.0 g, 21.2 mmol) in 1,2-dichloroethane at 0° C. was added ZnI2 (10.15 g, 31.8 mmol) in portions. The reaction mixture was stirred for 30 minutes, followed by the addition of NaCNBH3 (2.0 g, 31.8 mmol) in portions. The reaction mixture was slowly warmed to RT and stirred for 2 hours. The reaction was quenched with ice, extracted with CH2Cl2 (2×50 mL), washed with brine solution, dried (Na2SO4), filtered, and concentrated to obtain tert-butyl 4-(thiophen-2-yl)piperidine-1-carboxylate, which was used as is for subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]=[CH:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].CC[O:14]CC>>[CH2:1]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCC=CC1=O
Reactant: CCOCC
Product: CCCC[C@@H]1CCCC(=O)C1
Yield: 75 %

Procedure:
Prepared according to the general procedure from 3-butylcyclohexen-2-one (168 mg, 1.09 mmol) in 0.2 M Et2O for 43 h at room temperature to provide the title compound as a colorless oil (128.3 mg, 75% yield, 88% ee) after purification by flash chromatography on silica gel (5% Et2O/pentane). The physical data were identical in all respects to those previously reported (Jones et al. (1998). Tetrahedron 54:1471; and Moritani et al. (2000), J. Am. Chem. Soc. 122:6797 (reported a rotation of −17° for the (S)-enantiomer that is 87% ee)). The enantiomeric ratio was determined by GLC using a Hydrodex-B-TBDAc (50 m×0.25 mm) column (150° C. isotherm, 1 mL/min.); (S) isomer tr=37.0 min. and (R) isomer tr=36.0 min. [α]D22=+15.5° (c=1.00, CHCl3).
Reaction SMILES: C([O:4][C:5](=[O:35])[CH:6]([N:16]([C:26](=[O:34])[CH:27]([CH2:31][CH2:32][Cl:33])[C:28](=[O:30])[CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C=C.N1CCOCC1>C1COCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([O:8][CH2:7][CH:6]([N:16]([C:26](=[O:34])[CH:27]([CH2:31][CH2:32][Cl:33])[C:28](=[O:30])[CH3:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C:5]([OH:35])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCOC(=O)C(COCc1ccccc1)N(Cc1ccc(OC)cc1)C(=O)C(CCCl)C(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CN(C(=O)C(CCCl)C(C)=O)C(COCc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.3 %

Procedure:
To a solution of allyl ester 76 (1.24 g, 2.47 mmol) in THF (20 mL) was added morpholine (646 mg, 7.41 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 7 h and diluted with Et2O (200 mL). The organic layer was washed with 0.2 N HCl and brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on SiO2 (15:85 acetone:CH3Cl) to give acid 77 (620 mg, 75%). Data provided for only one diastereomer: IR (neat) 1721, 1639 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.20-7.40 (m, 7H), 6.89 (d, J=8.7 Hz, 2H), 4.82 (d, J=16.5 Hz, 1H), 4.70 (d, J=16.5 Hz, 1H), 4.48 (s, 2H), 4.41-4.45 (m, 1H), 4.00-4.10 (m, 3H), 3.84 (s, 3H), 3.50-3.65 (m, 2H), 2.20-2.50 (m, 2H), 2.13 (s, 3H); LRMS (ESI) Calcd. for C24H28ClNO6 [M−H] 460, found 460.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9]
Reactant: C1COCCN1
Reactant: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (2.00 g, 8.54 mmol) and morpholine (0.744 g, 8.54 mmol) in THF (100 mL), was added N,N-diisopropylethylamine (2.21 g, 17.08 mmol). The resulting solution was stirred at 50° C. overnight. In the morning, the reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to obtain N-methyl-4-(4-morpholinyl)-3-nitrobenzenesulfonamide (2.5 g, 97%) as a red oil. MS (m/z) 302.0 (M+H+)
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:4][C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.ClCCl>CO.[Pd]>[CH3:1][C:2]([CH3:36])([CH3:35])[CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: CC(C)(C)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(Cc1c[nH]cn1)c1ccccc1
Reaction time: 17 h
Yield: 42.4 %

Procedure:
To a stirred solution of 4-(3,3-dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (121 mg) at r.t. in methanol (5 ml) and dichloromethane (1 ml) under an argon atmosphere was added 10% Pd/C (12 mg). The mixture was stirred under a hydrogen atmosphere (balloon) for 17 hours. The catalyst was filtered off and washed with methanol. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 4-(3,3-dimethyl-2-phenyl-butyl)-1H-imidazole (25 mg) as colorless gum. MS (ISP): 229.4 ([M+H]+)