Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:37][C:36]=2[CH:46]([OH:48])[CH3:47])=[CH:31][CH:30]=1>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=[CH:4][C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][C:36]=2[CH:46]([OH:48])[CH3:47])=[CH:33][CH:34]=1)=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C(C)O)c1
Product: CC(O)c1cc(CC(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (137 mg, 0.325 mmol) obtained in Example (28-5) and methyl [4′-hydroxy-2-(1-hydroxyethyl)-1,1′-biphenyl-4-yl]acetate (93 mg, 0.325 mmol) obtained in Example (88-1), the title compound was obtained as a pale yellow oil (60 mg, yield: 34%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]1[CH2:17][NH:16][C@@H:15]([CH3:18])[CH2:14][NH:13]1>C(#N)C>[CH3:11][C@H:12]1[CH2:17][NH:16][C@H:15]([CH3:18])[CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1

Procedure:
1-Fluoro-4-nitrobenzene (6 g, 42.52 mmol) and (2R,5S)-2,5-dimethylpiperazine (21.9 g, 191.34 mmol) were heated in acetonitrile (20 ml) at 100° C. for 11 h. The solution was concentrated in vacuo, then the residue was partitioned between DCM and water+sat. sodium hydrogen carbonate. The organic extract was washed with water (4 times), brine, dried and concentrated. Chromatography on silica gel with MeOH: DCM (1:99 to 5:95) gave the title compound as an oil which solidified on standing overnight (8.32 g, 83%). NMR (400 MHz) 1.08 (d, 3H), 1.16 (d, 3H), 2.55 (dd, 1H), 3.18 (m, 2H), 3.34 (m, 2H), 3.95 (m, 1H), 6.91 (d, 2H), 8.03 (d, 2H); m/z 236.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](=[O:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexyl}oxy)propan-2-one (259 mg) in ethanol (5 mL) was added sodium borohydride (57 mg) under ice-cooling. The reaction mixture was stirred at 0° C. for 1 hr, and extracted with ethyl acetate and 1M hydrochloric acid. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (271 mg).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH2:13][CH2:12]2)[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:14]1[C:15]2[C:11](=[CH:10][C:9]([C:2]([C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])=[O:1])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)C#CC(O)c1ccc2c(c1)CCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C#CC(=O)c1ccc2c(c1)CCC2
Reaction time: 0.33 h

Procedure:
A solution of 6 g (26 mmol) of methyl 4-hydroxy-4-(5-indanyl)-2-butynoate in 200 ml of methylene chloride was added dropwise at 0° to a suspension of 68 g (0.78 mol) of manganese dioxide in 200 ml of methylene chloride. The reaction mixture was stirred at 0° for 20 minutes, filtered over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 3-(5-indanylcarbonyl)propiolate as a yellow oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([I:16])[CH:15]=1)[N:12]=[CH:11][C:10]([C:17]([O:19]CC)=O)=[C:9]2[OH:22])(=O)C.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CCOCC>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:17]([C:10]2[CH:11]=[N:12][C:13]3[C:8]([C:9]=2[OH:22])=[CH:7][C:6]([CH2:5][OH:4])=[CH:15][C:14]=3[I:16])=[O:19])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc2c(I)cc(COC(C)=O)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CO)cc2c1O
Temperature: 180 °C
Yield: 73 %

Procedure:
A suspension of ethyl 6-[(acetyloxy)methyl]-4-hydroxy-8-iodo-3-quinolinecarboxylate (0.90 g) and 4-chlorobenzylamine (2.6 mL) is heated at 180° C. for 1 h. The reaction is cooled to room temperature and diluted with Et2O. The resulting solid is filtered and triturated with acetone to yield 0.74 g (73%) of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]([O:7][CH2:8][CH3:9])=[O:6].B.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)cc1F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)cc1F

Procedure:
A solution of 5 g of ethyl 3-fluoro-4-(hexadecanoylamino)benzoate in 50 ml of tetrahydrofuran is slowly added with stirring to 13 ml of 1 M borane in tetrahydrofuran. The resulting solution is then poured into 50 ml of 10% aqueous hydrochloric acid and the resulting mixture is filtered. The residue is crystallized from acetonitrile to yield ethyl 3-fluoro-4-(hexadecylamino)benzoate as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([CH3:12])([OH:11])[CH3:10]>C(O)C>[CH3:8][C:9]([OH:11])([CH3:12])[CH2:10][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)CCl
Reactant: C1CNCCN1
Solvent: CCO
Product: CC(C)(O)CN1CCNCC1
Temperature: 110 °C
Reaction time: 6 h
Yield: 59.8 %

Procedure:
piperazine (6.88 g, 80.0 mmol) was dissolved in ethanol (40 mL), and 1-chloro-2-methyl-2-propanol (2.18 g, 20.0 mmol) was added thereto, and then, the mixture was stirred at 110° C. for 6 hours. After the mixture was left to cool to room temperature, the solvent was evaporated. Then, ethyl acetate was added to the residue, and the precipitated solid was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=90/10) to give 2-methyl-1-(piperazin-1-yl)propan-2-ol (1.89 g, 11.96 mmol, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:27][C:28]=2[CH3:29])=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[O:27][C:28]=3[CH3:29])=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2cccs2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (300 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-(2-thienyl)oxazole (450 mg), and N,N-dimethylformamide (5 ml), sodium hydride (60%, oily, 70.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained colorless oily substances, 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid (460 mg, yield: 70%) was obtained. This was recrystallized from acetone-hexane. Melting point: 156–157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Nc1cc(F)ccc1C(=O)Nc1ccccc1Cl
Yield: 52 %

Procedure:
Prepared according to Procedure A using 2-amino-4-fluorobenzoic acid (1.15 g, 7.41 mmol) and SOCl2 (1.4 mL, 18.5 mmol) in benzene (25 mL), followed by 2-chloroaniline (1.6 mL, 14.8 mmol) and CHCl3 (25 mL) The product was chromatographed in CH2Cl2, then triturated from hexanes to provide 1.02 g of an off-white solid (52%). 1H NMR (CDCl3) δ: 12.91 (br s, 1H); 8.72 (dd, J=2.7, 12 Hz, 1H); 8.34 (dd, J=6.4, 9.2 Hz, 1H); 8.29 (dd, J=5.9, 8.8 Hz, 1H); 7.81 (dd, J=6.2, 8.8 Hz, 1H); 7.28 (dt, J=2.4, 8.4 Hz, 1H); 7.21 (dd, J=2.4, 9.0 Hz, 1H); 6.92 (ddd, J=2.4, 7.3, 9.1 Hz, 1H); 6.54 (ddd, J=2.4, 7.8, 8.8 Hz, 1H); 6.45 (dd, J=2.4, 11 Hz, 1H); 5.93 (br s, 2H). MS (ES): m/z 265.0 (M+)
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:32]=O>C(O)C.N1CCCCC1>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:32]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.1 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (40.6 mg, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:13]1([O:12][C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: OC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCCCC2)cc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 3.00 g portion of methyl 2,4-dihydroxybenzoate was dissolved in 30 ml of tetrahydrofuran, and 2 ml of cyclohexanol, 9.00 g of triphenylphosphine and 7.38 ml of diisopropyl azodicarboxylate were added, followed by stirring for 12 hours at room temperature. After completion of the reaction, the solvent was evaporated, the resulting residue was mixed with hexane-ethyl acetate, and insoluble matter was removed by filtration. Solvent of the filtrate was evaporated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=12:1-2:1) to give 1.70 g of methyl 4-cyclohexyloxy-2-hydroxybenzoate. Nuclear magnetic resonance spectrum (DMSO-d6, TMS internal standard) δ: 1.10-2.10 (10H, m), 3.86 (3H, s), 4.40-4.48 (1H, m), 6.43-6.58 (2H, m), 7.63-7.75 (1H, m), 10.71 (1H, s)
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[C@@H:19]([CH3:21])[OH:20].[CH:28]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[CH2:29]>C(OCC)(=O)C>[CH:31]1([O:30][CH:28]([O:20][C@H:19]([CH3:21])[C:18]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:29])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)COC(=O)[C@@H](C)O
Reactant: C=COC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)[C@@H](C)OC(C)OC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 29.2 g (0.2 mole) of isobutyl (R)-(+)-lactate and 28.0 g (0.22 mole) of cyclohexyl vinyl ether. The resulting mixture was stirred at room temperature for 4 hours to give rise to a reaction. Thereto was added 100 ml of ethyl acetate, followed by washing with 100 ml of a saturated aqueous sodium hydrogen carbonate solution, 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 54.2 g (yield: 99.4%) of an oily title compound (diastereomixture).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:44]=[CH:43][C:21]3[N:22]([CH3:42])[C:23]([NH:25][C:26]4[CH:27]=[C:28]([CH:38]=[CH:39][C:40]=4[Cl:41])[CH2:29][NH:30]C(=O)OC(C)(C)C)=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:30][CH2:29][C:28]1[CH:38]=[CH:39][C:40]([Cl:41])=[C:26]([NH:25][C:23]2[N:22]([CH3:42])[C:21]3[CH:43]=[CH:44][C:18]([C:16]([NH:15][C:12]4[CH:11]=[CH:10][C:9]([Br:8])=[CH:14][CH:13]=4)=[O:17])=[CH:19][C:20]=3[N:24]=2)[CH:27]=1
Reactant: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
TFA (1.5 mL) was added to tert-butyl 3-[5-(4-bromophenylcarbamoyl)-1-methyl-2-benzimidazolylamino]-4-chlorobenzylcarbamate (960 mg. 1.7 mmol prepared in analogy to the experimental procedures described above) in DCM (20 mL) at rt. After 16 h at rt TFA (2 mL) was added and the mixture was stirred at rt for 16 h, diluted with DCM and washed with NaHCO3 (aq, sat) and brine, dried and concentrated to give the sub-title compound which was used in the next step without further purification. Yield: 706 mg (90%)
Reaction SMILES: C1(C)C=CC(S(O[CH:11](C)[C:12](OC)(OC)[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]=2)(=O)=O)=CC=1.CO.[C:33](=[O:36])(O)[O-:34].[Na+]>O>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:12]([CH3:11])[C:33]([OH:34])=[O:36])[CH:22]=[CH:21]2
Reactant: O=C([O-])O
Reactant: COc1ccc2cc(C(OC)(OC)C(C)OS(=O)(=O)c3ccc(C)cc3)ccc2c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
A mixture of the oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl p-toluenesulfonate, from Example 30, 50 ml of water, 100 ml of methanol and 19.5 g of sodium bicarbonate is refluxed (70° C.) for 14 hours. After that time, the mixture is cooled, poured into 6 volumes of water and extracted twice with 100 ml of toluene. The aqueous layer is acidified with concentrated hydrochloric acid to a pH of about 3 to yield 4.8 g of 2-(6-methoxy-2-naphthyl)propionic acid (melting point: 151.5°-153° C.).
Reaction SMILES: N#N.[C:3]1([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:17]([NH:19][O:20]CC(NC(OCC2C=CC=CC=2)=O)C(OC)=O)=[O:18])[CH2:15]O)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CCCCCCC=CCCC>O1CCCC1>[OH:20][N:19]1[CH2:15][C@H:14]([NH:13][C:11]([O:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:12])[C:17]1=[O:18]
Reactant: COC(=O)C(CONC(=O)[C@H](CO)NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: CCCC=CCCCCCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N#N
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN(O)C1=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a cold (0°-5° C.) solution of N2 -[[(phenylmethyl)oxy]carbonyl]-N-[2-[[[(phenylmethyl)oxy]carbonyl]amino]-3-methoxy-3-oxopropoxy]-L-serinamide (6.08 g) in distilled tetrahydrofuran (100 ml) is added triphenylphosphine (3.6 g) followed by diethylazodicarboxylate (2.15 ml, 2.38 g). The reaction mixture is allowed to stir for twelve hours under nitrogen, whereupon 7.0 ml of 1,8-diazabicyclo[5.4.0.]undecan-7-ene is added. After 30 minutes, tetrahydrofuran is removed by evaporation and the resulting residue is partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer is washed once with ethyl acetate, then adjusted to pH 2 with saturated potassium bisulfate, and extracted with ethyl acetate (five times). The combined extracts are dried and concentrated to a crystalline solid (1.8 g). A portion is recrystallized from acetone/hexane (two times) to give an analytical sample, melting point 128°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Fc1ccc2[nH]cc(C3CCNCC3)c2c1

Procedure:
This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 0.7 g (5.5 mmol) of 5-fluoroindol and 2.1 g (13.6 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 0.8 g (67% of yield) of the desired product were obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.CO>CC(C)=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:16][C:17]#[N:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCl
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CO
Product: N#CCOc1cccc(CN2CCCCC2)c1
Yield: 66.4 %

Procedure:
A mixture of 3-(piperidinomethyl)phenol (7 g), chloroacetonitrile (2.77 g) and potassium carbonate (5.06 g) in dry acetone (100 ml) was stirred under reflux overnight. The reaction mixture was filtered and the filtrate was evaporated to give a residue which was subjected to column chromatography on silica using chloroform:methanol (20:1) as eluant to afford 3-(piperidinomethyl)phenoxyacetonitrile (5.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.B(F)(F)F.O.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCl
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccccc1Cc1ccccc1
Reaction time: 6 h
Yield: 90 %

Procedure:
A solution of 140 parts of o-xylyl chloride and 500 parts of benzene is added to a mixture of 162 parts of boron fluoride dihydrate and 16 parts of sulfuric acid monohydrate at from 75° to 78° C, whilst stirring vigorously. After a further 6 hours, the organic phase is separated off and 162 parts (90% of theory) of o-benzyltoluene boiling at 98° C at 0.2 mm Hg are isolated by distillation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:31])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH:19]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:17][CH2:16]1)[C:7]2=[O:30].[N].[H][H]>C(O)C.[Pd]>[Cl:31][C:4]1[CH:5]=[C:6]2[C:11](=[CH:2][CH:3]=1)[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:19][CH2:20]1)[C:7]2=[O:30]
Reactant: O=c1c2cc(Cl)cc(Br)c2ncn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: [N]
Solvent: CCO
Product: O=c1c2cc(Cl)ccc2ncn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Yield: 37 %

Procedure:
Catalytic 10% Pd/C was added to a dried hydrogenation bottle under N2 and slowly under nitrogen 8-bromo-6-chloro-3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone (1.52 g, 3.05 mmol) in 150 mL of ethanol was added. This sample was hydrogenated at 30-40 psi hydrogen pressure overnight. The mixture was filtered over celite and concentrated then chromatographed; 6-chloro-3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone was isolated as a yellow powder (0.47 g). Yield 37%; mp 170° C.; MS: 418.8 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 2.14 (m, 2H), 2.51 (m, 4H), 2.67 (m, 2H), 3.31 (m, 2H), 4.10 (t, J=4.8 Hz), 6.15 (t, 1H), 7.06 (m, 2H), 7.36 (d, 1H), 7.75 (m, 1H), 7.80 (m, 2H), 8.12 (d, 1H), 8.32 (s, 1H), 8.45 (s, 1H), 11.2 (s, 1H).