Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc(F)ccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)-1,4-difluorobenzene (1.06 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.88 g, 54%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:16](Br)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1>CN(C=O)C>[NH2:10][C:11]1[C:16]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1
Reactant: Sc1ccccc1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccccc2)nc1Sc1ccccc1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a cooled solution of thiophenol (0.10 mL, 1.00 mmol) in dry DMF (10 mL), sodium hydride (NaH) (0.025 g, 1.00 mmol) was added the resulting mixture was stirred for 15 min at 5-10° C. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.25 g, 1.00 mmol) was added and the mixture refluxed for 20 h, cooled and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using petroleum ether-EtOAc (60:40 v/v) as eluent, to obtain 0.22 g of the title compound 18b as a brown solid (mp 109-112° C., 79% yield). 1H-NMR (CDCl3): 4.92 (br s, 2H), 7.29-7.50 (m, 8H), 7.74-7.77 (m, 2H), 8.35 (s, 1H). MS (ESI): m/z 280 (M+H1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(Cl)(=O)C([Cl:17])=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([Cl:17])=[O:13])=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: O=C(Cl)c1cc2cc(F)ccc2[nH]1
Reaction time: 24 h

Procedure:
5-Fluorindole-2-carboxylic acid is dissolved in oxalylchloride and stirred 24 hr at 20°-25° in the dark. The reaction mixture is concentrated under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C>ClCCl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Nc1ncc(CO)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 5643.2 %

Procedure:
A solution of methyl 6-amino-5-iodonicotinate (335 mg, 1.205 mmol) in dichloromethane (18 mL) was added DIBAL (1.5 M in toluene, 1.61 mL, 2.41 mmol) via syringe dropwise at 0° C. The reaction was monitored by LC MS, and added more DIBAL (0.8 mL, 1.2 mmol) to drive the reaction to complete. The reaction was quenched with addition of MeOH (1 mL) dropwise at 0° C., stirred at rt for 2 h and filtered through a CELITE® pad, rinsed with ethyl acetate and dichloromethane. The organic layers were combined and concentrated onto SiO2 which was purified by a flash column using 50%, 80% and100% ethyl acetate in heptane as an eluent to give the product (204 mg, 68 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[N:27]1([CH:33]2[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:20])[CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCN(C2CCCNC2)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCCC(N4CCCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1,3′-bipiperidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=12.88 Hz, 2H) 1.62-1.89 (m, 7H) 2.17 (d, J=10.86 Hz, 1H) 2.43 (s, 3H) 2.97-3.51 (m, 6H) 3.56-4.15 (m, 1H) 4.32-4.88 (m, 1H) 7.62-7.85 (m, 3H) 7.82-7.83 (m, 1H) 7.95-8.64 (m, 4H) 9.40 (br. s., 1H) 12.56-13.62 (m, 1H). ESI-MS m/z [M+H]+ 471.3.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:16]=1[C:24]1[C:36]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]([NH2:37])[C:28]=2[CH:27]=[CH:26][CH:25]=1.[CH:38]([C:40]1[CH:48]=[C:47]2[C:43]([CH:44]=[CH:45][NH:46]2)=[CH:42][CH:41]=1)=O.C(N(C(C)C)CC)(C)C.[B-].[Na+]>C(O)C>[N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:16]=1[C:24]1[C:36]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]([NH:37][CH2:38][C:40]3[CH:48]=[C:47]4[C:43]([CH:44]=[CH:45][NH:46]4)=[CH:42][CH:41]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: NC1c2ccccc2-c2c(-c3nc4ccncc4[nH]3)cccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [B-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1ccc2c(c1)-c1c(-c3nc4ccncc4[nH]3)cccc1C2NCc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Carry out the procedure as in Example 18, starting from 94 mg of dihydrochloride of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluorene-9(R,S)-amine, 55 mg of 6-formyl-indole and 90 μL of diisopropylethylamine in 0.7 ml of ethanol for 2 hours at room temperature, then add 28 mg of sodium hydroborate and stir for 1 hour at room temperature. After purification on silica gel, eluting with mixtures of dichloromethane and methanol (95-5 by volume), we obtain 58 mg of N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9(R,S)-yl]-(1H-indol-6-ylmethyl)-amine, in the form of a pale pink solid with the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C@@H:14]([OH:28])[C@@H:15]([N+:25]([O-])=O)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:13]([C@@H:14]([OH:28])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][CH3:31])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])CO1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCO[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.145 g, 0.325 mmol) in methanol (5 mL) at room temperature add nickel (II) chloride (0.063 g, 0.487 mmol) and then sodium borohydride (0.061 g, 1.62 mmol) portionwise. Stir 30 minutes, add water (˜3 mL) and concentrate. Dilute with ethyl acetate and filter through Celite®. Partition the filtrate between ethyl acetate and water. Dry the ethyl acetate layer (magnesium sulfate), filter and concentrate to give the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12]([OH:15])(=[O:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:16]F>C(#N)C>[F:16][N+:4]1[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[S:12]([O-:15])(=[O:14])=[O:13]
Reactant: FF
Reactant: O=S(=O)(O)c1ncc(C(F)(F)F)cc1Cl
Solvent: CC#N
Product: O=S(=O)([O-])c1c(Cl)cc(C(F)(F)F)c[n+]1F

Procedure:
To a mixture of 3-chloro-5-(trifluoromethyl)pyridine-2-sulfonic acid (262 mg, 1 mmol) and acetonitrile (60 ml) in a flask on a cooling bath kept at -10° C., a mixed gas of 10% fluorine/90% nitrogen was introduced at a flow rate of 15 ml/min. The total amount of the fluorine gas was 3.6 mmol. Thereafter, the nitrogen gas alone was introduced for 30 minutes. After the reaction mixture was concentrated, ethyl acetate was added to the residue. The precipitated crystal was recovered by filtration to obtain N-fluoro-3-chloro-5-(trifluoromethyl)pyridinium-2-sulfonate (231 mg, 0.83 mmol). Yield, 83%. Melting point, 220°-250° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O>[CH2:18]([S:25][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1cncc(SCc2ccccc2)c1
Yield: 25.7 %

Procedure:
In a similar fashion using route 38 general procedure 92, 3-bromo-5-(trifluoromethyl)pyridine (400 mg, 1.76 mmol), K2CO3 (366 mg, 2.65 mmol), benzylmercaptan (330 mg, 2.65 mmol) and DMSO (3.2 ml) at 150° C. for 4 h in sealed tube gave the title compound (122 mg, 25%) after purification by column chromatography with n-hexane/EtOAc (99:1) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22](OCC)=[O:23])=[C:12]2[CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=[O:23])=[C:12]2[CH3:27])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(C=O)cc(-c2ccccc2)n1S(=O)(=O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
Ethyl 1-[(4-fluorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (380 mg) was dissolved in tetrahydrofuran (15 mL), and the mixture was cooled to −78° C. A 1.5 mol/l solution (1.96 mL) of diisobutylaluminum hydride in toluene was added dropwise, and the mixture was further stirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 min and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1). The obtained brown oil was dissolved in acetonitrile (5 mL), and the mixture was cooled to 0° C. Tetra-n-propylammonium perruthenate (34 mg), N-methylmorpholine N-oxide (172 mg) and molecular sieves 4A powder (500 mg) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield 210 mg, 62%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)[CH:16]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C>>[CH3:29][C:27]1[CH:28]=[C:23]([CH2:22][O:21][C@@H:17]2[CH2:18][CH2:19][CH2:20][NH:15][C@H:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=[C:25]([CH3:30])[CH:26]=1
Reactant: Cc1cc(C)cc(COC2CCCN(C(=O)OC(C)(C)C)C2c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(CO[C@@H]2CCCN[C@H]2c2ccccc2)c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3 ml) was added to 1-t-butyloxycarbonyl-3-((3,5-dimethylphenyl)methyloxy)-2-phenylpiperidine (800 mg Example 2d) under nitrogen and the solution was stirred at 23° C. for 1 h. Excess trifluoroacetic acid was removed in vacuo, and the residue was partitioned between 2M sodium hydroxide and dichloromethane. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (K2CO3) and concentrated to leave a clear, colourless oil. Purification on silica gel (CH2Cl2 /MeOH/NH3 97:3:0.5 then CH2Cl2 /MeOH 95:5→90:10→80:20) provided, in order of elution, trans-3-((3,5-dimethylphenyl)methyloxy)-2-phenylpiperidine as a colourless oil. 1H NMR (CDCl3) δ7.5-7.24 (m), 6.80 (s), 6.50 (s), 4.20 (d, J=11 Hz), 3.98 (d, J=11 Hz), 3.48 (d, J=8.4 Hz), 3.32 (ddd, J=4.2, 9.8, 9.8 Hz), 3.08 (m), 2.70 (ddd, J=2.8, 12.6, 12.6 Hz), 2.10 (m), 2.19 (s), 1.84-1.4 (m), and cis-3-((3,5-dimethylphenyl)methyloxy)-2-phenylpipieridine as a colourless oil. 1H NMR (CDCl3) δ7.4-7.2 (m), 6.55 (s), 6.31 (s), 4.33 (d, J=12.2 Hz), 4.10 (d, J=12.2 Hz), 3.78 (s), 3.63 (s), 3.26 (app. dt, J=2.16, 2.16, 12.5 Hz), 2.82 (ddd, J=3.0, 3.0, 12.6 Hz), 2.20 (s), 1.86 (m), 1.62 (m), 1.48 (m). m/z (CI+) 296(MH).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C@@H:6]3[C@H:19]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:17][CH2:16][N:7]3[C:8]3[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=3[O:10][C:4]=2[CH:3]=1.[Cl-].[CH3:30][Zn+].[NH4+].[Cl-]>C1COCC1.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][C:4]3[CH:3]=[C:2]([CH3:30])[CH:28]=[CH:27][C:5]=3[C@@H:6]3[C@H:19]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[CH2:18][CH2:17][CH2:16][N:7]3[C:8]=2[CH:14]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3cc(Br)ccc3[C@H]12)C(F)(F)F
Reactant: C[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)Oc1ccc(Cl)cc1N1CCC[C@@H](NC(=O)C(F)(F)F)[C@@H]21
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of trans-N-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido-[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (80 mg, 0.17 mmol) in THF (2 mL) was added ferrocene PdCl2 (5 mg, 7 μmol), and the reaction mixture was stirred for 5 min. Methylzinc chloride was added dropwise whereafter the reaction mixture was heated to 60° C. and stirred overnight at 60° C. The mixture was poured into sat (aq) NH4Cl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. After purification on silica and with HPLC the title compound was obtained (13.2 mg, 19%). Data: 1H-NMR (400 MHz, DMSO) 1.60-1.85 (m, 3H), 2.0 (m, 1H), 2.23 (s, 3H), 3.11 (td, J=2.8, 13.2, 1H), 3.85 (d, J=14, 1H), 4.10 (d, J=10, 1H), 4.40 (m, 1H), 6.69-7.10 (6 ArH), 9.16 (d, J=10, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([I:17])[C:11]=2[O:10][N:9]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:26][C:27]([OH:29])=[O:28])=[C:16]([I:17])[C:11]=2[O:10][N:9]=1
Reactant: Oc1ccc2c(-c3ccccc3F)noc2c1I
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc2c(-c3ccccc3F)noc2c1I
Temperature: 90 °C

Procedure:
3-(2-fluorophenyl)-6-hydroxy-7-iodo-1,2-benzisoxazole (7.80 g) in 80 ml of DMF is treated at 60° C. with 6.6 g of K2CO3 and 7.9 g of ethyl bromoacetate. After one hour the temperature is increased to 90° C. and 80 ml of H2O and 8 ml of 50% NaOH are added. After an additional 30 minutes the mixture is poured into H2O and acidified and then extracted into ether, dried and evaporated to yield {[3-(2-fluorophenyl)-7-iodo-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 178°-180° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH:2]=1.O.NN.[OH-].[K+]>C(O)CO.O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:13]1
Reactant: O=C(CCCN1CCN(c2ccccn2)CC1)c1cccnc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: c1ccc(N2CCN(CCCCc3cccnc3)CC2)nc1
Yield: 40.2 %

Procedure:
A solution of 1-(3-pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone (Example 2) (5.2 g, 0.0168 mol), hydrazine hydrate (1.9 g, 0.0603 mol), and potassium hydroxide (3 g, 0.0538 mol) in ethylene glycol (100 mL) is refluxed 12 hours removing the water formed with a Dean-Stark trap. The cooled reaction mixture is diluted with water (100 mL) and extracted with dichloromethane. The organic layer is dried (sodium sulfate) and the solvent evaporate in vacuo. The resulting residue is crystallized from 2-propanol and diethyl ether to give 2 g of 1-(2-pyridinyl)-4-[4-(3-pyridinyl)butyl]piperazine as a white solid; mp 54-64° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[NH:25][C:24](=[O:26])[O:23][N:22]=4)=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][CH2:2]1.C(O)([C:29]([F:32])([F:31])[F:30])=O.N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1.[C:59]1([CH2:65][CH:66]=O)[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.N1C=CN=C1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>>[CH2:66]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[NH:25][C:24](=[O:26])[O:23][N:22]=4)=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][CH2:6]1)[CH2:65][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[C:24]([OH:23])([C:29]([F:32])([F:31])[F:30])=[O:26]
Reactant: O=CCc1ccccc1
Reactant: O=c1[nH]c(-c2ccc3c(c2)Oc2ccccc2N3C2CCNCC2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: O=Cc1ncc[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2ccc3c(c2)Oc2ccccc2N3C2CCN(CCc3ccccc3)CC2)no1

Procedure:
Using an adaptation of the method described in Procedure 7, substituting the TFA salt of 3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one, 2b for the TFA salt of 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, phenyl acetaldehyde for 1H-imidazole-2-carboxaldehyde and sodium triacetoxyborohydride for tetramethylammonium triacetoxyborohydride, the title compound 3-[10-(1-phenethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]oxadiazol-5-one, 4b was obtained as a TFA salt after purification via reverse phase HPLC (eluent: CH3CN in H2O containing 0.1% TFA). MS m/z (MH+) 454.8.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[NH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:20][C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccsc1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: Cl
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccsc1
Yield: 82.2 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 400 mg of 3-aminothiophene hydrochloride in place of the 2,4-difluoroaniline. 252 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(thiophen-3-yl)acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[BH4-].[Na+].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:10]
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(Br)cc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Amino-5-bromo-phenyl)-phenyl-methanone (4.00 g, 14.49 mmol) is dissolved in methanol (50 mL). Sodium borohydride (0.55 g, 14.49 mmol) is added in small portions over 45 minutes. The reaction mixture is stirred at room temperature overnight. Water (10 mL) is added and the mixture stirred at room temperature for 15 minutes. The solvent is removed and the residue purified by column chromatography on silica gel using a petrol ether/ethylacetate gradient. This affords the desired compound as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](O)=[O:21])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1>C1COCC1>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 1-Boc-4-(2-carboxy-phenyl)-piperazine from Step 1 in 340 mL of THF at 0° C. was added BH3-THF (120 mL of a 1 M solution in THF). The cold bath was removed, and the solution stirred overnight. The solution was cooled to about 0° C. and then 60 mL of 2 M NaOH was added followed by EtOAc and brine. After separation, the aqueous solution was extracted with EtOAc (3×). The combined organic solutions were washed with water (2×) and brine, and then dried (Na2SO4), filtered and concentrated to give about 11.2 g (38.3 mmol, 96%) of the title compound. LRMS (ESI+): 393.2 [M+1]
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](Cc2ccccc2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 3.90 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 64-2 (16.8 mmol, crude form) as starting material, respectively 1.91 g (Isomer A, colorless powder) and 2.99 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.