Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[OH:38][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[N:10][C:9]3=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccccc1
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp >205° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.70 (m, 9H), 3.70-4.00 (m, 7H), 4.95 (brs, 1 H), 6.64-6.94 (m, 3 H), 7.01(d, J=8.9 Hz, 2 H), 7.27-7.30(m, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 262.0 ((M+2H)2+, 100%); 523.0 (MH+, 10%); HRMS Calcd. for C27H35N6O3S (MH+): 523.2491. Found: 523.2511.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=O)[C:7]2=[O:15].Cl.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:28])[NH:26][NH2:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[N:27][NH:26][C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[OH:17])=[O:28])[C:7]2=[O:15]
Reactant: COc1ccc2c(=O)c(=O)c(=O)c2c1
Reactant: NNC(=O)Nc1ccccc1O
Agent: Cl
Solvent: O
Product: COc1ccc2c(=O)c(=NNC(=O)Nc3ccccc3O)c(=O)c2c1

Procedure:
5-methoxyindan-1,2,3-trione, monohydrate, 4-(2-hydroxyphenyl)-semicarbazide hydrochloride; reflux for 5 hours
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)[C:5]([F:22])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[NH2:28].O.[OH-].[Na+]>CN1CCCC1=O>[F:22][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)=[N:7][C:2]([NH:28][C:27]2[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:25]([O:24][CH3:23])[CH:26]=2)=[N:3][CH:4]=1
Reactant: CC1(C)Oc2ccc(Nc3nc(Cl)ncc3F)nc2NC1=O
Reactant: COc1cc(N)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)NC(=O)C(C)(C)O4)n2)cc(OC)c1OC
Temperature: 120 °C
Yield: 160270.8 %

Procedure:
6-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step A) (568 kg, 1.00 mol eq) is mixed with 3,4,5-trimethoxyaniline (402 kg, 1.25 mol eq) in N-methylpyrrolidin-2-one (2835 kg) with stirring under a nitrogen atmosphere. To this is added water (11 kg) and the mixture heated to about 120° C. and stirred for about 10 hours. This is then cooled to about 65° C. and the pH adjusted to pH 8.5 with 4% w/w aqueous sodium hydroxide solution. The resulting slurry is further cooled to about 20° C., stirred for at least 6 hours and then filtered. The filtered solid is washed twice with water (2×1440 kg) then twice with acetone (2×1140 kg) and finally dried under vacuum at about 40° C. to give the title compound (754 kg, 91%) as a colored solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>ClCCCl>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: COCCOCCl
Reactant: Cc1cc(C=O)cc(C)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCCOCOc1c(C)cc(C=O)cc1C

Procedure:
A mixture of 4-hydroxy-3, 5-dimethylbenzaldehyde (5 g), N, N-diisopropylethylamine (6.9 ml), (2-methoxyethoxy)methylchloride (4.26 ml) and 1, 2-dichloroethane (65 ml) was refluxed for 5 hours. The reaction mixture was washed with water and dried over magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (8:2 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 4-[(2-methoxyethoxy)methoxy]-3, 5-dimethylbenzaldehyde (6.54 g).
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=[C:2]1[C:9]([O:11]C)=[O:10].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CO.C[O-].[Na+]>CO>[C:13]1([C:7]2[C:8]3[S:1][C:2]([C:9]([OH:11])=[O:10])=[CH:3][C:4]=3[NH:5][CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1cc2[nH]ccc2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of methyl 4H-thieno[3,2-b]pyrrole-2-carboxylate (12 g, 68 mmol) and cyclohexanone (21 ml, 204 mmol) in methanol (300 ml) was added 28% sodium methoxide methanol solution (100 ml) and the mixture was stirred with heating under reflux for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 6N Hydrochloric acid (100 ml) was added and the precipitated solid was collected by filtration. The solid was washed successively with water (300 ml×5) and n-hexane (300 ml×3), and dried under reduced pressure to give 6-(cyclohex-1-enyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (17 g, yield 100%).
Reaction SMILES: [N:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:9][OH:10].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15].O>CN(C=O)C>[CH2:15]([O:8][CH2:7][C:6]1[N:1]=[C:2]([CH2:9][OH:10])[CH:3]=[CH:4][CH:5]=1)[CH:14]=[CH2:13]
Reactant: OCc1cccc(CO)n1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCc1cccc(CO)n1
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A solution of 2,6-pyridinedimethanol (5.0 g, 35.9 mmol) in DMF (30 mL) at 0° C. was treated with sodium hydride (1.44 g, 35.9 mmol), stirred for 30 min, treated with allyl bromide (3.42 ml, 39.5 mmol), stirred for 16 h at room temperature, poured into water (150 mL), extracted with EtOAc (3×30 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1 to 1:1)] to give the title compound (1.56 g, 24%) as a colourless oil: NMR δH (400 MHz, CDCl3) 7.69 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz), 6.04-5.93 (1H, m), 5.38-5.21 (2H, m), 4.74 (2H, d, J 5.0 Hz), 4.65 (2H, s), 4.15-4.09 (2H, m) and 3.76 (1H, t, J 5.0 Hz).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]3[N:30]=[C:31]([CH2:33][OH:34])[CH:32]=[C:26]3[C:25]2=[O:35])=[CH:20][CH:19]=1.[CH:36]1[C:41](O)=[CH:40][CH:39]=[C:38]([CH3:43])[CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]3[N:30]=[C:31]([CH2:33][O:34][C:41]4[CH:40]=[CH:39][C:38]([CH3:43])=[CH:37][CH:36]=4)[CH:32]=[C:26]3[C:25]2=[O:35])=[CH:20][CH:19]=1
Reactant: O=C1c2cc(CO)nn2CCN1c1ccc(F)cc1
Reactant: Cc1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(OCc2cc3n(n2)CCN(c2ccc(F)cc2)C3=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
Di-tert-butyl azodicarboxylate (0.027 g, 1.2 mmol) was added portionwise to a stirred solution of 5-(4-fluoro-phenyl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (104 mg, 0.4 mmol), p-cresol (0.13 mL, 1.2 mmol) and triphenylphosphine (0.31 g, 1.2 mmol) in THF (2 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. More di-tert-butyl azodicarboxylate (0.027 g, 1.2 mmol), p-cresol (0.13 mL, 1.2 mmol) and triphenylphosphine (0.31 g, 1.2 mmol) were added at 0° C. and the mixture was stirred at 130° C. for 20 minutes. The mixture was diluted with AcOEt and washed with a 10% solution of NaOH. The organic layer was separated, dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude product was purified by open column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was dissolved in a mixture of TFA (2.5 mL) and DCM (2.5 mL) and stirred at room temperature for 2 days. The mixture was basified with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with DIPE to yield 5-(4-fluorophenyl)-2-(p-tolyloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (54 mg, 38% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 2.29 (s, 3H), 4.16 (dd, J=6.8, 5.3 Hz, 2H), 4.53 (dd, J=6.9, 5.2 Hz, 2H), 5.09 (s, 2H), 6.90 (d, J=8.7 Hz, 2H), 7.01 (s, 1H), 7.09 (d, J=8.4 Hz, 2H), 7.13 (t, J=8.7 Hz, 2H), 7.28-7.35 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Br:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([CH3:16])[N:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example A.41) (0.4 g, 0.5 mmol) and commercially available 3-bromo-benzene-boronic acid (0.38 g, 1.89 mmol) according to the general procedure IVb. Obtained as an orange solid (0.23 g, 40%). MS (ISP) 394.9 [(M+H)+]; mp 132.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:29].C(N(CC)C(C)C)(C)C.[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>C(Cl)Cl>[CH2:25]([O:24][C:22]([C:19]1[N:11]2[C:10]([CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:42](=[O:43])[C:41]4[CH:45]=[CH:46][C:47]([Cl:49])=[CH:48][C:40]=4[Cl:39])=[C:3]([CH3:29])[CH:4]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12]2)=[CH:21][CH:20]=1)=[O:23])[CH3:26]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(N)c(C)c1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)c(C)c1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 0.30 g of ethyl 10,11-di-hydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate in 20 ml of methylene chloride is added 0.15 g of N,N-diisopropylethylamine and 0.24 g of 2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated NaHCO3 and dried with Na2SO4. The organic layer is passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.24 g of solid, m.p. 174°-184° C.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]3[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:21][C:13]2=3)=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:4][CH2:3][CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]3[C:19]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:21][C:13]2=3)=[CH:10][CH:11]=1
Reactant: OCCBr
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(O)cc2)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCO)cc2)c1-c1ccccc1
Yield: 17.6 %

Procedure:
2-Bromoethanol (0.148 mL, 2.08 mmol) was added to the compound of Example 89 (370 mg, 0.95 mmol) and Cs2CO3 (342 mg, 1.04 mmol) in DMF (5 mL) and the mixture heated at 80° for 2 days. The solvent was removed in vacuo and the residue partitioned between EtOAc and HCl (10%). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica (2% to 10% MeOH in DCM) to give the title compound (73 mg, 18%). δH (CDCl3) 7.44–7.28 (8H, m), 7.07 (2H, d, J 8 Hz), 6.52 (1H, d, J 9.6 Hz), 4.12–3.93 (6H, m), 1.06 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.42 minutes, 436 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]1=[O:31]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:31])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: O=c1ccc2ccccc2n1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCCCn2c(=O)ccc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.73 g) in dimethylformamide (10 mL) was treated with 55% sodium hydride (0.164 g), stirred for 15 minutes and then 1-(3-bromopropyl)-1,2-dihydro-2-oxoquinoline (1 g) was added and rinsed in with dimethylformamide (4 mL). The mixture was stirred at room temperature for 22 hours and worked up as in Example 20. The residual solid was purified by flash chromatography over silica gel (ethyl acetate-hexane; 1:4). Crystallization of the resulting solid furnished 1.0.g of 4-[3-(1,2-dihydro-2-oxo-1-quinolinyl)propoxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 108°-109° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CCOCC.C1COCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:13][CH:12]=1
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
In a 100 ml round bottom flask with a Y-adapter, condensor, and a 10 ml addition funnel was added 0.38 g (15.63 mmol) of Mg turnings which had been ground with a mortar and pestle. The apparatus was then flushed with argon and flamed dried. After allowing the apparatus to cool under argon, 4 ml of anhydrous diethyl ether was added to the Mg. While vigorously stirring the Mg in the ether, 2.52 g (13.05 mmol) of 1-bromooctane in 3 ml of diethyl ether was added dropwise. After 5 drops, the Grignard reaction started and the addition was continued at a rate sufficient to maintain a steady reflux. After addition was complete, 4 ml of dry THF was added to the Grignard reagent and it was stirred at R.T. for an additional 1/2 hour. A warm water bath was then placed under the flask, and refluxing was continued for 15 minutes. Afterwards, the reaction was cooled to 0° C. with an ice bath and 2.00 g (16.81 mmol) of p-bromobenzaldehyde in 4 ml of THF was added. The reaction was stirred at R.T. for 1.5 hr., whereupon the Grignard was quenched with saturated NH4Cl. The organic layer was washed with H2O and brine, then dried (MgSO4). Rotary evaporation of the solvent under reduced pressure produced 2.96 g of a crude yellow oil. The oil was dissolved in a diethyl ether and loaded onto a silica gel column. Elution with diethyl ether/hexane yielded 2.22 g of the titled product as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:29]1([CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:27][N:15]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:41])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cc(OC)cc(OC)c2)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CN(CCCOc2cccc(CC(=O)O)c2)CC(c2ccccc2)c2ccccc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(3,5-dimethoxy-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4j). (0.26 g, 0.00047 mol) in methanol (3 mL) was treated with 2N NaOH (2 mL) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (15 mL) and water was added (5 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 0.23 g in 92% yield. Solidification of the waxy oil from pet. ether gave white solid (5j), mp: 44.4° C. 1H NMR (CD3OD) δ 7.19 (d, 9H), 7.11 (m, 2H), 6.82 (d, 1H), 6.60 (s, 1H), 6.56 (d, 1H), 6.30 (s, 2H), 6.27 (s, 1H), 4.21 (t, 1H), 3.62 (t, 2H), 3.60 (s, 2H), 3.57 (s, 6H), 3.52 (s, 2H), 3.16 (d, 2H), 2.68 (t, 2H), 1.81 (t, 2H); 13C NMR (CD3OD) δ 176.0, 162.1, 160.4, 144.8, 143.7, 137.6, 130.2, 129.4, 129.3, 127.4, 122.5, 116.5, 114.1, 107.9, 100.6, 66.7, 60.8, 60.6, 55.7, 52.0, 50.9, 42.5, 27.7. Anal. Calcd for C34H37NO5: C, 75.67; H, 6.91; N, 2.60. Found: C, 75.62; H, 6.94; N, 2.42.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)[C:10]=2[O:9]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3ccc(F)cc3)c2O1

Procedure:
The title compound was prepared (0.049 g, 21%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-fluorophenylboronic acid (0.173 g, 1.24 mmol). mp 209-211° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[NH:11]1[CH:15]=[N:14][C:13]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:12]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 39.2 g of alpha-bromo-p-tolunitrile in 1 L of acetone are added sequentially 20.72 g of 1,2,4-triazole, 27.8 g of potassium carbonate and 1.7 g of potassium iodide. The reaction is stirred for 8 hours at 55° under argon, cooled to room temperature, filtered and evaporated. The residue is partitioned between methylene chloride and water. The organic phase is separated, washed with brine, dried over sodium sulfate and evaporated. The resulting crystalline crude product is chromatographed on 300 g of silica with toluene and ethyl acetate (1:1 to 0:1) to yield 4-[1-(1,2,4-triazolyl) methyl] benzonitrile (see example 9).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].COCCOC.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1sccc1-c1ccc(Cl)cc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromothiophene-2-carbaldehyde (10 g, 52.34 mmol, 1.00 equiv), ethylene glycol dimethyl ether (120 mL), (4-chlorophenyl)boronic acid (9 g, 57.55 mmol, 1.10 equiv), Pd(PPh3)4 (3 g, 2.60 mmol, 0.05 equiv), sodium carbonate (16.4 g, 154.73 mmol, 2.96 equiv), water (40 mL). The resulting solution was heated to reflux for 4 h. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (30/1). This resulted in 12 g (93%) of 3-(4-chlorophenyl)thiophene-2-carbaldehyde as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:42]([OH:44])=O)[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:48])=O>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1([C:42]([Cl:48])=[O:44])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester (0.8 g, 0.0014 mol) in dichloromethane (20 mL), oxalyl chloride (0.343 g, 0.0027 mol) is added slowly at 0-50 C. A few drops of N,N-dimethyl formamide is added into it. The reaction mixture is stirred at room temperature for 1.5 hrs. It is then concentrated under reduced pressure to get 4-chlorocarbonyl-1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4-carboxylic acid benzyl ester.