Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](O)=[O:22])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH:26]([N:29](CC)C(C)C)(C)C.CN.CCO.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[CH3:26][NH:29][C:21](=[O:22])[CH2:20][O:19][CH:16]1[C:12]2[CH:13]=[N:14][CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:9][CH:8]=3)[C:11]=2[CH2:18][CH2:17]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (70 mg, 0.19 mmol) in THF (0.6 mL) was added N,N-diisopropylethylamine (131 μL, 0.75 mmol), 8M methylamine in EtOH (47 μL, 0.38 mmol) and 1-propanephosphonic acid cyclic anhydride (284 μL, 0.47 mmol). The reaction was stirred at room temperature for 16 h. The mixture was evaporated and purified by flash chromatography (20 g SiO2, Telos-cartridge, 2 to 10% 2-propanol in CH2Cl2) to give the title compound (41 mg, 63%) as light yellow oil. MS: 351.5 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][NH2:10])[CH:4]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22]>O1CCOCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][NH:10][S:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NCc1cccc(CN)c1
Solvent: C1COCCO1
Product: NCc1cccc(CNS(=O)(=O)c2ccc3ccccc3c2)c1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
α,α′-Diamino-m-xylene (24 g, 176 mmol) was dissolved in 50 ml 1,4-dioxane, and at 15-20° C. naphthalene-2-sulfonyl chloride (4 g, 17.6 mmol) dissolved in 50 ml of 1,4-dioxane was slowly added over 3 hours under stirring. Stirring was continued at RT. After standing overnight the formed precipitate was filtered off and the filtrate concentrated in vacuo. The residue was distributed between DCM and water. The organic layer was separated and washed with water and 1 N HCl. The oily layer formed between the organic and aqueous layer was separated. It solidified on standing. This solid material was treated with ethyl acetate, sucked off, and washed with ethyl acetate. The residue was dissolved in water and treated with potassium carbonate solution. The aqueous solution was extracted three times with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated to yield 3.2 g of the title compound. MS=327.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=O.C(N)C.O>O1CCCC1>[CH3:20][NH:22][C:17](=[O:19])[CH2:16][C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nn2cccnc12
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 3 hours under a nitrogen atmosphere. A solution of monoethylamine in tetrahydrofuran (16 ml; 0.041 mole; 2.59M) was added, and the mixture was stirred at room temperature for one hour. Water (50 ml) was added to dissolve a precipitate that had formed. The solvents were evaporated under reduced pressure, and the residue was triturated in isopropanol to give 2.96 g of solid, mp 211°-213° C. Recrystallization from a mixture of isopropanol and water provided 2.58 g (70%) of product, mp 212°-214° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])([O:12][CH2:13][CH3:14])=[O:11].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1N=C(C)c1ccccc1

Procedure:
A solution of acetophenone (100 ml), o-carbethoxyaniline (90 ml), benzene (100 ml) was refluxed in the presence of molecular sieve (40 g) with continuous removal of water. N-(α-methyl benzylidene)-o-carbethoxyaniline (XV) was obtained by fractional distillation. XV had a boiling point of 123° at 0.1 millimeter.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2nccn2Cc2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1

Procedure:
To a solution of 5 mol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 100 ml of ethyl alcohol is added 0.5 g of 10% Pd/C and 10 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography to give the desired product as a solid.
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[C:16]([CH3:25])[CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:24][CH2:23][N:22]([CH3:1])[CH2:21]3)=[C:16]([CH3:25])[CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(C3CCNC3)c(C)c2)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)c2ccc(C3CCN(C)C3)c(C)c2)cc1
Temperature: 0 °C
Yield: 76.7 %

Procedure:
A solution of formaldehyde (37% in water, 1.47 mL, 19.53 mmol) was added to a solution of 3-[4-(4-methoxy-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidine (0.20 g, 0.6301 mmol) in MeOH (2 mL) and the reaction mixture was heated at reflux for 30 minutes. The mixture was cooled to 0° C. and NaBH4 (0.833 g, 22.05 mmol) was slowly added. The mixture was allowed to reach room temperature and it was stirred for an additional hour. The solvent was evaporated under reduced pressure and the residue was partitioned between water and DCM. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.167 g (77% yield) of 3-[4-(4-methoxy-benzenesulfonyl)-2-methyl-phenyl]-1-methyl-pyrrolidine as a white foam: MS (M+H)=346.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[NH:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([O:1][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[NH:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C/C=C/C(=O)Nc1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C/C=C/C(=O)Nc1cccc(OC(=O)Nc2ccc(Cl)c(Cl)c2)c1
Temperature: 55 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate, 17.7 parts of 3'-hydroxycrotonanilide and 18.8 parts of 3,4-dichlorophenyl isocyanate. The reaction mixture is heated to about 55°C and one part of triethylamine is added. An additional 100 parts of ethyl acetate is added and the reaction mixture heated at reflux for about one-half hour, cooled and filtered. The solids are washed with ethyl acetate and air dried to give 31 parts of 3'-(3,4-dichlorophenylcarbamoyloxy)crotonanilide, m.p. 193°-194°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[CH:23]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[S:25][CH:26]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[S:25][CH:26]=[C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])[CH:23]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2cc(C(=O)C(F)(F)F)cs2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2cc(C(=O)C(F)(F)F)cs2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 30 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(4-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 30%). 1H NMR (400 MHz, DMSO-d6) δ 8.21-8.16 (m, 1H), 8.11-8.10 (m, 1H), 8.02-7.96 (m, 3H), 7.91-7.90 (m, 1H), 7.88-7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.67-7.48 (m, 2H), 7.31-7.25 (m, 2H), 3.56-3.54 (m, 2H), 1.33 (d, J=2.1 Hz, 6H). MS (ESI) m/z: Calculated for C26H20F4N2O3S: 516.11. found: 515.7 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:30][CH2:29][C@@H:19]3[CH2:20][N:21]([C:23]4[CH2:27][CH2:26][C:25](=[O:28])[CH:24]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].CC([N-]C(C)C)C.C1C[O:51]CC1>>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:30][CH2:29][C@@H:19]3[CH2:20][N:21]([C:23]4[CH2:27][CH:26]([OH:51])[C:25](=[O:28])[CH:24]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[C@@H](O[C@H]1OC[C@@H]2CN(C3=CC(=O)C(O)C3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 20 mg (0.0359 mmol) of 3-[(3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)hexahydropyrano[3,4-c]pyrrol-2(3H)-yl]cyclopent-2-en-1-one (example 3) and 19 mg (0.0430 mmol) MoOPH in 1.0 mL dry THF under nitrogen atmosphere at −78° C. was added 0.045 mL (0.15 mmol) of 2.0 M solution of LDA. The resulting mixture was stirred at −78° C. for 1 hr then quenched by the addition of sat. aq. Na2S2O3. The mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and filtered through a fritted funnel. The residue was purified by prep TLC eluting with 95/5 DCM/(10% NH4OH/methanol) to afford the title compound as a mixture of diastereomers. 1H-NMR (CD3OD): δ: 1.38 (d, 3H, J=6.5 Hz), 2.15-2.50 (m, 3H), 2.60-2.82 (m, 1H), 2.90-3.22 (m, 4H), 3.40-3.86 (m, 2H), 4.14-4.24 (m, 1H), 4.25-4.32 (m, 1H), 4.38-4.44 (m, 1H), 4.73-4.85 (m, 1H), 4.09 (q, 1H, J=6.5 Hz), 6.60-7.12 (m, 2H), 7.16-7.22 (m, 2H), 7.38 (s, 2H), 7.76 (s, 1H) ppm. MS: (MH)+574.
Reaction SMILES: [NH2:1]CC(N1CCC(C)CC1)=O.[CH2:12]([O:19]C1(OC)C=CC(C(O)=O)=CC1OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([NH2:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Reactant: CC1CCN(C(=O)CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-amino-1-(4-methylpiperidin-1-yl)ethanone represented by Formula 120 (24 mg, 0.15 mmol) was slowly added to 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (48.72 mg, 0.17 mmol) prepared in Preparative Example 1 and diisopropylethylamine (0.11 mL, 0.61 mmol) in DMF (3 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 58.41 mg, 0.15 mmol) thereto, the mixture was agitated for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (5 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure and the concentrate mixture was recrystallized using chloroform and hexane, resulting in a benzamide compound represented by Formula 37 as a desired product (VVZ-040; 27.2 mg, 42% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:20])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12]3)[CH:5]=[CH:4][C:3]=1[NH2:21].[F:22][C:23]([F:28])([F:27])[C:24](O)=O>>[CH2:14]([N:11]1[CH2:10][CH:9]2[CH:13]([C:8]2([C:6]2[CH:5]=[CH:4][C:3]3[NH:21][C:24]([C:23]([F:28])([F:27])[F:22])=[N:1][C:2]=3[CH:7]=2)[CH3:20])[CH2:12]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc(N)c(N)c1
Reactant: O=C(O)C(F)(F)F
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc2[nH]c(C(F)(F)F)nc2c1
Yield: 54 %

Procedure:
A solution of 2-amino-4-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 48, 99.0 mg, 0.345 mmol) in trifluoroacetic acid (2.0 ml) was heated under reflux for 1 hour. The mixture was cooled and the solvent was removed in vacuo. The residue was suspended in 2N sodium hydroxide (5 ml) and the aqueous layer was extracted with diethyl ether (3×5 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica column chromatography eluting with ethyl acetate to afford the title compound (67 mg, 54%) as a colourless oil.
Reaction SMILES: [Na].[CH:2]1([CH2:8][CH2:9][CH2:10]Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[CH2:13]([OH:16])[CH2:14][OH:15]>C1(C)C(C)=CC=CC=1>[CH:2]1([CH2:8][CH2:9][CH2:10][O:15][CH2:14][CH2:13][OH:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OCCO
Reactant: BrCCCC1CCCCC1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1C
Product: OCCOCCCC1CCCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
85 ml of xylene are added to a solution of 15.75 g of sodium in 182.2 g of ethylene glycol. The mixture is heated to 100° C., and a solution of 140.5 g of 3-cyclohexylpropyl bromide in 70 ml of xylene is added dropwise within 3 hours. When the addition has ended, the mixture is boiled for 4 hours under reflux, cooled, and then 500 ml of water are added. The mixture is extracted with twice 500 ml of petroleum ether, the combined organic phases are dried over sodium sulphate and the remaining oil is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate). 105.3 g of 2-(3-cyclohexylpropyloxy)-ethanol are obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][S:9]C1C=CC(O)=CC=1>>[CH3:8][S:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7]
Reactant: Oc1ccccc1
Reactant: CSc1ccc(O)cc1
Product: CSc1ccccc1O
Yield: 221.7 %

Procedure:
Phenol (12.5 g, 0.13 moles), methyl disulfide (8.4 g, 0.089 moles), and H ELZ-20 (2.5 g) were combined and heated under nitrogen at reflux for 3 hours during which the temperature increased to 180° C. and GC analysis indicated no further increase in the amount of ortho-(methylthio)phenol. Methyl mercaptan was allowed to escape continuously. The mixture was cooled to room temperature and filtered. The catalyst was washed several times with ether and allowed to dry leaving solid weighing 3.2 g. The filtrate and ether washings were combined, and volatiles were removed on a rotary flash evaporator leaving 15.2 g of liquid. GC analysis indicated the presence of phenol (5.3 g, 43% recovered), ortho-(methylthio)phenol (5.1 g, 41% yield), para-(methylthio)phenol (2.3 g), and di(methylthio)phenols (2.2 g).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:25])([CH3:24])[O:4][C:5]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:23])[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:8][C:6]=12.[CH2:26]([OH:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>C(#N)C.S(=O)(=O)(O)O>[CH3:25][C:3]1([CH3:24])[C@@H:2]([OH:1])[C@H:7]([O:34][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[CH:8]=[C:9]([NH:12][C:13](=[O:23])[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: COc1ccc(CC(=O)Nc2ccc3c(c2)C2OC2C(C)(C)O3)cc1
Reactant: OCCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc3c(c2)[C@@H](OCCc2ccccc2)[C@H](O)C(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-2H-1-benzopyran (200 mg, 0.68 mmol) and phenethyl alcohol (0.32 mL, 2.72 mmol) in acetonitrile (1.0 mL), sulfuric acid (0.01 mL) was added and stirred at the room temperature for 2 hours. Thereto, ice-cooled ethyl acetate was added and the formed crystals were filtered, to obtain the intended substance as white solid (yield:77%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[O:15]=[C:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>>[OH:15][C:16]1([C:7]2[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: COCCCn1cnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Product: COCCCn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: -78 °C

Procedure:
1-(3-methoxypropyl)-1H-benzo[d]imidazole (137A) (9.62 mmoles; 1.83 g) was added to an oven dried 250 mL round-bottomed flask equipped with an addition funnel and for stirring under nitrogen. Et2O (75 mL) was added and the solution was cooled to −78° C. with an acetone/CO2(s) bath. N-BuLi (2.5M in hexanes, 10.1 mmoles, 4.0 mL) was added drop-wise via syringe and the resultant solution was allowed to stir at −78° C. for 45 minutes. Tert-butyl 3-oxopiperidine-1-carboxylate (10.1 mmoles, 2.01 g) in END (25 mL) was then added drop-wise to the reaction solution at −78° C. via addition funnel and allowed to stir for 1 hr. The reaction solution was then allowed to warm to rt and stir for ihr. The reaction solution was then poured into ice-water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na.2SO4 and filtered. The filtrate was collected, concentrated, and dried in-vacuo. The residue was then partially purified by chromatography on silica gel (5-15% CH3OH/CH2Cl2) to afford tert-butyl 3-hydroxy-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (137E) as a mixture of products that was carried onto the next step without further purification. ESI-MS: m/z 390.4 (M+H)+.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccccc4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and phenylisocyanate (0.12 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (10 mL) was added and the solids were isolated by filtration and washed with water (20 mL). The solids were triturated in EtOAc (10 mL) for 18 h, then isolated by filtration, washed with EtOAc (40 mL) and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-phenyl-urea as a white solid (0.38 g, 97% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 6.94 min (96.31%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 1.88-2.12 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.59 (d, J=17.6 Hz, 1H, CHH), 2.77-3.06 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.37-4.56 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 6.73 (t, J=5.9 Hz, 1H, Ar), 6.82-6.98 (m, 1H, Ar), 7.22 (t, J=7.9 Hz, 2H, Ar), 7.33-7.49 (m, 3H, Ar), 7.52 (s, 1H, NH), 7.70 (d, J=7.7 Hz, 1H, Ar), 8.62 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.76, 47.12, 51.56, 117.72, 121.13, 121.86, 122.93, 126.88, 128.61, 130.29, 140.36, 142.39, 144.85, 155.22, 167.95, 170.99, 172.85; LCMS: MH=393; Anal Calcd for C21H20N4O4: C, 64.28; H, 5.14; N, 14.28. Found: C, 64.23; H, 4.94; N, 14.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:12][C:10]2[O:11][C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2ccccc2)c2oc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)c2oc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To a stirred solution of 100 mg (0.42 mmol) 4-methoxy-7-phenyl-benzooxazol-2-ylamine, 0.087 ml (0.62 mmol) triethylamine and 5.1 mg N,N-dimethyl-4-aminopyridine in 5 ml THF at room temperature was added dropwise a solution of 0.064 ml (0.54 mmol) 4-fluoro-benzoyl chloride in 2 ml THF and stirring continued at 65° C. for 16 h. The reaction mixture was then concentrated in vacuo. To the residue was added water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4 then 4/1 ethyl acetate/hexane) followed by trituration in ether afforded 50 mg (33%) 4-fluoro-N-(4-methoxy-7-phenyl-benzooxazol-2-yl)-benzamide as a light yellow crystalline solid. EI-MS m/e (%): 362 (M+, 90), 123 ([FC6H4CO+, 100).