Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)(O)[O-].[Na+]>O.C(COC)OC.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>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:23]4[CH:24]=[CH:25][O:21][CH:22]=4)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccoc2)c1
Temperature: 80 °C

Procedure:
A mixture of 1-(3-Bromophenyl)-5-formylbenzimidazole O-methyloxime (29a) from Example 8 (0.7 g, 2.1 mmol), 3-furanylboronic acid (0.26 g, 2.34 mmol), sodium bicarbonate (0.89 g, 10.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg) in a mixture of water (5 ml) and dimethoxyethane (10 ml) is stirred at 80° C. under nitrogen over night. After cooling water is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is eluted through silica gel with a mixture of ethyl acetate and petroleum ether (1:1). The pure fractions are evaporated to dryness. Trituration with petroleum ether affords a white, crystalline product. Yield: 0.42 g (63%). Mp 147-148° C.
Reaction SMILES: [Mg].[CH2:2](I)[CH3:3].C([Mg]I)C.[CH:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[C:10]1=[O:19])[CH2:16]2.C12CC3CC(CC(C3)C1O)C2>CCOCC.O1CCCC1>[CH2:11]([C:10]1([OH:19])[CH:9]2[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:2][CH:3]1[CH2:17]3)[CH2:18]2)[CH3:12]
Reactant: CCI
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC[Mg]I
Agent: OC1C2CC3CC(C2)CC1C3
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC1(O)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5 mL of ether was added 3.7 g (0.15 gram atom) of magnesium. To the mixture was added dropwise a solution of ethyl iodide (30 g, 0.19 mol) in ether (30 mL). The solution of ethylmagnesium iodide thus prepared was added dropwise to a solution of 2-adamantanone (20 g, 0.13 mol) in tetrahydrofuran (100 ml), and the mixture was stirred at room temperature overnight. GC analysis indicated that reduction products, i.e., 2-adamantanol and 2-ethyl-2-adamantanol were formed in 75% and 25%, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C@@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=C)[CH:19]=3)[CH2:14]2)=[O:11])=[CH:4][CH:3]=1.C([OH:43])(C)(C)C.C1COCC1.O.C[N+]1([O-])CCOCC1.P([O-])([O-])([O-])=O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=2)(=[O:27])=[O:28])[CH2:9][C:10]([NH:12][C@@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[O:43])[CH:19]=3)[CH2:14]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)C[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)C2
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc2c(c1)CC[C@@H](NC(=O)C[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(R)-(4-fluoro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-N-(6-vinyl-1,2,3,4-tetrahydro-naphthalen-2-(R)-yl)-propionamide (314 mg, 0.575 mmol) in 13 mL of a mixture solvent t-butanol/THF/water (10:2:1) was added NMO (135 mg, 1.15 mmol), followed by OsO4 (2.5% w/w in t-butanol, 175 mg, 0.017 mmol). After stirring overnight at RT, 4 mL of pH=7.2 phosphate buffer was added, followed by NaIO4 (615 mg, 2.875 mmol). After stirring for 5 h at RT, the solution was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vacuo. Flash chromatography (SiO2, EtOAc/hexane=1:1) afforded the desired compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:7][CH:8]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:43])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:43])[NH:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To the suspension of 4-(3-trifluoromethyl-phenyl)1H-indole (3.37 g, 12.90 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (155 mL) was added pyridinium tribromide (12.38 g, 38.70 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (63 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (2.07 g, 58%) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6]2.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: Fc1cc(C(F)(F)F)cc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(C(F)(F)F)cc2c1CNC2

Procedure:
Prepared in analogy to Example A2 (c) from 4-Fluoro-6-trifluoromethyl-2-trityl-2,3-dihydro-1H-isoindole and trifluoroacetic acid. Yellow oil. MS (m/e): 206.1 ([M+H+, 100%).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1[CH2:36]COCC1.C(N(CC)CC)C.C(Cl)(Cl)=O.[C:48]([CH2:50][CH2:51][NH2:52])#[N:49]>C1(C)C=CC=CC=1>[C:48]([CH2:50][CH2:51][NH:52][C:36]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([C:12]2[N:13]=[C:8]([N:7]3[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]3[CH3:1])[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:26]=[CH:27][CH:28]=[CH:29][N:30]=4)[CH2:21][C:10]=3[N:11]=2)=[CH:15][CH:16]=1)=[O:31])#[N:49]
Reactant: C1COCCO1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Reactant: N#CCCN
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCC#N)cc2)nc2c1CCN(c1ncccn1)C2
Temperature: 50 °C
Reaction time: 72 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0501 g, 0.000124 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0190 mL, 0.000136 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.080 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added β-Cyanoethylamine (0.0546 mL, 0.000744 mol). The reaction mixture was stirred for 3 days. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.44 (d, J=4.7, 2H), 8.22 (d, J=8.8, 2H), 7.52 (d, J=8.8, 2H), 6.69 (t, J=4.7, 1H), 6.62 (t, J=5.9, 1H), 4.90 (d, J=18.6, 1H), 4.73 (d, J=18.7, 1H), 4.19-4.06 (m, 2H), 3.92-3.77 (m, 2H), 3.73-3.67 (m, 1H), 3.60 (t, J=9.1, 3H), 3.43 (d, J=11.6, 1H), 3.36 (m, 2H), 2.80-2.63 (m, 4H), 1.25 (d, J=6.6, 3H). LC/MS-m/z+500.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21]N=C(N4CC5C=CN=CC=5C4=O)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:44]1SC2C(C3C=CC(Cl)=CC=3)=C([C@H](OC(C)(C)C)C(OCC)=O)[C:50]([CH3:71])=[CH:49][C:47]=2[N:48]=1.N1C2C=CN=CC=2C=C1.C1C2C=CN=CC=2C(=[O:90])N1>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>[C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:49]4[C:47](=[CH:21][CH:22]=3)[N:48]([CH3:44])[C:71](=[O:90])[CH2:50]4)[S:16][C:12]=2[C:11]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: O=C1NCc2ccncc21
Reactant: Cc1cc2nc(-c3ccnc(N4Cc5ccncc5C4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
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: c1cc2[nH]ccc2cn1
Product: Cc1cc2nc(-c3ccc4c(c3)CC(=O)N4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-oxoindolin-5-yl)benzo[d]thiazol-6-yl)acetic acid was prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid except (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate was used instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate, 1H-pyrrolo[3,2-c]pyridine was used instead 1H-pyrrolo[3,4-c]pyridin-3(2H)-one and Pd(P-tBu3)2 was used instead of Pd2(dba)3 LCMS-ESI+: calc'd C27H25ClN3O3S: 506.0 (M+H+); Found: 506.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 9.31 (s, 1H), 9.18 (d, 1H), 8.66 (d, 1H), 8.31 (d, 1H), 7.90 (s, 1H), 7.72-7.70 (m, 1H), 7.63-7.61 (m, 3H), 7.32 (d, 1H), 5.26 (s, 1H), 2.63 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].N(=[CH:8][C:9]([NH:11][C:12]1[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=1)=[O:10])O>O>[CH3:17][O:16][C:15]1[CH:14]=[C:13]2[C:12](=[CH:19][CH:18]=1)[NH:11][C:9](=[O:10])[C:8]2=[O:2]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(NC(=O)C=NO)cc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 60 °C
Yield: 65 %

Procedure:
Concentrated sulfuric acid (45 mL) containing 5 mL of water was warmed to 60° C. and 8.6 g of N-(2-hydroximinoacetyl)anisidine was added in one portion. The stirred mixture was heated to 93° C. for 10 minutes and then allowed to cool to room temperature. The mixture was poured into 500 g of ice and extracted 3 times with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 5.1 g (65% yield) of 5-methoxyisatin as a dark red solid. 5-Methoxyisatin (5.0 g) and 30 mL of hydrazine hydrate were heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL of water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 1.1 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrazinocarbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluting with ethyl acetate:hexane (1:1) to give 0.7 g of 5-methoxy-2-oxindole as a yellow solid. The 1.1 g of 2-hydrazinocarbonylmethyl-4-anisidine was refluxed for 1 hour in 20 mL of 1N sodium hydroxide. The mixture was cooled, acidified to pH 2 with concentrated hydrochloric acid and extracted 3 times with 25 mL of ethyl acetate each time. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of 5-methoxy-2-oxindole as a yellow solid. The combined yield was 1.5 g or 33%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)O)[C:5]2[O:6][CH2:7][O:8][CH2:9][C:4]=2[CH:3]=1>C(O)(=O)C.[Pd]>[ClH:1].[O:6]1[C:5]2[C:10]([CH2:12][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)=[CH:11][CH:2]=[CH:3][C:4]=2[CH2:9][O:8][CH2:7]1
Reactant: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cc(Cl)cc2c1OCOC2
Agent: [Pd]
Solvent: CC(=O)O
Product: Cl
Product: c1cc2c(c(Cc3c[nH]cn3)c1)OCOC2
Yield: 83.9 %

Procedure:
50.85 g (0.1 mole) of alpha-(6-chloro-4H-1,3-benzodioxin-8-yl)-1-triphenylmethyl-1H-imidazole-4-methanol (prepared in Example 1.C.1.), dissolved in 500 ml of acetic acid, are hydrogenolyzed in the presence of 3 g of 10% palladium on carbon for 2 hours at 80° C., under a hydrogen pressure of 2.41 bars. The catalyst is then filtered off and the solvent is distilled under reduced pressure. The residue obtained is extracted three times with diethyl ether to remove the triphenylmethane formed. It is subsequently recrystallized from 50 ml of acetonitrile. 21.2 g of 4-[(4H-1,3-benzodioxin-8-yl)methyl]-1H-imidazole hydrochloride are obtained. Yield: 83% of theory; M.P.: 168°-173° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2C(C#N)=CC=[CH:12][C:7]=2[N:6]=[CH:5]1.[Li][CH3:16].O.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[OH:1][CH2:2][CH2:3][N:4]1[C:8]2[C:18]([C:22](=[O:21])[CH3:16])=[CH:19][CH:20]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: N#Cc1cccc2ncn(CCO)c12
Reactant: [Li]C
Reactant: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc2ncn(CCO)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile (0.29 g, 1.5 mmol) in dry THF (6.2 ml) is cooled to −78° C. and MeLi (5.8 mL, 9.3 mmol) is added slowly. After the addition the reaction mixture is allowed to warm up to ambient temperature and kept such for 30 min. The temperature is brought down to −78° C. again and water (4 ml) was added slowly. After warming up the reaction mixture is acidified to pH 4 and heated at 50° C. for 30 min. Solvents are removed under reduced pressure and the residue is partitioned between ethyl acetate and aq. NaHCO3. The organic extract is further washed with water and brine, dried over Na2SO4 and concentrated. Purification is performed on flash silica column using ethyl acetate-methanol as the eluent to give the desired product (0.25 g, 80%).
Reaction SMILES: C([O:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=1)C1C=CC=CC=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH3:26][O:25][C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:11]1[N:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([OH:27])=[O:8])=[O:24]
Reactant: COC(=O)c1cccc(Oc2ncccc2C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Yield: 76.2 %

Procedure:
To a solution 2-(3-Methoxycarbonyl-phenoxy)-nicotinic acid benzyl ester (1.1 g) in methanol (15 ml) and ethyl acetate (15 ml) was added 10% palladium on carbon (0.2 g). This was shaken under 30 psi hydrogen for 2 hours. The catalyst was removed by filtration, and the solution was concentrated to give a solid which was triturated in methylene chloride/hexane to give a white solid (0.630 g). MW 273.26; MS (m/e) 274 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([C:13]#[N:14])=[C:4]([CH3:15])[N:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([C:13]#[N:14])=[C:4]([CH3:15])[N:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1Cl
Reactant: CCCCN
Product: CCCCNc1nc(C)c(C#N)cc1C(=O)OCC

Procedure:
112 g of 2-chloro-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester (0.5 mol) are dissolved in 300 ml of alcohol and 73 g of n-butylamine are dropped in at reflux temperature with stirring. After the addition is completed, the mixture is refluxed for an additional hour and then poured onto ice. 2-butylamino-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester precipitates. Yield 116 g (89%); m.p. 61°-63° C. (petrol ether).
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[C:17]1(=[O:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.C(OCC)(=O)C>[C:7]([C:6]1[CH:15]=[CH:16][C:3]([CH2:2][N:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]2=[O:26])=[CH:4][CH:5]=1)(=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: O=C1N=Cc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccc(CN2Cc3ccccc3C2=O)cc1
Yield: 91 %

Procedure:
A mixture of 4-(bromomethyl)benzophenone (138 mg, 0.5 mmol), isoindolone (67 mg, 0.5 mmol), cesium carbonate (407 mg, 1.25 mmol), and 18-crown-6 (13 mg, 0.05 mmol) in acetone (10 mL) was stirred heating at reflux for 3 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-(4-benzoylbenzyl)-2,3-dihydroisoindol-1-one (149 mg, 91%). GC/MS gave: m/z (rel.int.) 327 (M+, 97), 250 (5), 222 (42), 196 (20) 165 (31), 146 (31), 133 (53), 119 (94), 105 (71), 91 (100), and 77 (98). 1H NMR (300 MHz, CDCl3): δ 4.33 (s, 2H), 4.89 (s, 2H), 7.42 (d, 2H), 7.45-7.59 (m, 6H), 7.77 (dd, 4H), 7.91 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)=[S:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)=[S:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=S)Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 84.0 mg (0.184 mmol) ethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)thiocarbonyl]amino]-benzoate (Compound 42) in 2.0 ml EtOH and 2.0 ml of THF was added 60.0 mg NaOH (1.50 mmol, 1.5 ml of a 1 M aqueous solution). After stirring at room temperature overnight, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a yellow solid. 1H NMR (d6-acetone): δ 10.96 (1H, s), 8.05 (4H, m), 7.72 (1H, dd, J=2.0, 8.0 Hz), 7.54 (1H, s), 7.46 (1H, d, J=8.1 Hz), 7.20 (4H, m), 6.04 (1H, t, J=4.7 Hz), 2.38 (2H, d, J=4.7 Hz), 2.33 (3H, s), 1.35 (6H, s).
Reaction SMILES: [H-].[Na+].[C:3](=[O:17])([S:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:4].[CH3:18]I>C1COCC1>[C:3](=[O:17])([S:5][CH2:6][CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:18])[CH3:4]
Reactant: CI
Reactant: CC(=O)SCCCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of NaH (0.57 g, 60%, 14.25 mmol) in 20 ml of THF at 0° C. was added S-3-(tert-butoxycarbonylamino)propyl ethanethioate (1.25 g, 5.36 mmol) under Ar. After stirring at 0° C. for 30 min, MeI (1.0 ml, 16.06 mmol) was added to the mixture. Stirring was continued at 0° C. for 2 h then RT overnight. The mixture was concentrated, redissolved in 120 ml of EtAc/Hexane (1:2), washed with 1 M NaH2PO4 NaCl (conc.), dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with EtAc/Hexane (1:7) to afford 1.121 g (85%) of the title compound. 1H NMR (CDCl3) 3.69 (t, 2H, J=7.3 Hz), 2.41 (t, 2H, J=7.3 Hz), 2.39 (s, 3H), 2.03 (s, 3H), 1.76 (m, 2H), 1.47 (s, 9H); 13C NMR 173.21, 153.39, 83.28, 43.67, 31.84, 28.26, 28.19, 27.11, 15.65; MS m/z+ 270.0 (M+Na).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][CH2:8][N:9]([CH3:36])[C:10](=[O:35])[CH2:11][CH2:12][O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]([CH3:34])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:16][CH2:15]1)C.C1COCC1.CO>O>[OH:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:36])[C:10](=[O:35])[CH2:11][CH2:12][O:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([N:20]([CH3:34])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)(=[O:22])=[O:23])[CH2:18][CH2:19]1
Reactant: CCOC(=O)CCN(C)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCO)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
181 mg (4.78 mmol, 10 eq) of NaBH4 were added portionwise to a solution of 250 mg (0.48 mmol) of trans-3-[methyl-(3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionyl)-amino]-propionic acid ethyl ester in 6 mL of a mixture of THF:MeOH (1:1) at 0° C. The reaction mixture was stirred at RT for 4 h. Water was added and the reaction was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography with a gradient of CH2Cl2:MeOH 98:2 to 95:5 to yield 55 mg (24%) of trans-N-(3-hydroxy-propyl)-N-methyl-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionamide as colorless oil, MS: 481(MH+).
Reaction SMILES: [Br:1]Br.[Br-].[Br-].[Br-].[CH2:6]([N+:9]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:7][CH3:8].[CH2:31]([N+:34]([CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])([CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])[CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[CH2:32][CH3:33].[CH2:56]([N+:59]([CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH3:80])([CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH3:73])[CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[CH2:57][CH3:58]>>[Br-:1].[Br-:1].[Br-:1].[CH:6]([N+:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:7][CH3:8].[CH:31]([N+:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])([CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])[CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:32][CH3:33].[CH:56]([N+:59]([CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])([CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH3:80])[CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH3:73])=[CH:57][CH3:58]
Reactant: BrBr
Reactant: CCC[N+](CCOCCOC)(CCOCCOC)CCOCCOC
Agent: [Br-]
Product: CC=C[N+](CCOCCOC)(CCOCCOC)CCOCCOC

Procedure:
The crude quaternary ammonium salt (5.36 g, 12 mmoles) was placed in a round bottom flask and bromine (0.61 ml, 1.92 g, 12 mmoles) added dropwise from a buret with vigorous stirring. The product, N-propyl-N,N,N-tris(3,6-dioxaheptyl)ammonium tribromide, was a dark red oil (yield 7.27 g, 100%). %Brtot =39.18 (exp), 39.54 (calc): %Brox =20.38 (exp), 26.36 (calc).