Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C(O)C.[Cl:6][C:7]1[C:15]([Cl:16])=[C:14]2[C:10]([CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:18][C:19]#[C:20][Si](C)(C)C)[C:13]2=[O:17])=[CH:9][C:8]=1[O:31][CH2:32][C:33]([O:35]CC)=[O:34]>O>[Cl:6][C:7]1[C:15]([Cl:16])=[C:14]2[C:10]([CH2:11][C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([CH2:18][C:19]#[CH:20])[C:13]2=[O:17])=[CH:9][C:8]=1[O:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
A solution of 50% sodium hydroxide (2.5 g.) in 50 ml. of abs. ethanol is added to a suspension of ethyl [6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate (3.08 g., 6.3 mmol) in 100 ml. of abs. ethanol under an argon atmosphere. The mixture stirred at room temperature for a period of 5 hr. (excluding light) and mixed with water provides a clear yellow solution which is first extracted with ether and then acidified with dilute hydrochloric acid. The acidified solution is extracted with 1:1 ether-ethyl acetate which, after washing with brine and drying over magnesium sulfate, is concentrated under reduced pressure to afford 2.22 g. (91% yield) of (6,7-dichloro-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)acetic acid as a tan solid, m.p. 238.5°-241.5° (corr.). Crystallization from isopropanol affords the indanyloxyacetic acid product as white needles, m.p. 237.5°-240° (corr.). This material is solvated with 0.17 mole of isopropanol, according to NMR analysis, and has the following elemental analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[C:23]4[CH2:22][C:21]([O:24]CC)=[CH:20][CH2:19][C:18]=4[CH:17]=[CH:16][CH:15]=3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC1CC2C(NC3O[C:43]([C:46]4[CH:51]=CC(C(F)(F)F)=CC=4)=[CH:44][N:45]=3)=CC=CC=2CC=1)C>>[N:45]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][C:11]([NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]5[C:23]=4[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]5)=[N:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:44][CH2:43][CH2:46][CH2:51]1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(Cl)cc4)o3)c2C1
Product: O=C1CCc2cccc(Nc3ncc(-c4ccc(N5CCCC5)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 7B for the product of Example 1H.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].CO.[OH-].[Na+].Cl>O>[C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:7][O:8][C:9]=1[CH3:10])([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2F)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2F)c1C(=O)O
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of 4-methoxycarbonyl-5-methyl-3-(2-fluorophenyl)isoxazole (2.20 g, 8.84 mmol), MeOH (25 ml), and 2N NaOH (8.8 ml) was heated at 50° C. overnight (19 h). The reaction was cooled to room temperature, diluted with H2O, and acidified (2N HCl) to less than pH 3. The mixture was extracted with EtOAc (twice) and the combined extracts were washed (brine), dried (MgSO4), filtered, and concentrated to give the title compound (1.88 g, 96%). This material was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12]C(=O)C)[CH2:5][CH2:4][CH2:3]1.[OH-].[K+]>O.C(O)CO.O>[OH:1][C@H:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C@H:6]([NH2:12])[CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCCC(O)c2sccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: N[C@@H]1CCC[C@@H](O)c2sccc21

Procedure:
A sample of a cis/trans mixture of N-(5,6,7,8-tetrahydro-8-hydroxy-4H-cyclohepta[b]thien-4-yl)acetamide is added to 2 equivalents of KOH in water/ethylene glycol mixture. The mixture is heated at reflux under nitrogen atmosphere until starting material is no longer detectable by thin-layer chromatography. The mixture is cooled, diluted with water and extracted exhaustively with CHCl3. The chloroform extract is added to an equal volume of water and acidified with hydrochloric acid until the mixture is at pH 2. The mixture is then extracted with CHCl3 and then the remaining aqueous solution is made alkaline with NaOH solution. The alkaline solution is then extracted with CHCl3 exhaustively and the extracts are dried over MgSO4 and evaporated to dryness to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][C:24](=O)OC)=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][CH3:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl {2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbamate (115 mg, 0.303 mmol) was dissolved in 10 mL of THF at 0° C. 1M Ha/ether (0.425 mL, 0.424 mmol) was added and the solution was stirred at 0° C. for 15 min. LiAlH4 (57 mg, 1.52 mmol) was added slowly and the solution was stirred at rt overnight. The reaction was quenched at 0° C. by the addition of MeOH (1 mL) and water (2 mL). Anhydrous Na2SO4 (5.0 g) was added and the solution was stirred at rt for 30 min. The solution was filtered and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. Yield: 95 mg (93%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.41-1.51 (m, 2H), 1.54 (s, 9H), 1.57-1.67 (m, 2H), 1.68-1.76 (m, 3H), 2.07-2.17 (m, 3H), 2.87 (s, 3H), 4.15 (d, J=7.42 Hz, 2H), 6.61 (dd, J=8.59, 2.34 Hz, 1H), 7.01 (d, J=1.95 Hz, 1H), 7.09 (d, J=8.59 Hz, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)C>[Cl:15][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1ccc(Cl)c(CC(=O)O)c1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Dissolve 2-(3-isopropoxyphenyl)acetic acid (3.24 g, 16.6 mmol) in dimethylformamide (11.1 mL). Cool on an ice bath and add a solution N-chlorosuccinimide (2.44 g, 18.3 mmol) in dimethylformamide (12.2 mL). Stir overnight allowing the reaction to reach ambient temperature. Dilute the reaction mixture with diethyl ether. Wash with water. Extract the water wash with diethyl ether. Combine the diethyl ether extracts and wash with water and brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with acetone: hexanes (0-25% gradient) to give the title compound (3.08 g, 13.47 mmol). MS (m/z): 245.8 (M+18).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:35](=O)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=O)=[CH:23][CH:22]=1)=O)(C)(C)C.O.[OH-].[Na+]>C1COCC1>[CH3:12][N:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:35]2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1COc1ccc(N2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a 25 mL press resistant vial which contained a suspension of LiAlH4 (100 mg, 3 mmol) in anhydrous THF (15 mL) was added the product from step 1 (120 mg, 0.3 mmol) at −78° C. The reaction mixture was allowed to warm to rt and stir at rt for 2 h then was heated to 78° C. and stirred at 78° C. for 24 h. After cooled to 5° C., 1 eq of water was added to the mixture which was followed by addition of 1 eq of 15% NaOH and then 3 eq of water. The solid which formed was filtered out and washed with THF water (2×20 mL). The combined organic solvent was removed under vacuo to obtain the crude product which was purified by recrystallization with ether-EtOAc-hexane to afford the title product, (50 mg, 57%);LCMS; 99%, ESI+ Calcd: 308.4 m/z, found: 309.7 m/z (M+1);
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH2:17]([N:19]([CH2:33][CH3:34])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31])[CH3:18]>>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][N:19]([CH2:17][CH3:18])[CH2:33][CH3:34])=[C:24]([N+:30]([O-:32])=[O:31])[CH:25]=1)=[O:8]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1[N+](=O)[O-]
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 4-(2-diethylamino-ethoxy)-3-nitro-phenylamine (Z31a).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1>CC(O)C.Br.C(O)(=O)C>[NH2:30][CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][CH:22]([NH:21][C:13]2[N:12]([CH2:11][O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)O
Product: NCCN1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Yield: 18.7 %

Procedure:
A mixture of compound (7) (0.0026 mol) in 2-propanol (30 ml) and HBr/acetic acid (2 ml) was stirred and refluxed for 90 minutes and then cooled. The solvent was evaporated. The residue was taken up in CH2Cl2 and H2O. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent. CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in diisopropyl ether. The precipitate was filtered off and dried. This fraction was purified again by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in diisopropyl ether. The precipitate was filtered off and dried, yielding 0.23 g of (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine (compound 9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1coc(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1coc(-c2ccc(Cl)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 2 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)oxazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (4 mgs, 2% yield). 1H NMR (CDCl3) δ 8.55 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.8 Hz, 2H), 7.68-7.54 (m, 2H), 7.41 (d, J=8.4 Hz, 2H), 3.86 (m, 2H), 3.94 (m, 2H). MS (ESI) m/z: Calculated for C21H14ClF3N4O3: 462.07. found: 463.1 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1C=CC(C)=CC=1)[CH2:7][OH:8].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:9])[CH2:7][OH:8]
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCBr
Yield: 99 %

Procedure:
According to the procedure described for the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted with LiBH4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in CH2Cl2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil. 1H NMR (CDCl3): δ 3.38 (t, 2H, J=7.4), 3.50-3.40 (br. s, 1H, OH), 3.22 (d, 2H, J=5.6), 1.85 (qv, 2H, J=7.4), 1.50-1.35 (m, 2H), 1.30-1.20 (m, 2H), 0.85 (s, 6H). 13C NMR (CDCl3) δ 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[O:2].[CH2:24](O)[CH2:25][OH:26]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:26]1[CH2:25][CH2:24][O:2][CH:1]1[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: NCCCOc1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A solution of 2-[3-(3-formylphenoxy)propyl]-1H-isoindole-1,3-(2H)-dione (90 g) and p-toluenesulphonic acid, monohydrate (200 mg) in benzene (900 ml) and ethane-1,2-diol (25 g) was heated under reflux using a Dean-Stark separator for 8 h. The cooled solution was washed successively with sodium carbonate solution, water, sodium chloride solution, and evaporated in vacuo. The resulting oil was dissolved in tetrahydrofuran (1 liter) and stirred with hydrazine hydrate (50 ml) at room temperature for 24 hr. The mixture was diluted with ether and filtered. The filtrate was distilled to give the title compound as a colourless oil (55.2 g) b.p. 134°-6° (0.7 mm). TLC silica; methanol:ammonia 80:1; Rf 0.4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)=[CH:4][CH:3]=3)[N:35]=2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Product: c1ccc(COc2ccc(-c3nc(COc4ccc(CCCCn5ccnc5)cc4)co3)cc2)cc1
Yield: 54 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 2-(4-benzyloxyphenyl)-4-chloromethyloxazole to give 2-(4-benzyloxyphenyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole. The yield was 54%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 118-120° C.
Reaction SMILES: C(O[C:6](=[O:14])[NH:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(C)(C)C.[CH3:15][C:16]1OC(C(O)=O)=C[CH:17]=1>>[C:6]([NH:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=[O:14])[CH:16]([CH3:17])[CH3:15]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)o1
Reactant: Cc1ccc(C(=O)O)o1
Product: Cc1ccc(NC(=O)C(C)C)o1

Procedure:
tert-Butyl-5-methyl-2-furylcarbamate, (mp 80° C, 24 g, 0.12 mole) prepared as in Example 1 from 5-methyl-2-furoic acid was reacted as in Example 2 to give 2-isobutanamido-5-methylfuran (13.4 g) mp 78° C which was then reacted as in Example 4 to give the title compound. b.p. 94° C/0.3 mm.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62]C=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].C[O:65]C(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:58]1[CH2:59][CH2:60][O:65][CH2:62][CH2:63]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]3)cc2CO4)[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C5CCOCC5)[nH]3)cc2CO4)[nH]1)C(C)C

Procedure:
This compound was made in an analogous manner to methyl (S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amide coupling. LCMS-ESI+: calculated for C47H54N8O8: 858.98; observed [M+1]+: 860.02.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: NCc1ccncc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2ccncc2)c1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (68 mg, 0.2 mmol), 4-aminomethyl pyridine (0.024 ml, 0.24 mmol) in DMF 3.0 mL was added EDC (57.5 mg, 0.3 mmol), HOBt (40.6 mg, 0.3 mmol) and DIPEA (0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-pyridine-4-ylmethyl-benzamide as a white solid (60.6 mg, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[CH3:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([NH:22][CH3:21])=[O:20])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2
Reactant: CN
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: CNC(=O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid and excess monomethylamine in a closed container in an aprotic solvent. The unused methylamine is allowed to escape and the solution is washed with hydrochloric acid followed by aqueous base and evaporated. The title compound is obtained by conventional crystallization from alkanolic solution or by chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.O.NN>CCO.C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Sc3ccccc3)c([N+](=O)[O-])c2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Sc3ccccc3)c(N)c2)CC1
Reaction time: 2 h
Yield: 102.4 %

Procedure:
To a solution of tert-butyl 4-[3-nitro-4-(phenylsulfanyl)phenyl]-1-piperazinecarboxylate (1.7 g, 3.8 mmol) in 42 mL of a 4:1 EtOH:THF solvent system is added Raney nickel (260 mg suspension in EtOH) followed by hydrazine monohydrate (0.92 mL, 19 mmol). The mixture is stirred vigorously for 2 h and then filtered through celite that is pretreated with water. The filtrate is concentrated, the residue crystallized from MeOH/EtOAc/hexane to give 1.5 g (92%) of the aniline as a white foam.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(C(=O)OC)cc1
Yield: 53 %

Procedure:
Alkylation of 5-n-butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step A) with methyl 4-(bromomethyl)benzoate was carried out according to the procedure of Example 13, Step A. Purification of the crude product by flash chromatography on silica gel (gradient elution with 0.3-1% MeOH in CH2Cl2) provided a 53% yield of the title compound as a clear, glassy solid; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 434 (M+1)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:25](=[O:40])[CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])C.O[Li].O>C1COCC1.CO.O>[CH:12]([N:10]1[CH2:9][CH2:8][N:7]([C:25](=[O:40])[CH2:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:11]1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CN(C(c2ccccc2)c2ccccc2)CCN1C(=O)CC(c1ccccc1)c1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)CCN1C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
A mixture of 4-Benzhydryl-1-(3,3-diphenyl-propionyl)-piperazine-2-carboxylic acid ethyl ester (0.51 g, 0.957 mmol), and LiOH.H2O (0.12 g, 2.87 mmol) in THF/MeOH/H2O (15:5:5) was stirred at room temperature for two days. The solvent was evaporated under reduced pressure, the residue was dissolved in water, acidified with 1N HCl to pH 3. The product was extracted with EtOAc, dried with MgSO4, and evaporated under reduced pressure. The product was purified by column chromatography (CH2Cl2:MeOH 15:1) to give the title compound in 95% yield.