Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)=[O:5].O.O.Cl[Sn]Cl.Cl>C(O)C>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH2:14])[CH:8]=1)=[O:5]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(NC(=O)c2ccc(F)cc2F)ccc1F
Yield: 89.2 %

Procedure:
Using a method similar to Preparation 14 using 2,4-Difluoro-N-(4-fluoro-3-nitrophenyl)benzamide (Preparation 13) (1.0 g, 3.38 mmol), SnCl2.2H2O (3.8 g, 16.9 mmol), ethanol (25 mL), and concentrated HCl (25 mL), gives the title intermediate (803 mg, 89% yield): mass spectrum (ion spray): m/z=267.0 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:25]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)C1CNCC(c2ccc(CC)cc2)C1
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)C2CCCC2)C1

Procedure:
5.2 g (14.0 mmol) of ethyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 2.1 g (2.1 mmol, 1.2 eq.) of cyclopentanecarbonyl chloride were reacted according to the General Method 3A. Yield: 4.8 g (96% of theory)
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[C:22]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:11]=2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)c2ccccc2)c1
Reactant: COc1cccnc1N
Product: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)c2ccccc2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(phenylsulfonyl)benzoic acid and 3-methoxypyridine-2-amine as the starting materials.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=1[CH:19]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:18]=1[CH2:19][NH:15][C@H:14]1[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cl)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
To a stirred suspension of Compound 1 (150 mg, 0.60 mmol) and 2-chloro-5-(trifluoromethyl)benzaldehyde (126 mg, 0.60 mmol) in dry CH2Cl2 (6 ml) was added NaBH(OAc)3 (179 mg, 0.84 mmol) portionwise under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 17 hr. This was basified with sat. NaHCO3 aq., extracted with CH2Cl2, dried with MgSO4, and concentrated to give crude (2S,3S)-3-(2-chloro-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a colorless oil. This was purified with chromatography to give pure (2S,3S)-3-(2-chloro-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a colorless oil (135 mg). This was diluted with ethyl acetate, added HCl-MeOH, and concentrated. The white solid was recrystallized from MeOH to give Compound 3 as a white crystalline (64 mg, 24.1%).
Reaction SMILES: [Br-:1].[C:2]([CH2:5][CH2:6][N+:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[S:9][C:8]=1[CH3:17])([OH:4])=[O:3].[Br-].N([CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N+:33]([CH2:40][CH3:41])=[CH:32][CH:31]=1)C1C=CC=CC=1.C(O)C>C(N(CC)CC)C>[Br-:1].[CH2:40]([N+:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30]([CH:29]=[CH:28][CH:27]=[CH:26][CH:17]=[C:8]2[N:7]([CH2:6][CH2:5][C:2]([OH:4])=[O:3])[C:11]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=3[S:9]2)=[CH:31][CH:32]=1)[CH3:41]
Reactant: Cc1ccc2c(c1)sc(C)[n+]2CCC(=O)O
Reactant: CC[n+]1ccc(C=CC=CNc2ccccc2)c2ccccc21
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[n+]1ccc(C=CC=CC=C2Sc3cc(C)ccc3N2CCC(=O)O)c2ccccc21
Yield: 15.2 %

Procedure:
To reaction were subjected 3.7 g of 3-(2-carboxyethyl)-2,6-dimethylbenzothiazolium bromide, 4.3 g of 4-(4-anilino-1,3-butadien-1-yl)-1-ethylquinolinium bromide, 150 ml of ethanol and 5 ml of triethylamine under reflux for one hour. After completion of the reaction, the reaction product was cooled, and the crude crystals thus obtained were purified by means of methanol to obtain 0.9 g of the objective compound (melting point 190° C.) which was glittering green. Its maximum absorption wavelength as measured in triethylamine-containing methanol was 740 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20]([OH:22])=O)[C:6]2=[O:17].[C:34](N1C=CN=C1)([N:36]1C=CN=[CH:37]1)=O.CNC.O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](=[O:22])[N:36]([CH3:37])[CH3:34])[C:6]2=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (0.62 g, 1.3 mmol) in tetrahydrofurane (5 ml) was added carbonyldiimidazole (0.3 g, 2 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added THF solution of dimethylamine (2 M, 1.3 ml, 2.6 mmol). The resulted mixture was stirred at room temperature for 4 hrs. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and to the resulted mixture was added ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was stirred with ether (5 ml) for 2 hrs and filtered to give (1R)-cyclopropanecarboxylic acid {7-chloro-2-[2-dimethylcarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.5 g, 77%): mp 163-165° C.; 1HNMR (CDCl3): δ 0.86-0.89 (m, 2H, c-CH2), 1.08-1.11 (m, 2H, c-CH2), 1.46 (t, J=7.5 Hz, 3H, OCH2CH3), 1.65-1.68 (m, 1H, c-CH), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 16 Hz, 1H, CHH), 3.12 (s, 3H, NCH3), 3.56 (dd, J=5, 16 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.10 (q, J=7.5 Hz, 2H, OCH2CH3), 4.25 (d, J=17 Hz, 1H, NCHH), 4.60 (d, J=17 Hz, 1H, NCHH), 5.58-5.64 (m, 1H, CHN), 6.83-6.97 (m, 3H, Ar), 7.35 (d, J=9 Hz, 1H, Ar), 8.41 (d, J=9 Hz, 1H, Ar), 10.51 (s, 1H, NH); 13C NMR (CDCl3): 8.9, 15.4, 16.8, 36.2, 36.6, 38.0, 48.6, 54.3, 56.6, 65.2, 112.1, 113.1, 119.8, 120.0, 120.1, 122.3, 132.2, 133.2, 137.3, 139.9, 149.2, 149.8, 169.4, 170.1, 173.2; Anal. Calcd. for C26H30ClN3O5: C, 62.46; H, 6.05; N, 8.40. Found: C, 62.43; H, 5.42; N, 8.51.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)=[O:25]
Reactant: COC(=O)C1CCN(c2ncc(N)cc2C)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1cnc(N2CCC(C(=O)OC)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To an ice-water cooled solution of methyl 1-(5-amino-3-methylpyridin-2-yl)piperidine-4-carboxylate (2.14 g; 8.59 mmol) in DCM (43 mL) was added methyl chloro(oxo)acetate (1.03 mL; 11.17 mmol) followed by pyridine (834 μL; 10.31 mmol) and the reaction mixture was allowed to stir at ˜0° C. for 30 mins, then allowed to warm to room temperature. The reaction solution was washed with water (40 mL) then saturated brine (40 mL). The organics were dried over MgSO4, filtered and evaporated under vacuum to yield a pale tan solid (2.01 g, 70% yield). This was used for the next stage without further purification. 1H NMR δ 1.60-1.80 (m, 2H), 1.85-1.99 (m, 2H), 2.18 (s, 3H), 2.54-2.62 (m, 1H), 2.69-2.88 (m, 2H), 3.26-3.40 (m, 2H), 3.56 (s, 3H), 3.82 (s, 3H), 7.87 (d, 1H), 8.40 (d, 1H), 10.75 (s, 1H). MS m/e MH+ 336.20.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 38 h

Procedure:
66.02 g of 5-bromosalicylaldehyde was dissolved in 260 ml of N,N-dimethylformamide. Then 113.35 g of anhydrous potassium carbonate and 111.71 ml of (2-bromoethyl)benzene were added thereto and the resulting mixture was stirred at room temperature for 38 hours. After evaporation of the solvent under reduced pressure, ethyl acetate and water were added to the residue and the mixture was separated. The organic layer was collected and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was recrystallized from isopropanol to give 82.62 g of 5-bromo-2-(2-phenylethoxy)benzaldehyde. m.p. 79°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[N:10][OH:11])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[ClH:17]>O>[OH:11][N:10]=[C:9]([Cl:17])[C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=NO)cn1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(Cl)=NO)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To oxime 1c (1.25 g; 8.18 mmol) in concentrated hydrochloric acid (6.0 mL) at 0° C., was added dropwise bleach (9 mL). The reaction mixture was stirred at 0° C. for 1 h, diluted with water (20 mL) and brought to about pH=3 with saturated sodium bicarbonate. The resulting solid was collected, washed with water and dried. 2c was isolated as a white solid.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)=[CH:18][N:19]=3)=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[O:16][C:15]([NH:14][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]4)=[N:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(OC)cc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: COc1ccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)cc1

Procedure:
The title compound was prepared using the procedure as described in Example 11, substituting the product of Example 10B for the product of Example 1H.
Reaction SMILES: [F:1]/[C:2](=[C:8](/[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[O:16][C:15]([CH3:23])([CH3:22])[CH:14]=[C:13]2[CH:24]([CH3:26])[CH3:25])\[CH3:9])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>>[F:1]/[C:2](=[C:8](/[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[O:16][C:15]([CH3:23])([CH3:22])[CH:14]=[C:13]2[CH:24]([CH3:26])[CH3:25])\[CH3:9])/[CH2:3][OH:4]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl (2E)-2-fluoro-3-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-but-2-enoate (Compound 69, 145 mg, 0.40 mmol) and a diisobutylaluminum hydride (1M in hexanes, 1.60 mL, 1.60 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 to 1:4 ethyl acetate/hexane).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.O>C(O)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=CC=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C=CC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 28.5 h
Yield: 94.9 %

Procedure:
Ethyl 5,5-diphenylpenta-2,4-dienoate (3.70 g) was dissolved in ethanol (68 mL), and 1N sodium hydroxide solution (22 mL) was added thereto, followed by stirring at room temperature for 28.5 hours. Subsequently, while the mixture was stirred under ice-cooling, 1N hydrochloric acid was added thereto, and pH of the resultant mixture was adjusted to about 2. The mixture was condensed to a certain volume under reduced pressure. Water was added to the condensed product, and the thus-obtained solid was collected through filtration and washed several times with water, followed by air-drying, to thereby yield 3.16 g of the product of interest (yield 94.9%).
Reaction SMILES: [OH:1][C@H:2]([CH2:25][NH:26][C:27]([CH3:40])([CH3:39])[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([O:22]CC)=[O:21])[CH:14]=1)[CH3:6].[OH-].[Na+]>CO.O1CCCC1>[OH:1][C@H:2]([CH2:25][NH:26][C:27]([CH3:39])([CH3:40])[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=1)[CH3:6]
Reactant: CCOC(=O)Cc1cccc(-c2ccccc2[C@@H](C)OC[C@H](O)CNC(C)(C)Cc2ccc3ccccc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.7 %

Procedure:
ethyl [2′-[(1R)-1-[(2R)-2-Hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-3-yl]acetate (400 mg) obtained in Step 3 was dissolved in methanol (2 ml) and tetrahydrofuran (4 ml), 1N-aqueous sodium hydroxide (1.5 ml) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water and neutralized with 10% aqueous citric acid. The precipitated white solid was collected by filtration and dried in vacuo to give the title compound (325mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:12]([CH3:14])[CH3:13])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH:2]([CH3:4])[CH3:3].C(C1NC(C)=C(CO)N=1)(C)(C)C>>[CH2:1]([C:5]1[NH:6][C:7]([CH:12]([CH3:14])[CH3:13])=[C:8]([CH:10]=[O:11])[N:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1nc(CO)c(C(C)C)[nH]1
Agent: Cc1[nH]c(C(C)(C)C)nc1CO
Product: CC(C)Cc1nc(C=O)c(C(C)C)[nH]1

Procedure:
The procedure of Example 30 is repeated substituting an equimolecular amount of 2-isobutyl-5-isopropyl-4-imidazolemethanol for the 2-tert-butyl-5-methyl-4-imidazolemethanol employed in that example. There is thus obtained the title compound in equally good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: COc1cc2c(cc1N1CCN(C)CC1)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Agent: [Ni]
Solvent: CO
Product: COc1cc2c(cc1N1CCN(C)CC1)CC(Cc1cccc(C(F)(F)F)c1)C2=O
Reaction time: 6 h

Procedure:
The 155 (100 mg, 0.241 mmol) was dissolved in methanol and Raney-Nickel (10 mg, 10% v/v) added and the reaction stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude product 156 which was purified by flash chromatography using 100-200 mesh silica gel. The compound 156 was eluted at 20% ethyl acetate in hexane as half white coloured solid 6-methoxy-5-(4-methylpiperazin-1-yl)-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one 156. 1HNMR (400 MHz, CDCl3) δ ppm 7.42 (m, 4H), 7.17 (s, 1H), 6.83 (s, 1H), 3.41 (dd, 1H), 3.21 (bs, 4H), 3.03 (m, 1H), 2.95 (m, 1H), 2.68 (m, 2H), 2.61 (bs, 4H), 2.35 (s, 3H); MS (ESI) m/z 419.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][CH2:37][CH3:38])[N:30]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:36]([CH2:37][CH3:38])[CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([NH:28][CH2:26][CH3:27])[N:30]=2)=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCNCc1cccc(NCC)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCNc1cccc(CN(CC)C(=O)CN(c2ccc(C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)n1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-ethylaminomethyl-pyridin-2-yl)-amine
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](O)=O)[CH2:11]CC2)=[CH:4][CH:3]=1.C1(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl.[OH-].[NH4+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:29])[CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CCC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NC1(c2ccc(Br)cc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 1-(4-bromophenyl)cyclobutanecarboxylic acid (200 mg, 0.78 mmol), diphenylphosphoryl azide (202 μL, 0.94 mmol), and triethylamine (131 μL, 0.94 mmol) in toluene (3 mL) was heated under reflux with stirring for 2 h. To the reaction mixture was added concentrated hydrochloric acid (1 mL). The resulting mixture was heated under reflux with stirring for 3 h. Then an ammonium hydroxide solution (5 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate (15 mL×3). The combined organic phase was washed with brine (30 mL) and concentrated to give [1-(4-bromophenyl)cyclopropyl]amine as black oil. The crude amine was reacted with 5-chloro-2-(3-fluorophenoxy)nicotinic acid (step 1 of Example 128) according to the procedure described in step 3 of Example 1 to give the title compound: 1H-NMR (CDCl3) δ 8.47 (1H, d, J=2.4 Hz), 8.24 (1H, br.s), 8.14 (1H, d, J=2.4 Hz), 7.51–6.92 (8H, m), 2.74–1.43 (6H, m); MS (ESI) m/z 475 (M+H)+, 473 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:17])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[N+:18]([C:21]1[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](O)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([O:4][CH2:3][CH2:2][O:1][C:27](=[O:28])[CH:26]([O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:32][CH:31]=2)[CH3:30])=[O:17])=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.8 %

Procedure:
To a mixture of [4-nitrophenoxy]-acetic acid-2-hydroxyethyl ester 23 (100 grams, 410 mmol) and 2-(4-nitrophenoxy)-propionic acid 29 (95 g, 450 mmol ) in anhydrous dichloromethane (1000 ml) under nitrogen atmosphere was added dropwise a solution of 1,3-dicyclohexyl carbodiimide (240 g, 1160 mmol) in anhydrous dichloromethane (600 ml). The reaction mixture was stirred at room temperature for 12 hrs. The solids were filtered off and dichloromethane distilled off to get crude 38. The crude 38 was purified by column chromatography on silica gel using benzene as eluant to give pure 38 (53 grams, 29%) as a yellow low melting solid.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:6]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([Cl:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.[OH-].[Na+]>[ClH:26].[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:4]([CH3:3])[C@H:5]2[CH2:9][CH2:8][C@@H:7]([N:10]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]3)[CH2:6]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN[C@H]1CC[C@@H](N2CCC(C)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(C)[C@H]2CC[C@@H](N3CCC(C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.5 %

Procedure:
A mixture of cis-1-methylamino-3-(4-methylpiperidin-1-yl)cyclopentane dihydrochloride (24.5 mg, 0.091 mmol) and 4-toluenesulfonyl chloride (27.9 mg, 0.146 mmol) in dichloromethane (2 ml) and 1M aqueous sodium hydroxide (2 ml) was rapidly stirred at room temperature overnight (22 hours). The phases were separated and the aqueous extracted with more dichloromethane (5 ml). The combined organics were dried (MgSO4) and evaporated. The residue was dissolved in methanol-ethyl acetate and treated with excess 1M hydrogen chloride in diethyl ether. Recrystallization of the resulting solid from methanol-ethyl acetate gave the title compound (31.5 mg, 89%) as a white solid; δH (400 MHz, CD3OD) 1.00 (3H, d, J 6.1 Hz), 1.43 (2H, m), 1.62-1.83 (5H, m), 1.91 (2H, m), 2.04-2.18 (2H, m), 2.43 (3H, s), 2.77 (3H, s), 2.89 (2H, m), 3.50 (3H, m), 4.41 (1H, m), 7.40 (2H, d, J 8.5 Hz), 7.71 (2H, d, J 8.5 Hz); m/z (ES+) 351 ([M+H]+, 100%).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([NH:5][C:6]([CH3:14])([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH3:16]>C(O)C>[CH3:13][C:6]([NH:5][C:3](=[O:4])[C@H:2]([CH3:15])[NH2:16])([CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(Br)C(=O)NC(C)(C)c1ccccc1
Reactant: N
Solvent: CCO
Product: C[C@H](N)C(=O)NC(C)(C)c1ccccc1
Reaction time: 168 h

Procedure:
A solution of 2-bromo-N-(α,α-dimethylbenzyl)propionamide (24.0 g; 0.088 mole) in ethanol (500 ml) was cooled to 0°C. The solution was saturated with ammonia (5 hours). Stirring was continued at room temperature for about 7 days. The solvent was removed under vacuum. The oily residue was taken up in benzene. The benzene phase was extracted with 5N HCl. The aqueous phase was washed with ether, made alkaline with 5N NaOH, saturated with NaCl and extracted several times with benzene. The benzene solution was dried over anhydrous Na1SO4 and the solvent was evaporated. The N1 -(α,α-dimethylbenzyl)alanineamide was obtained as an almost colourless oil. Yield: 14.6 g (79.8 %).