Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:5][NH:4][CH2:3]1.N1C=CC=CC=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1.O>C(Cl)Cl>[CH:36]1([C:39]([N:4]2[CH2:3][C:2]([F:1])([C:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH2:16][C:15]([C:21]5[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=5)([C:17]([F:19])([F:20])[F:18])[O:14][N:13]=4)=[CH:8][CH:7]=3)[CH2:5]2)=[O:40])[CH2:38][CH2:37]1
Reactant: O=C(Cl)C1CC1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(C1CC1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of the 3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 9, 94 mg) in 2 mL CH2Cl2 was added pyridine (0.05 mL) followed by cyclopropane carbonyl chloride (31 mg). The reaction was allowed to stir at room temperature for 1 hour. Water (10 mL) was added. The reaction was diluted with an additional 10 mL of CH2Cl2, stirred for 30 minutes at room temperature then passed through a phase separation tube. The CH2Cl2 layer was collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 20% EtOAc/hexane to 80% EtOAc/hexane. Fractions containing the desired material were combined and concentrated. Et2O (˜½ mL) was added to the resulting film. Placing the flask on high vac overnight resulted in formation of the product as a white foam (87 mg). 1H NMR (CDCl3) δ ppm 7.76 (d, 2H), 7.67 (s, 2H), 7.58 (d, 2H), 4.8-4.7 (m, 1H), 4.6-4.2 (m, 3H), 4.12 (d, 1H), 3.72 (d, 1H), 1.5-1.4 (m, 1H), 1.08 (m, 2H), 0.86 (m, 2H). LC/MS retention time=3.710 minutes, MS calculated for (C23H17Cl3F4N2O2), 534.03; found 535.0 M+H.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[N:27]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([C:13]4[C:14]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:15][O:16][C:17]=4[CH3:18])=[N:11][N:12]=3)=[C:4]([O:25][CH3:26])[CH:3]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(-n2ccnc2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 36 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using imidazole instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 82 mg, 36%) which was obtained as an off-white solid. MS: m/e=400.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(-c2cncnc2)c1

Procedure:
(R)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 75.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (24.2 mg, 0.196 mmol), Pd(PPh3)2Cl2 (9.15 mg, 0.013 mmol) and Na2CO3 (41.5 mg, 0.391 mmol) were added to a MW vial and treated with a mixture of DME (553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed, evacuated/purged with argon and was subjected to MW irradiation at 80° C. for 2 h. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 51.3 mg, 0.065 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 25% for 0.2 min then 25% to 55% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.13 min, m/z=460.1-461.1 [M+H]+, m/z=458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.64 (m, 1H) 1.81-1.90 (m, 1H) 2.19-2.28 (m, 1H) 2.97 (dd, J=10.76, 6.85 Hz, 1H) 3.15-3.39 (m, 5H) 4.61 (t, J=5.01 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.09 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.19 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: NC1C(O)=CC=CC=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:10].BrC(Br)C.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(C(=O)c2cccc(O)c2N)cc1
Agent: CC(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)c1ccc(C=O)cc1

Procedure:
A solution of 0.5 g (1.96 mmol) (2-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone, 0.85 ml (9.8 mmol) dibromoethane and 0.67 ml (3.9 mmol) N-ethyl-diisopropylamine in 3 ml dioxane is heated to 100° for 5 d. After extraction with water/dichloromethane the crude product is purified by flash chromatography using a gradient going from hexanes to hexanes/ethyl acetate 7:1 to yield (3,4-dihydro-2.H.-benzo[1,4]oxazin-5-yl)-(4-isopropyl-phenyl)-methanone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:35][C@@H:36]([CH2:49][NH2:50])[CH2:37][O:38][C:39]1[C:47]2[NH:46][C:45](=[O:48])[NH:44][C:43]=2[CH:42]=[CH:41][CH:40]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([NH:50][CH2:49][C@H:36]([OH:35])[CH2:37][O:38][C:39]5[C:47]6[NH:46][C:45](=[O:48])[NH:44][C:43]=6[CH:42]=[CH:41][CH:40]=5)[CH2:32][CH2:33]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1N=C(NC2CCN(Cc3ccccc3)CC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 21) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>165° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.9 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.75-4.05 (m, 5H), 4.87 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.61 (d, J=8.1 Hz, 1 H), 6.84 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8H), 9.46 (brs, 1 H), 10.57 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 341.6 ((M+2 H)2+, 100%); 682.1 (MH+, 5%); HRMS Calcd. for C37H44N7O4S (MH+): 682.3176. Found: 682.3211.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:25])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH:5]=1.[OH-].[Na+]>CO>[C:23]([C:19]1[CH:18]=[C:17]([NH:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:26])=[O:2])=[O:25])[CH:22]=[CH:21][CH:20]=1)#[N:24]
Reactant: COC(=O)c1cccc([C@H]2CCCN2C(=O)Nc2cccc(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1cccc(NC(=O)N2CCC[C@@H]2c2cccc(C(=O)O)c2)c1
Temperature: 5 °C
Yield: 41.6 %

Procedure:
To a stifling solution of 3-[(R)-1-(3-cyano-phenylcarbamoyl)-pyrrolidin-2-yl]-benzoic acid methyl ester (1.086 g, 2.487 mmol) in MeOH (30 mL) at room temperature add 5 M NaOH aqueous solution (10 mL, 49.74 mmol) and stir the reaction at ambient temp for 18 h. Cool the reaction to 0° C. in ice and quench with slow addition of conc. HCl (5 mL) over 15 min, maintaining internal temp at 5° C., to a final pH of 1. Extract the cold suspension with EtOAc (2×100 mL), and wash the organics with water (2×100 mL). Dry the organic layer (Na2SO4), concentrate to a residue in vacuo. Purify this by silica gel chromatography eluting with a gradient of 50% EtOAc/hexane to 100% EtOAc. Pool and concentrate fractions containing product, and triturate the residue in Et2O and hexane to afford 3-[(R)-1-(3-cyano-phenylcarbamoyl)-pyrrolidin-2-yl]-benzoic acid as a solid (347 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:17])=[CH:4][C:3]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccncc1Oc1ccccc1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cc[n+]([O-])cc1Oc1ccccc1
Temperature: 60 °C

Procedure:
A solution of 25 g of 4-methyl-3-phenoxypyridine, [J.Med.Chem., 18, 1 (1975)] in 90 ml of glacial acetic acid is treated with 30 ml of 40% peracetic acid in acetic acid and the mixture is stirred and heated at 60° C. for 12 hours. Two further 10 ml portions of 40% peracetic acid are added and the mixture heated 4 hours at 60° C. 100 ml of isopropanol is added and the mixture is heated at 90° C. for 4 hours. The mixture is stripped at reduced pressure and dissolved in 500 ml of dichloromethane. The organic layer is washed with an excess of 25% sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, concentrated, and distilled to yield 4-methyl-3-phenoxypyridine-1-oxide. B.P. 150°-152° C./0.3 mm
Reaction SMILES: [C:1]1([CH:7]([C:9]2C=CC=C[CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[C].[Pd]>[CH3:10][CH2:9][CH:7]([OH:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 86.6 %

Procedure:
A Grignard reagent was prepared from 4-(3-benzyloxypropyl)bromobenzene (3.2 g), magnesium (0.25 g), a catalytic amount of iodine and tetrahydrofuran (10.5 mL). To the obtained Grignard reagent solution was added a solution of 2-(methoxymethoxy)benzaldehyde (1.1 g) in tetrahydrofuran (24 mL), and the mixture was stirred at 65° C. for 25 minutes. After cooling to ambient temperature, a saturated aqueous ammonium chloride solution (10 mL) and water (20 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water (20 mL) and brine (20 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give a diphenylmethanol compound (2.5 g). The obtained diphenylmethanol compound (2.5 g) was dissolved in ethanol (42 mL), a catalytic amount of 10% palladium-carbon powder was added to the solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 7.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/2) to give a phenylpropanol compound (1.6 g). After the obtained phenylpropanol compound (1.6 g) was dissolved in dichloromethane (29 mL), 4-(dimethylamino)pyridine (0.069 g), triethylamine (1.0 mL) and benzoyl chloride (0.79 mL) were added to the solution, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added ethyl acetate (100 mL) and water (30 mL), and the organic layer was separated. The extract was washed with brine (30 mL) and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=20/1) to give an ester compound (2.2 g). A mixture of the obtained ester compound (2.2 g), p-toluenesulfonic acid monohydrate (0.21 g) and methanol (28 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-[4-(3-benzoyloxy-propyl)benzyl]phenol (1.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[F:15])=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Cl>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1ccc(-c2ccc(Br)cc2F)cc1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2F)cc1
Reaction time: 12 h
Yield: 81.4 %

Procedure:
A reaction vessel was charged with 12 g of 4-hydroxy-2'-fluoro-4'-bromobiphenyl obtained in Example 4(b), 14.2 g of decyl bromide, 15.7 g of potassium carbonate and 100 ml of 2-butanone (MEK), and the mixture was refluxed with stirring for 12 hours (the disappearance of the starting materials were confirmed by TLC). The reaction liquid was poured into diluted hydrochloric acid and the mixture was extracted with benzene. The extract was washed with water and dried over Glauber's salt. The solvents were distilled off and the residue was purified by way of column chromatography on silica gel (eluent:hexane) and then recrystallized from hexane to obtain 14.9 g (81.5%) of 4-decyloxy-2'-fluoro-4'-bromobiphenyl.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:13]=[C:12]([CH3:27])[N:11]=1>CS(C)=O>[CH2:2]([CH:3]([O:6][C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[N:13]=[C:12]([CH3:27])[N:11]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)Oc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-pentanol (0.3 ml) and sodium hydride (60% in oil, 32 mg, 0.81 mmol) in DMSO was stirred at room temperature for 5 minutes. 4-Chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (150 mg, 0.54 mmol) was added and the resulting mixture was heated at 150° C. for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a beige solid. The solid was purified through silica gel column chromatography using 20% chloroform in hexane as eluent to give the title compound as white crystals, mp 93.5–95.5° C. 1H NMR (CDCl3) δ 6.85 (s, 2H), 5.11 (t, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 2.03 (s, 6H), 1.68 (p, 4H), 0.92 (t, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[O:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[O:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc2c(=O)c(CBr)c(-c3ccccc3)oc12
Yield: 79.6 %

Procedure:
A mixture of 9.2 g of ethyl 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate (prepared as described by Da Re et al., J. Med. Chem., 2, 263 (1960)), 6.4 g of N-bromosuccinimide and 0.04 g of benzoylperoxide in 80 ml of anhydrous carbon tetrachloride was stirred at reflux for 1.5 hours. After cooling to room temperature the formed succinimide was collected by suction and washed with cold carbon tetrachloride. The mother liquors were evaporated to dryness in vacuo and the residue was rinsed with diethyl ether and collected by suction yielding 9.2 g of the title compound melting at 133°-134° C. after crystallization from acetone-n-hexane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][C:21]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([OH:24])[CH2:20][CH2:19]2)=O)=[O:13])=[CH:10][CH:9]=1.O>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]([OH:13])[CH2:14][CH2:15][CH2:16][N:18]2[CH2:19][CH2:20][C:21]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([OH:24])[CH2:22][CH2:23]2)=[CH:32][CH:33]=1
Reactant: O=C(CCC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.0 g of lithium aluminum hydride and 50 ml of tetrahydrofuran, was gradually added a solution of 5.0 g of 1-[β-(p-fluorobenzoyl)propionyl]-4-(p-chlorophenyl)-4-hydroxypiperidine in 40 ml of tetrahydrofuran. The mixture was stirred at room temperature for one hour, and at 60°to 65°C for 4 hours. Then 15 ml of cold water was added dropwise to the reaction mixture while the mixture was kept below 20°C in an ice bath. The precipitate was filtered off and the tetrahydrofuran was removed from the filtrate by distillation under reduced pressure. The residue was kept cooled for 2 hours and the solid matter was collected by filtration, washed with water, and dried to obtain 1-(p-fluorophenyl)-4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-1 -butanol, melting at 128° - 130°C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10](Cl)[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCCCCC.CCOC(C)=O>[CH:1]1([NH:7][C:10]2[CH:9]=[CH:8][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(NC2CCCCC2)nc1
Temperature: 120 °C
Yield: 96.6 %

Procedure:
Add cyclohexylamine (7.1 g, 72 mmol) to a mixture of 6-chloronicotinitrile (1 g, 7.2 mmol), potassium carbonate (3 g, 21.7 mmol) and anhydrous DMF (10 mL). Heat the mixture in a sealed flask at 120° C. for 1.5 h. Cool the reaction to ambient temperature, dilute with hexane/EtOAc (1:1, 100 mL) and wash the mixture with aqueous 5% sodium chloride (3×30 mL). Collect the organic layer and concentrate in vacuo to obtain the desired intermediate (1.4 g, 97%). GC-MS m/z: 201 (M+).
Reaction SMILES: [N+:1](=[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6][N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:4]1=[O:22])=[N-:2].C(P(CCCC)CCCC)CCC.Cl[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH:48]=[CH:47][N:46]=[CH:45]2)=[CH:40][CH:39]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:14][C:9]1[C:8]2[C:7]3[C:3]([C:4](=[O:22])[N:5]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])[N:6]=3)=[N:1][N:2]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([N:44]4[CH:48]=[CH:47][N:46]=[CH:45]4)=[CH:42][CH:43]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccc(-n2ccnc2)cc1
Reactant: [N-]=[N+]=C1C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: O=c1c2nn(Cc3ccc(-n4ccnc4)cc3)c3cccc(F)c3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Diazo-2,5-bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (0.17 g, 0.56 mmol) was dissolved in acetonitrile (5 mL) and treated with tri-n-butylphosphine (0.11 g, 0.56 mmol, 1.0 equiv). After stirring for 30 minutes at ambient temperature, 1-[4-(chloromethyl)phenyl]-1H-imidazole (0.11 g, 0.56 mmol, 1.0 equiv), potassium iodide (47 mg, 0.28 mmol, 0.5 equiv) and potassium carbonate (97 mg, 0.70 mmol, 1.25 equiv) were added at ambient temperature. After 45 minutes, the reaction mixture was warmed to 85° C., stirred for 2.5 hours and then cooled to ambient temperature. The mixture was poured into water (100 mL), extracted with ethyl acetate (2×75 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified twice by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol; and then 100:0 to 90:10; dichloromethane:methanol containing 10% ammonium hydroxide), providing the titled compound as a deep red solid: 1H-NMR (400 MHz, CDCl3) δ 8.33 (1H, dd, J=7.6, 1.8 Hz), 7.85 (1H, br s), 7.67-7.53 (4H, m), 7.46 (2H, d, J=8.5 Hz), 7.40 (2H, d, J=8.5 Hz), 7.42-7.37 (1H, m), 7.31-7.20 (4H, m), 5.88 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 437.1526 [(M+H)+; calculated for C25H18FN6O: 437.1521].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][N:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[O:2][CH3:1])[CH3:32]
Reactant: CCOC(=O)CCCCBr
Reactant: COC(=O)c1ccc(CNCCc2ccccc2OC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CCCCN(CCc1ccccc1OC)Cc1ccc(C(=O)OC)cc1

Procedure:
15.0 g (50.0 mmol) of methyl 4-{[(2-methoxyphenethyl)amino]methyl}benzoate from Example I.1., 11.52 g (55.0 mmol) of ethyl 5-bromovalerate and 6.37 g (106.0 mmol) of sodium carbonate are dissolved in 30 ml of acetonitrile and heated at reflux for 18 hours. After cooling, most of the solvent is distilled off under reduced pressure and the residues are mixed with water. The mixture is extracted repeatedly with ethyl acetate, the organic phases are washed with saturated sodium chloride solution and, after drying over magnesium sulphate, the solvent is removed under reduced pressure. The crude product is purified by flash chromatography over silica gel (0.04-0.063 nm) using the mobile phase cyclohexane/ethyl acetate 4/1.