Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1.[BrH:26]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:26])=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1
Reactant: Br
Reactant: COc1ccc(CO)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CBr)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Temperature: 25 °C

Procedure:
To a solution of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl alcohol (195 mg, 0.57 mmol) in acetic acid (glacial, 3 mL) was added HBr (48%, 1 mL) and the resulting mixture heated at reflux for 2 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 200 mg of crude 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl bromide. To a stirred solution of 2,4-thiazolidinedione (133 mg, 1.14 mmol) in anhydrous THF (6 mL) was added, at −78° C. under argon, n-BuLi (1.6M in hexane, 1.5 mL, 2.4 mmol) dropwise. The mixture was maintained at −78° C. for 15 minutes and then warmed to 0° C. for 30 minutes to complete the dianion formation. Upon recooling to −78° C., 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl bromide was added in THF (3 mL). After 30 minutes the orange solution was allowed to warm to room temperature. After 1.5 hours, the solution was treated with 2N HCl, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane 2:8) to give 61 mg of 5-[4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl] thiazolidine-2,4-dione (24% for 3 steps from benzaldehyde). 1H NMR (500 MHz; CDCl3): δ1.27 (s, 6 H); 1.26 (s, 6 H); 1.69 (s, 4 H); 2.08 (s, 3 H); 3.12 (dd, J1=14.0 Hz, J2=9.5 Hz, 1 H); 3.50 (dd, J1=14.0 Hz, J2=4.0 Hz, 1 H); 3.76 (s, 3 H); 4.54 (dd, J1=9.5 Hz, J2=4.0 Hz, 1 H); 6.89 (d, J=8.0 Hz, 1 H); 7.03 (d, J=2 Hz, 1 H); 7.07 (s, 1 H); 7.14 (s, 1 H); 7.17 (dd, J1=8.0 Hz, J2=2.0 Hz, 1 H), 7.95 (br, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.Cl.[NH2:23][CH2:24][C:25]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:23][CH2:24][C:25]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)C1(CN)CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Reaction time: 4 h
Yield: 62.5 %

Procedure:
A solution of 4-chloro-3-nitroquinoline (10.96 g, 52.5 mmol) in dichloromethane (200 mL) was cooled to approximately 0° C., and triethylamine (22.0 mL, 158 mmol) and a solution of ethyl 1-(aminomethyl)cyclohexanecarboxylate hydrochloride (11.65 g, 52.5 mmol) in dichloromethane (30 mL) were sequentially added. The reaction was stirred for four hours, and the solvent was removed under reduced pressure. The residue was stirred in deionized water (50 mL) for one hour, and the mixture was extracted several times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange oil was purified by chromatography on silica gel (eluting with 3-5% methanol in dichloromethane) to provide 11.72 g of ethyl 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanecarboxylate as art orange oil that solidified upon standing.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=S)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:32])[CH2:3]1.C[OH:34].Cl.O>O1CCOCC1.[Hg]=O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:34])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:32])[CH2:3]1
Reactant: CO
Reactant: CC1CCN(C(=O)NCCc2ccc(S(=O)(=O)NC(=S)NC3CCCCC3)cc2)C(=O)C1
Agent: Cl
Agent: O=[Hg]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2)C(=O)C1

Procedure:
0.5 g N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamide)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-isourea methyl ether (m.p. 138°-140° C., prepared by desulfurization of N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-thiourea with mercury oxide in the presence of methanol) is dissolved in 5 ml of dioxan, and heated for a short time on a steam bath with 2 ml of concentrated hydrochloric acid. Subsequently, the water is added to the reaction mixture, the product is suction-filtered, reprecipitated from dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea obtained has a melting point of 176°-178° C. and, with the substance obtained according to Example 8, shows no depression.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1CCCO1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11 mg, 44%), MS (ISP) m/z=444.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-(tetrahydrofuran-2-yl)acetic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.C1COCC1.C[O:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:33](=[O:32])[C:34]([CH3:39])([CH3:38])[CH2:35][OH:36])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: COCC(C)(C)C(=O)O
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 9.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.100 g, 0.271 mmol), THF:DMF (5 mL:1 mL), 3-methoxy-2,2-dimethylpropanoic acid (0.053 g, 0.407 mmol), TBTU (0.261 g, 0.813 mmol), TEA (2.0 mL). The obtained crude was purified by column chromatography using basic alumina as stationary phase and eluting with the solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.012 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.05 (s, 6H), 3.30 (s, 211), 4.30 (d, J=4.5 Hz, 1H), 4.36 (s, 1H), 7.53 (d, J=6.3 Hz, 1H), 7.75 (s, 1H), 8.08 (t, J=4.5 Hz, 1H), 8.21 (d, J=6.3 Hz, 2H); MS (m/z): 469.04 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].[NH3:6].[N+]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-])=O>C(OCC)(=O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:3][CH2:2][C:1]([NH2:6])=[O:5])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N
Reactant: CCC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)CCc1ccc(O)cc1

Procedure:
Preferentially, when in that in the manufacture of anti-aging compositions the synthesis of 3-(4-hydroxyphenyl)propanoic acid amide 0.5-5 g of 3-(4-hydroxyphenyl)propanoic acid solution are used, with 0.5-5 g 4-nitrophenol in ethyl oxide, 5-15 times excess N,N′-dicyclohexylcarbodiimide in relation to 4-nitrophenol, and the anhydrous methanol saturated with ammonia is between 5-30 cm3, wherein the reaction mixture is mixed in a temperature range of 0-10° C. for 10-50 min, whereafter it is mixed at room temperature for 1.5-3 h, then the precipitated N,N′-dicyclohexylurea is filtered out and washed in 2-15 cm3 ethyl acetate. The next subject of the present invention is an anti-aging composition, characterized in that it contains 3-(4-hydroxyphenyl)propanoic acid amide at a concentration between 1 and 500 μmol. Preferentially, the composition contains 3-(4-hydroxyphenyl)propanoic acid amide, obtained through the synthesis of 3-(4-hydroxyphenyl)propanoic acid amide is performed using active 4-nitrophenyl ester where the concentration of 3-4-hydroxyphenyl)propanoic acid is 0.12-0.0012 mol, where the reaction is performed with ammonia at room temperature, and the 4-nitrophenol in ethyl acetate is supplemented with N,N′-dicyclohexylocarbodiimide, then the reaction mixture is stirred, the N,N′-dicyclohexylurea precipitate is then filtered out and dried under vacuum, the remainder is supplemented with anhydrous methanol saturated with ammonia (10 cm3) and the reaction mixture is stirred and evaporated until dry, then the remainder is loaded onto a silica gel chromatography column, and the latter is washed with chloroform-metanol (50:1, v/v), whence the chromatographically clean product is crystallized from methanol and then dried in a vacuum dessicator over phosphorus pentoxide yielding 3-(4-hydroxyphenyl)propanoic acid amide. Preferentially, 0.5-5 g of 3-(4-hydroxyphenyl)propanoic acid solution are used, with 0.5-5 g 4-nitrophenol in ethyl oxide, 5-15 times excess N,N′-dicyclohexylcarbodiimide in relation to 4-nitrophenol, and the anhydrous methanol saturated with ammonia is between 5-30 cm3, wherein the reaction mixture is mixed in a temperature range of 0-10° C. for 10-50 min, whereafter it is mixed at room temperature for 1.5-3 h, then the precipitated N,N′-dicyclohexylurea is filtered out and washed in 2-15 cm3 ethyl acetate. Preferentially, the composition is applicable in the cosmetics and/or pharmaceutical industries.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(c1ccc(OC)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ccc3OC)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-4-methoxyphenyl)propanoate (190 mg) in methanol (2.0 mL) and THF (4.0 mL) was added 1N aqueous sodium hydroxide solution (4.5 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (144 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[CH3:14]>C(O)C.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]([CH3:14])=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH:10]=1
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1cc(N)ccc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2-Methyl-5-nitrophenyl)acetic acid methyl ester 14 (32 g, 153 mmol) was dissolved in ethanol (750 mL). To this solution was added 10% palladium on carbon (3.2 g). After the mixture was degassed, a balloon filled with hydrogen was fitted. The reaction was stirred at rt for 16 h. After removing the catalyst by filtering through a celite plug and removing the solvent in vacuo, the crude product was purified using flash chromatography (ethyl acetate:petroleum ether=5:1). The product 7 was isolated as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.9 (d, J=7.8 Hz), 6.59 (m, 1H), 6.56 (m, 1H), 3.69 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: C1CCNCC1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)ccc2C)cc1
Yield: 83 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 100° C. for 16 hours rather than for 6 days, N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with piperidine. There was thus obtained the title compound in 83% yield; NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 1.3-1.7 (m, 8H), 2.2 (s, 3H), 2.4-2.5 (m, 2H), 3.2-3.4 (m, 4H), 6.85-6.95 (m, 1H), 7.0-7.1 (m, 1H), 7.2-7.3 (m, 2H), 7.45 (d, 2H), 7.5-7.6 (m, 1H), 7.8 (m, 1H), 7.9 (d, 2H), 9.8 (s, 1H), 10.13 (broad s, 1H); Mass Spectrum: M+H+517.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[CH:31][CH:30]=1>>[N:35]1([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:1][C:2]3[C:3]([CH2:25][NH2:26])=[C:4]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][CH3:24])[C:5]4[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=4[N:15]=3)=[CH:30][CH:31]=2)[CH:39]=[CH:38][CH:37]=[N:36]1
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Reactant: BrCc1ccc(-n2cccn2)cc1
Product: COc1ccc(F)cc1-c1c(CN)c(NCc2ccc(-n3cccn3)cc2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
The synthesis of title compounds started from Compound 70a and 1-(4-(bromomethyl)phenyl)-1H-pyrazole, according to procedures described in the synthesis of Compound 56. MS [m+H] calc'd C27H27FN7O3 516; found 516.
Reaction SMILES: [OH:1][C@@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1O>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:1][C@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@@H](O)C(C)C
Reactant: Cc1ccc(Cl)c(O)c1
Product: COC(=O)[C@H](Oc1cc(C)ccc1Cl)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (S)-methyl 2-hydroxy-3-methylbutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenol instead of the m-cresol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([C:19]#[N:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:17]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=3)=[CH:16][C:15]([C:19]#[N:20])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2ncc(C#N)cc2N)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ncc(C#N)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of 0.043 g (0.15 mol) of (3′-amino-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (3 mL) is added 0.021 mL (0.16 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue is taken up in a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to give 0.047 g (73%) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)O)[C:6]3[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29][C:5]=3[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]3[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A solution of 2-(8-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1,1-diphenyl-ethanol (100 mg, 0.24 mmol) in DCM (5 mL) and DMF (2 drops) was stirred at 0-10° C. Thionyl chloride (1.5 mL, 20.67 mmol) was added and the reaction mixture was stirred at RT for 2 h. The solvent was removed under vacuum to obtain the crude yellow solid. 1N NaOH (10 mL) was added to the reaction mixture and the compound extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain the crude product (100 mg) which was purified by column chromatography on silica gel (100-200 mesh) [Eluent: 0-2.5% MeOH and DCM] to yield 35 mg product which was converted to HCL salt. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.46-7.40 (m, 6H), 7.25-7.16 (m, 5H), 7.10 (d, 1H), 6.98 (d, 2H), 4.62 (d, 1H), 4.30 (d, 1H), 3.70 (m, 1H), 3.40 (m, 1H), 3.0 (s, 3H), 2.90 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.O1[CH2:14][CH2:13][NH:12]C1=O>C(OCC)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:14][CH2:13][NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NCCO1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of 3-bromoaniline (0.50 g, 2.9 mmol) in diethyl ether (Et2O, 5 mL) was added 4 M HCl in dioxane (1 mL), and the mixture was stirred at 25° C. for 1 h. Solvent was removed under reduced pressure, and the resulting HCl salt was dissolved in 2-(2-methoxyethoxy)ethanol (2 mL). 2-Oxazolidinone (0.429 g, 4.93 mmol) was added, and the reaction mixture was heated to 180° C. for 24 h. The collected crude solid was purified by column chromatography (0-10% (1% NH4OH in MeOH)/CH2Cl2) to provide N1-(3-bromo-phenyl)-ethane-1,2-diamine (0.10 g, 16%). 3-(Piperidine-1-carbonyl)-benzaldehyde (Example 1, step D; 0.091 g, 0.42 mmol) was added to a solution of the phenyl-diamine in 1,2-dichloroethane (10 mL), and the reaction mixture was stirred at 25° C. for 15 min. The mixture was treated with NaBH(OAc)3 (0.128 g, 0.604 mmol), and the resulting suspension was stirred at 25° C. for 18 h. The suspension was partitioned with satd NH4Cl (20 mL) and CH2Cl2 (20 mL), and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (2-10% CH3OH/CH2Cl2), and then by preparative TLC (10% CH3OH/CH2Cl2) to provide the desired product (0.060 g, 34%). MS (ESI): mass calculated for C21H26BrN3O, 415.13. m/z found, 416.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.28-7.26 (m, 3H), 7.21-7.16 (m, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.74-6.71 (m, 1H), 6.67 (t, J=2.0 Hz, 1H), 6.47-6.44 (m, 1H), 4.23 (br s, 1H), 3.75 (s, 2H), 3.64 (br s, 2H), 3.25 (br s, 2H), 3.10 (t, J=5.6 Hz, 2H), 2.83-2.80 (m, 2H), 1.60-1.43 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][OH:20].NC1C=C(O[C@H](C)COC)C(C#N)=CN=1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:20][CH2:19][CH2:18][O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCCOC1CCCCO1
Reactant: N#Cc1cnc(N)cc1F
Agent: COC[C@@H](C)Oc1cc(N)ncc1C#N
Product: N#Cc1cnc(N)cc1OCCOC1CCCCO1

Procedure:
From intermediate 21 and (racemic) 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol, reacted in an analogous manner to the preparation of intermediate 146. (UPLC-MS 7) tR 0.70; ESI-MS 264.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[N+:14]([C:17]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:18]=1[CH:19]=[O:20])([O-:16])=[O:15].[Cl-].[NH4+]>O1CCCC1>[N+:14]([C:17]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:18]=1[CH:19]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[F:8])[OH:20])([O-:16])=[O:15]
Reactant: Fc1ccc(F)cc1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1cc(F)ccc1F
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To 15 g of 2,5-difluorobenzene dissolved in 150 ml of tetrahydrofuran are added, at −70° C., 50 ml of 1.6M butyllithium solution. After 2 hours at −70° C., 9.616 g of 2-nitro-5-chlorobenzaldehyde are introduced and the mixture is left at this temperature for 3 hours and then at room temperature for 18 hours. The medium is hydrolysed with ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is filtered through silica, eluting with dichloromethane, to give 8.89 g of the expected product.