Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:43])[CH2:38][C:39]([O:41]C)=[O:40])=[CH:32][C:31]=3[F:44])[CH:21]=2)=[N:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:43])[CH2:38][C:39]([OH:41])=[O:40])=[CH:32][C:31]=3[F:44])[CH:21]=2)=[N:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)OC)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.4 %

Procedure:
To a solution of compound 342 (540 mg, 0.864 mmol) in THF (12 ml) and water (6 ml) was added LiOH monohydrate (363 mg, 8.64 mmol). The mixture was stirred 48 h at room temperature and THF was removed under reduced pressure. The aqueous solution was diluted with water (10 ml) and acidified to pH 4 using 1N HCl. The suspension was filtered and the precipitate was dried under high vacuum to afford compound 343 (485 mg, 0.79 mmol, 92% yield) as a beige solid. MS (m/z): 611.5 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.O[N:23]1[C:27]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:27][NH:23][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.6 %

Procedure:
N-t-Butoxycarbonyl-L-phenylalanine (2.65 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (20 ml). To the solution were added a 40% aqueous solution (0.8 ml, 10.3 mmol) of methylamine, 1-hydroxybenzotriazole (1.48 g, 11.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12.0 mmol) under cooling with ice water. The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed twice with water and each once with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was separated by filtration, the solvent was distilled off under reduced pressure. The resultant solids were washed with diisopropyl ether to obtain 2.41 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:23])=[N:18][N:17]=[CH:16]2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:23])=[N:18][N:17]=[CH:16]2
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(C)nncc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(C)nncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 4-methyl-3-(1-methylphthalazin-6-yl)benzoate (51.7 mg, 169 μmol) in tetrahydrofuran (800 μl) and methanol (400 μl) was added 1N aqueous sodium hydroxide solution (338 μl, 338 μmol) and stirred at RT for 18 h. The reaction was concentrated in vacuo and the residue was taken up in water and the pH was adjusted with 10% aqueous HCl solution to ˜7. The aqueous mixture was extracted with 15% MeOH/CHCl3 (3×) and the organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to give 4-methyl-3-(1-methylphthalazin-6-yl)benzoic acid as a maize solid. MS (ES+): 279.1 (M+H)+.
Reaction SMILES: O[C:2]([C:4](F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[NH:20][C:21](=[O:48])[N:22]([C:24]1[N:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][C:32]=2[NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:25]=1)[CH3:23].CC([O-])=O.[Na+].C(=O)C.[BH3-]C#N.[Na+]>CCO>[Cl:19][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]([O:15][CH3:16])=[C:9]([Cl:8])[C:10]=1[NH:20][C:21](=[O:48])[N:22]([C:24]1[N:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:2][CH3:4])[CH2:39][CH2:38]3)=[CH:33][C:32]=2[NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:25]=1)[CH3:23]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CC(=O)Nc1cc(C2CCNCC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Agent: CC(=O)[O-]
Agent: CC=O
Agent: [BH3-]C#N
Solvent: CCO
Product: C=CC(=O)Nc1cc(C2CCN(CC)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
To a solution of N-(2-(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-ylamino)-5-(piperidin-4-yl)phenyl)acrylamide TFA salt (35 g, 0.049 mmol) in EtOH (1 mL), was added NaOAc (4 g, 0.05 mmol) and aqueous acetaldehyde (1 mL, 0.9 mmol, 40%). After the mixture was stirred at room temperature for 1 hour, NaBH3CN (12 g, 0.18 mmol) was added, and the solution was stirred at room temperature for another 3 hours. After removal of all volatiles in vacuo, the residue was partitioned between DCM and water. The aqueous layer was extracted with chloroform twice. The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum to give crude product, which was purified by prep-HPLC to afford the title compound (3 mg, yield: 10%). 1H NMR (400 MHz, MeOH-d4) δ 8.38 (s, 1H), 7.68 (s, 1H), 7.54 (d, 1H), 7.24 (dd, 1H), 6.83 (s, 1H), 6.46-6.35 (m, 3H), 5.81 (d, 1H), 3.97 (s, 6H), 3.74-3.70 (m, 2H), 3.37 (s, 3H), 3.26 (q, 2H), 3.17-3.11 (m, 2H), 2.99-2.96 (m, 1H), 2.26-2.22 (m, 2H), 2.06-1.99 (m, 2H), 1.43 (t, 3H); MS (ESI): 628 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:9]([CH3:22])[CH:8]=1>C1COCC1.O>[C:18]([O:17][C:15](/[CH:14]=[CH:13]/[C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:23])=[O:5])=[CH:8][C:9]=1[CH3:22])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
Lithium hydroxide monohydrate (384 mg, 9.2 mmol) was added to a solution of 4-((E)-2-tert-butoxycarbonyl-vinyl)-3-methyl-benzoic acid methyl ester from Example E30.1 (1.27 g, 4.6 mmol) in THF (50 ml) and water (20 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with 1M KHSO4, water then brine, dried and concentrated in vacuo to yield the title compound (1.1 g, 92%).
Reaction SMILES: [F-].[Cs+].[C:3]1([CH:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1>[Cu](I)I.CNCCNC.C(OCC)(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:19]2[CH:28]=[CH:29][C:16]([N:13]3[CH:9]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:10][CH2:11][C:12]3=[O:14])=[CH:17][CH:18]=2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(Oc2ccc(I)cc2)cc1
Reactant: O=C1CCC(c2ccccc2)N1
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccccc2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 85 °C
Yield: 100 %

Procedure:
Step A (Method 2, Using CsF as Base): To a 10 mL reaction tube fitted with a screw cap is charged with 5-phenylpyrrolidin-2-one (80.5 mg, 0.5 mmol), 1-(4-iodophenoxy)-4-chlorobenzene (248 mg, 0.75 mmol, 1.5 eq), copper iodide (5.0 mg, 0.025 mmol, 0.05 eq), CsF (189 mg, 1.25 mmol, 2.5 eq), N1,N2-dimethylethane-1,2-diamine (5.5 μL, 0.05 mmol, 0.1 eq) and ethyl acetate (1 mL). The system is degassed with argon then sealed and heated to 85° C. for 20 h. The reaction is cooled to room temperature, filtered and concentrated in vacuo. Purification on silica gel (0-33% ethyl acetate in hexane) gives 1-[4-(4-chlorophenoxy)phenyl]-5-phenylpyrrolidin-2-one as a colorless oil (182 mg, 100%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[N:28]=[C:29](N2CCC(F)(F)C2)[C:30]2N=NNC=2N=1)(C)(C)C.Br.BrCC1C=CN=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:30]=[CH:29][N:28]=[CH:27][CH:23]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: BrCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccncc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)pyridine hydrobromide and isolated as orange solid (5.4 mg, 35%). MS (m/e): 374.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)/[CH:10]=[CH:11]/[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.C(O)(=O)C>CO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](/[CH:10]=[CH:11]/[CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:19][C:4]=2[CH:3]=1
Reactant: O=C(/C=C/C1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: Brc1ccc2[nH]c(/C=C/C3CCOCC3)nc2c1
Temperature: 85 °C

Procedure:
A solution of (E)-N-(4-bromo-2-nitro-phenyl)-3-(tetrahydro-pyran-4-yl)-acrylamide (1.26 g, 3.55 mmol, as prepared in the previous step) in 25 mL anhydrous MeOH was treated with glacial acetic acid (4 mL) and Fe powder (0.991 g, 0.0177 mol) and heated to 85° C. under a reflux condenser for 2 h. The resulting mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 (200 mL) and extracted thrice with 125 mL CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2, and the resulting solid was filtered and air-dried. The mother liquor was purified on an 80-g Sepra Si 50 SPE column (Isco system: flow rate=30 mL/min; eluting with EtOAc/hexane, 40:60 v/v over 10 min and 40:60 to 100:0, v/v over 30 min to yield (E)-5-bromo-2-[2-(tetrahydro-pyran-4-yl)-vinyl]-1H-benzimidazole as a white solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7]>BrCCCO[Si](C(C)(C)C)(C)C.COCCOC>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:4][CH2:5][CH2:6][OH:7])[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCCBr
Solvent: COCCOC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCCO)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=530.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and (3-bromopropoxy)-tert.-butyldimethylsilane in 1,2-dimethoxyethane as solvent. HCl in ethanol (3% conc.) cleaved the intermediate TBDMS-ether.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C@@:3]([OH:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[F:16][C:17]1[C:22]([CH2:23][NH2:24])=[CH:21][C:20]([CH3:25])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[F:14][C:2]([F:1])([F:15])[C@@:3]([OH:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH:24][CH2:23][C:22]1[C:17]([F:16])=[N:18][CH:19]=[C:20]([CH3:25])[CH:21]=1)=[O:6]
Reactant: O=C(O)[C@](O)(c1ccccc1)C(F)(F)F
Reactant: Cc1cnc(F)c(CN)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(F)c(CNC(=O)[C@](O)(c2ccccc2)C(F)(F)F)c1
Reaction time: 14 h

Procedure:
A solution of (2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoic acid (6-e with R=CF3 and R′=H, 105 mg, 0.48 mmol), the amine (2-e, 67 mg, 0.48 mmol) and diisopropylethylamine (415 uL, 2.4 mmol) in N,N-dimethylformamide (1 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 274 mg, 0.53 mmol). After 14 h, the reaction mixture was partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the desired product (3-1); HRMS (M+H)=343.1059; 1H NMR (500 MHz, CDCl3) δ 7.89 (bs, 1 H), 7.63 (m, 2 H), 7.43 (m, 3 H), 7.39 (d, 1 H, J=7.8 Hz), 6.67 (br, 1 H), 4.72 (m, 1 H), 4.48 (d, 2 H, J=6.1 Hz), 2.26 (s, 3 H); compound 3-3 [(2R)-3,3,3-trifluoro-N-(2-fluoro-5-trifluoromethylbenzyl)-2-hydroxy-2-phenylpropanamide] was prepared by the same procedure (2-fluoro-5-trifluoromethylbenzylamine was purchased from Alfa Aesar); HRMS (M+H)=396.0825; 1H NMR (500 MHz, DMSO-d6) δ 8.95 (t, 1 H), 7.95 (s, 1 H), 7.65 (m, 3 H), 7.39 (m, 5 H), 4.40 (dq, 2 H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[C:9]([C:14]1[C:15](=[O:33])[CH2:16][CH:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]([CH3:31])[C:22]=2[CH3:32])[CH2:18][C:19]=1[OH:20])(=[O:13])[CH2:10][CH2:11][CH3:12].O>C(OC(=O)C)(=O)C>[C:9]([C:14]1[C:19](=[O:20])[CH2:18][CH:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([N+:1]([O-:4])=[O:2])=[C:23]([CH3:31])[C:22]=2[CH3:32])[CH2:16][C:15]=1[OH:33])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)c(C)cc3ccccc23)CC1=O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCC(=O)C1=C(O)CC(c2c(C)c(C)c([N+](=O)[O-])c3ccccc23)CC1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A mixture of fuming nitric acid (0.42), glacial acetic acid (0.27 g) and acetic anhydride (0.27 g) was added dropwise to a solution of 2-butyryl-5-(2,3-dimethylnaphth-1-yl)-3-hydroxy cyclohex-2-en-1-one (1.5 g) in acetic anhydride (8 ml) at 0° C. The mixture was stirred for 1 hr at 5°-10° C. and at 50° C. for 10 min. The cooled mixture was poured into water (150 ml) which was subsequently extracted with ether. The organic fraction was washed successively with a saturated sodium bicarbonate solution and with water. The dried (Na2SO4) organic extract was evaporated under reduced pressure and the residue was purified by column chromatography over silica with dichloromethane elution to give 2-butyryl-3-hydroxy-5-(2,3-dimethyl-4-nitronapth-1-yl)cyclohex-2-en-1-one a yellow foam. Pmr spectrum (CDCl3 ; δ in ppm): 1.03 (3H,t); 1.49-1.89 (2H,m); 2.40-3.89 (6H,m); 2.37 (3H,s); 2.52 (3H,s); 4.06-4.69 (1H,m); 7.32-7.66 (3H,m); 8.00-8.29 (1H,m); 18.38 (1H,s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([CH:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6](=[O:29])[CH:7]([CH:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(c1ccc(C(=O)OC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(c1ccc(C(=O)O)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1

Procedure:
To a solution of methyl 4-{1-[2-tert-butoxy-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoate (prepared as described in PCT Patent Publication WO 2008/042223 A1 published on 10 Apr. 2008, 20 g, 48 mmol) in MeOH was slowly added NaOH (5.0 N in H2O, 19 mL, 95 mmol) at ambient temperature. Once all the ester starting material was consumed by LC-MS analysis, the mixture was concentrated. The residue was partitioned between EtOAc and 1N HCl (aq). The organic layer was then washed with water then saturated NaCl (aq). The organic layer was then dried over Na2SO4, filtered, then concentrated. The resulting acid was used directly for the following step. 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H); 7.88 (d, J=8 Hz, 2H); 7.48-7.65 (m, 2H); 7.45-7.74 (m, 3H); 7.15 (s, 1H); 3.87 (d, J=11.6 Hz, 1H); 3.15-3.11 (m, 1H); 1.61-1.70 (m, 1H); 1.06-1.14 (m, 1H); 0.97 (s, 9H); 0.76-0.86 (m, 2H); 0.56 (t, 0.1=7.6 Hz, 3H). LC3 2.54 min. (M-tBu+H)+ 347.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:43]([CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH2:43]([CH:50]1[CH2:55][CH2:54][CH2:53][N:52]([C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([C:5]3[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)[CH:9]=2)=[O:13])[CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1ccc(CC2CCCNC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCCC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (100 mg, 0.4 mmol) was dissolved in dry DMF (3 mL) and HATU (183 mg, 0.48 mmol) was added followed by 3-benzylpiperidine (75 mg, 0.42 mmol) and NMM (0.13 mL, 1.2 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture was then diluted with EtOAc and the organic layer was washed with water, 1.5N HCl solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether) to get (3-benzylpiperidin-1-yl)(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanone (70 mg, yield 44%): 1H NMR (400 MHz, CDCl3) δ 8.15-8.01 (m, 2H), 7.59-7.47 (m, 2H), 7.32-7.21 (m, 2H), 7.06-6.97 (m, 3H), 4.63 (m, 1H), 3.59-3.56 (m, 1H), 2.83-2.51 (m, 4H), 1.93-1.84 (m, 3H), 1.26-1.22 (m, 2H). MS (ESI) m/z: Calculated for C22H20F3N3O2: 415.41. found: 416.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2Cl.CCOC(C)=O.CC(O)=O.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6]2
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C1CNc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-methoxy-4-chloro-3-ethoxycarbonyl-quinoline (Step B, 20 g, 0.075 mol) in 1/1 EtOAc/AcOH (560 mL) in a Parr hydrogenation apparatus bottle kept under inert atmosphere was added Pt/C 10% (2 g). The mixture was hydrogenated under 60 psi hydrogen at RT for 2 h using a Parr hydrogenation apparatus. The resulting mixture was diluted with MeOH and filtered. The solid was washed several times with a 1/1 MeOH/CH2Cl2 mixture and the solvents were removed under vacuum. The resulting solid was suspended into CH2Cl2 and 2N NaOH was added. The mixture was stirred at RT for 30 min. The organic layer was recovered and washed once with 2 N NaOH and twice with water to give crude 6-methoxy-3-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline, which was directly used in the next step.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH2:15]1[O:21][CH:18]([CH2:19]Br)[O:17][CH2:16]1>>[CH3:2][N:3]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[CH2:19][CH:18]1[O:21][CH2:15][CH2:16][O:17]1
Reactant: CNCc1cccc2ccccc12
Reactant: BrCC1OCCO1
Agent: Cl
Product: CN(Cc1cccc2ccccc12)CC1OCCO1

Procedure:
In a similar manner, the reaction of N-methyl-1-naphthalenemethylamine hydrochloride with bromoacetaldehyde ethylene acetal gives methylnaphthylmethyl-[1,3]-dioxolan-2-ylmethylamine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[NH2:9].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[C:11]([NH:9][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=1[Cl:2])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Triethylamine was added to a suspension of 3-chloro-4-aminophenol hydrochloride (1.80 g, 10.0 mmol) in tetrahydrofuran (200 ml), benzoyl chloride (3.00 ml, 20.0 mmol) was added and the reaction allowed to stir for 18 hours at ambient temperature. The reaction was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in methanol (200 ml), treated with aqueous potassium carbonate solution (0.6 N, 25 ml, 15 mmol) and the mixture stirred for 4 hours at ambient temperature. Addition of saturated aqueous sodium hydrogen carbonate solution (100 ml) caused precipitation of an off-white solid which was collected by suction filtration. Drying in vacuo yielded N-benzoyl 2-chloro-4-hydroxyaniline (2.08 g, 83% yield) as a pale purple solid: