Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[OH-].[K+].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[O:23][C:14]=12>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[O:23][C:14]=23)=[C:4]([F:9])[CH:3]=1
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Reactant: Oc1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1cnc2c(oc3ccccc32)c1Oc1ccc(Cl)cc1F
Yield: 45.9 %

Procedure:
A mixture of 0.530 mL (4.1 mmol) of 4-chloro-2-fluorophenol and 70 mg (1.25 mmol) of potassium hydroxide is heated until a homogeneous solution is formed. To this is added 170 mg (0.74 mmol) of 4-chlorobenzo[4,5]-furo[3,2-b]pyridine-3-carbonitrile and the mixture is heated for 1 hour. Ethyl acetate is added and the solution is washed with 1 N NaOH. The organic layer is dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo. The solid is collected to give 115 mg (46%) of a beige solid, mp 138–140° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([C:11](O[C@H]2CC[C@H](C3C=C(F)C(C#N)=C(F)C=3)CC2)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C(OCC1C=CC(C(O)=O)=CC=1)CCC.S(Cl)([Cl:49])=O>C1(C)C=CC=CC=1>[CH2:1]([O:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([Cl:49])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCOCc1ccc(C(=O)O[C@H]2CC[C@H](c3cc(F)c(C#N)c(F)c3)CC2)cc1
Agent: CCCCOCc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOCc1ccc(C(=O)Cl)cc1
Reaction time: 2 h

Procedure:
Preparation of trans-4-(3,5-difluoro-4-cyanophenyl)-cyclohexyl 4-(butoxymethyl)benzoate (in the formula (1), R=C4H9, l=1, m and n=both, 1, o=0, A1 =1,4-phenylene group, A2 =trans-1,4-cyclohexylene group, Z1 =--COO--, Z2 =covalent bond, X=CN, and Y1 and Y2 =both, F) (Compound No. 148) 4-(butoxymethyl)benzoic acid (1.5 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.8 mmol) pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C., for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(butoxymethyl)benzoyl chloride.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: c1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cccn3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), pyrazole (34 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 46 mg (56% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.36-1.54 (m, 4 H), 1.56 (s, 9 H), 2.15-2.41 (m, 1 H), 3.23-3.38 (m, 2 H), 3.88 (m, 2 H), 4.37 (d, J=7.62 Hz, 2H), 6.47 (dd, J=2.73, 1.56 Hz, 1 H), 7.73 (d, J=1.37 Hz, 1 H), 7.77-7.85 (m, 1 H), 7.86-7.94 (m, 1 H), 8.26 (d, J=1.56 Hz, 1 H), 8.30 (d, J=2.73 Hz, 1 H); MS (ESI) (M+H)+=403.0; Anal. Calcd for C20H26N4O3S+0.50 TFA+0.20 EtOAc (477.15): C, 54.88; H, 5.94; N, 11.74. Found: C, 54.78; H, 5.83; N, 11.69.
Reaction SMILES: C([O:8][C:9](=[O:36])[C@H:10]([CH2:33][CH2:34][CH3:35])[NH:11][C:12](=[O:32])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:31])[CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H].NCC(O)=O>CO.[Pd].O>[NH2:20][CH2:19][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:12]([NH:11][C@H:10]([C:9]([OH:36])=[O:8])[CH2:33][CH2:34][CH3:35])=[O:32])=[O:31]
Reactant: CCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: NCC(=O)O
Solvent: O
Solvent: CO
Product: CCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CN)C(=O)O
Reaction time: 18 h

Procedure:
Tripeptide 4 (0.308 g, 0.62 mmol) was dissolved in methanol (30 cm3). The reaction flask was flushed with nitrogen and 10 wt. % palladium on activated carbon (66 mg, 0.062 mmol) was added and the mixture was hydrogenated at 1 atmosphere of hydrogen. After 30 min a white solid precipitated. Water (15 cm3) was added to dissolve the solid and the reaction was stirred for 18 h. The reaction was filtered through Celite™ washed with methanol/water and the solvent removed to yield an oil which was contaminated with palladium. The filtration was repeated again and the solvent removed to yield a white sold which was suspended in methanol and placed in a freezer overnight. The solid was filtered, washed with ice-cold methanol and dried to yield GPNorval (0.142 g, 84%) as white flakes. GPNorval was shown to be a 78:22 trans:cis mixture of conformers by 13C NMR analysis (the ratio was estimated from the integration of the Proβ-C carbons at δ 29.4 and 31.6 and the Proγ-C carbons at δ 24.1 and 21.9 of the major and minor conformers respectively): [α]D −79 (c 0.1 in water); δH (300 MHz; D2O) 0.85 (3H, d, J 7.4, Eγ-CH3), 1.29 (2H, sextet, J 7.0, Eγ-H2), 1.53-1.75 (2H, m, Eβ-H2) 1.88-2.05 (3H, m, Proβ-HAHB, Proγ-H2) 2.09-2.27 (1H, m, Proβ-HAHB), 3.51-3.82 (4H, m, Proδ-H2, Glyα-H2), 4.09 (0.78H, dd, J 7.8 5.0, Eα-H), 4.14* (0.22H, dd, J 9 5.0, Eα-H) and 4.41 (1H, m, Proα-H); δC (75 MHz; D2O) 12.8* (CH3, Eγ-CH3), 12.9 (CH3, Eγ-CH3), 18.5 (CH2, Eγ-C), 18.7* (CH2, Eγ-C), 21.9* (CH2, Proγ-C), 24.1 (CH2, Proγ-C), 29.4, (CH2, Proβ-C), 31.6* (CH2, Proβ-C), 33.3* (CH2, Eβ-C), 33.8 (CH2, Eβ-C), 40.6 (CH2, Glyα-C), 46.8 (CH, Proδ-C), 47.5* (CH, Proδ-C), 55.1 (CH, Eα-C), 60.0* (CH, Proα-C), 60.4 (CH, Proα-C), 166.6 (quat., Gly-CO), 173.1 (quat., Pro-CON), 178.9* (quat., Eα-CO) and 179.0 (quat., Eα-CO); m/z (FAB+) 272.1641 (MH+.C12H22N3O4 requires 272.1610).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:10][CH:9]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+]>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[C:15]([C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(CC(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCNC(=O)c1ccc(C=C(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1

Procedure:
To a mixture of 3-(4-{2-(4-chlorophenyl)-2-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]ethyl}benzoylamino)propionic acid methyl ester (the product from step 5) (0.15 g, 0.255 mmol), N-bromosuccinimide (50 mg, 0.28 mmol) in tetrachloromethane (9 mL) was added a catalytic amount of dibenzoylperoxide and the resulting mixture was stirred at reflux for 4 hours. After cooling, the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water (2×) and brine, dried over MgSO4, treated with active carbon, filtered and concentrated in vacuo. The residue (157 mg) was dissolved in DMF (5 mL) and lithium carbonate (21 mg, 0.28 mmol) and lithium bromide (24 mg, 0.28 mmol) were added and the resulting mixture was refluxed for 3.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water (3×) treated with active carbon, dried (MgSO4) and concentrated in vacuo. The residue (56 mg) was purified by HPLC to afford 14 mg of 3-(4-{2-(4-chlorophenyl)-2-[4-(4-trifluoromethoxyphenyl)-thiazol-2-yl]vinyl}benzoylamino)propionic acid methyl ester.
Reaction SMILES: Cl.C[O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.C(OC([NH:38][C@H:39]([C:41](O)=[O:42])[CH3:40])=O)C1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[NH2:38][C@H:39]([C:41]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([OH:3])=[O:10])=[O:42])[CH3:40]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Temperature: -15 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
L-proline methylester hydrochloride (16.58 g, 100 mmole) was dissolved in chloroform (300 ml), and triethylamine (10.12 g, 100 mmole), 1-hydroxybenzotriazole (13.51 g, 100 mmole) and N-benzyloxycarbonyl-L-alanine (22.32 g, 100 mmole) were added thereto under cooling to -15° C. and stirring. To the solution, while keeping the temperature to less than 0° C., a chloroform solution of N,N'-dicyclohexylcarbodiimide (20.63 g, 100 mmole) was added dropwise. After that, the mixture was stirred for 2 hours at 0° C. and then overnight at room temperature. The thus precipitated N,N'-dicyclohexylurea was separated by filtration, and the solution was washed with 10% aqueous sodium bicarbonate, water, 1N hydrochloric acid and water in the order given, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and to the residue thus obtained 1N sodium hydroxide (150 ml) was added. The mixture was stirred for 3 hours at 30° C. The thus precipitated N,N'-dicyclohexylurea was separated by filtration, and the filtrate was adjusted to pH 2.5 with 6N hydrochloric acid and was extracted twice with chloroform (200 ml). The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The thus obtained residue was dissolved in 50% methanol (300 ml), and-hydrogen gas was passed through the solution in the presence of 2% palladium-carbon as a catalyst for 2 hours at 40° C. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure The residue thus obtained was recrystallized from water and ethanol to give L-alanyl-L-proline (13.41 g; 72.0%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:45][CH:44]=[N:43][CH:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1cncs1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cncs3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methylthiazole-5-carboxamide.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:10][C:5]=2[CH2:4][CH2:3]S1.C[N+]1([O-])CCOCC1.[OH:30][S:31]([O-:33])=O.[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[O:30]=[S:31]1(=[O:33])[CH2:3][CH2:4][C:5]2[CH:10]=[C:9]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:8]=[CH:7][C:6]=2[CH2:1]1
Reactant: O=S([O-])O
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCSC3)C(=O)O1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCS(=O)(=O)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A solution of (−)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzothiopyran-6-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 10, 545 mg, 1.78 mmol) in acetone/H2O (3/1, 36 mL) under N2 is treated with N-methylmorpholine N-oxide (521 mg, 4.45 mmol) and OsO4 (2.5 wt % in tBuOH, 1.11 mL, 5 mol %), and the resulting mixture is stirred at ambient temperature for 18 hrs and is then cooled in an ice bath and treated with half-saturated aqueous NaHSO3 (50 mL). The mixture is extracted with CH2Cl2 (3×75 mL), and the combined organic phase is washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product which is then chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-4/96). Those fractions with an Rf=0.39 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated and the product triturated with CH2Cl2/Et2O to give 517 mg (86%) of the title compound as a white solid, mp 177-178° C. MS (ESI+) for C15H18N2O5S m/z 339 (M+H)+; [α]25D=−23° (c 0.97, DMSO).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu](C#N)[C:19]#[N:20]>CN(P(N(C)C)(N(C)C)=O)C>[C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:19]#[N:20])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cccc2c(-c3ccccc3)nccc12
Reactant: N#C[Cu]C#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1cccc2c(-c3ccccc3)nccc12

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and benzoyl chloride were reacted in the same way as in step (a) of Example 13 to afford 1-benzoylamino-2-(2-chlorophenyl)-ethane having a melting point of 70.1° to 71.0° C. (b) 1-Benzoylamino-2-(2-chlorophenyl)ethane, phosphorus oxychloride and phosphorus pentoxide were reacted in the same way as in step (b) of Example 13 to afford 1-phenyl-5-chloro-3,4-dihydroquinoline as an oil. (c) 1-Phenyl-5-chloro-3,4-dihydroisoquinoline and diphenyl disulfide were reacted in the same way as in step (c) of Example 13 to afford 1-phenyl-5-chloroisoquinoline as colorless needles having a melting point of 66.0° to 66.6° C. (d) 1-Phenyl-5-chloroisoquinoline, copper cyanide and hexamethylphosphotriamide were reacted in the same way as in step (d) of Example 13 to afford 1-phenyl-5-cyanoisoquinoline as an oil. (e) 1-Phenyl-5-cyanoisoquinoline was treated in the same way as in step (e) of Example 13 to afford 1-phenyl-5-methoxycarbonylisoquinoline as colorless needles having a melting point of 102.2° to 103.1° C. (f) 1-Phenyl-5-methoxycarbonylisoquinoline and dihydrobis(2-methoxyethoxy)aluminum sodium (in 70% benzene) were reacted in the same way as in step (f) of Example 13 to afford 1-phenyl-5-hydroxymethylisoquinoline as colorless plates having a melting point of 97.3° to 97.9° C. (g) 1-Phenyl-5-hydroxymethylisoquinoline was treated in the same way as in step (g) of Example 13 to afford 1-phenyl-5-chloromethylisoquinoline having a melting point of 104.0° to 104.2° C. (h) 1-Phenyl-5-chloromethylisoquinoline was treated by the same way as in step (h) of Example 13 to afford 1-phenylisoquinoline-5-acetonitrile as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[N:15]1([C:21]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:22]=2[C:23](Cl)=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:23]([C:22]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:21]=2[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:24])[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Cc1ccc(N2CCNCC2)c(F)c1
Product: Cc1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)c(F)c1
Yield: 70 %

Procedure:
Title compound was prepared according to procedure described in example 46 from 1-(2-Fluoro-4-methyl-phenyl)-piperazine and 2-morpholin-4-yl-5-nitro-benzoyl chloride (70% yield, yellow oil, MS (m/e): 429.2 (M+H+, 100%).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]([N+:14]12[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.B(F)(F)[F:23].FF>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:1][B-:2]([F:5])([F:4])[F:3].[C:6]([N+:14]12[CH2:15][CH2:16][N+:17]([F:23])([CH2:18][CH2:19]1)[CH2:20][CH2:21]2)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ccccc1)[N+]12CCN(CC1)CC2
Reactant: FB(F)F
Agent: FF
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: O=C(c1ccccc1)[N+]12CC[N+](F)(CC1)CC2

Procedure:
A solution of 1-benzoyl-4-aza-1-azoniabicyclo[2.2.2]octane tetrafiuoroborate (32 g, 10 mmole) and boron trifluoride gas (6.7 g, 10 mmole) in acetonitrile (125 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10 % V/V, 12 mmole). The reaction was evaporated, the remaining solid washed with DME and dried to afford 1-benzoyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(O)(=[O:11])C.OO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N+:3]=1[O-:11]
Reactant: Cc1ccc(O)cn1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: Cc1ccc(O)c[n+]1[O-]
Reaction time: 18 h

Procedure:
A mixture of 100.0 g of 2-methyl-5-hydroxy-pyridine, 600 ml of acetic acid and 200 ml of 30-35% hydrogen peroxide is heated on a steam bath with occasional swirling for 18 hours. Then to the mixture is added 500 ml of water and the resulting solution is evaporated to leave a residue. The last traces of water from the residue are removed azeotropically with isopropanol to give a yellow solid. This solid is recrystallized from ethanol to give 2-methyl-5-hydroxy-pyridine-1-oxide melting at 185°-187°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)#[N:2].[NH:22]1[C:30]2[C:25](=[C:26]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:14][CH2:13][CH2:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:15]2[CH2:20][CH2:19][CH:18]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[C:25]5[CH:24]=[CH:23][NH:22][C:30]=5[CH:29]=[CH:28][CH:27]=4)[CH2:32][CH2:33]3)[CH2:17][CH2:16]2)=[CH:7]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: CCCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCn1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of 4-(5-cyano-1-n-propyl-indol-3-yl)-cyclohexanone (1.68 g, 6 mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.3 mmol), sodium triacetoxyborohydride (1.84 g, 8.9 mmol) and acetic acid (0.94 ml, 16 mmol) in 1,2-dichloroethane (80 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (20 ml), extracted with methylene chloride (3×100 ml) and washed with brine (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.42 g (15%) of product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[NH2:5].[Cl:19]N1C(=O)CCC1=O.C1C=CC=CC=1>C(OCC)(=O)C.ClN1C(=O)CCC1=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[O:9][C:8]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:5])=[C:6]([Cl:19])[C:7]=1[Cl:18]
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2F)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Nc1cc(Cl)c(Oc2ccc(F)cc2F)c(Cl)c1Cl
Reaction time: 1 h
Yield: 58.8 %

Procedure:
Into a 300 milliliter round bottom reaction flask was charged 14.9 grams (51.4 mmol) of 3,5-dichloro-4-(2,4-difluorophenoxy) aniline, 7.2 grams (53.9 mmol) of N-chlorosuccinimide (NCS), and 100 milliliters of benzene. The reaction mixture was refluxed for 2 hours after which time additional NCS (350 milligrams, 2.6 mmol) was added. Reflux was then continued for an additional 1 hour. The mixture was allowed to cool, diluted with ethyl acetate (200 milliliters), washed with H2O, saturated NaHCO3 and brine; dried over Na2SO4 and concentrated under reduced pressure. The oily product obtained was purified by flash column chromatography (1:1 hexane toluene) to afford 4-(2,4-difluorophenoxy)-2,3,5-trichloroaniline (9.8 grams, 30.2 mmol, 59%) as a dark brown oil. The structure of this material was verified by its H'-NMR spectrum (CDCl3) 7.30-6.10 (m, 3H), 6.75 (s, 1H), 4.18 (br s, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24]>ClCCCl.O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([F:16])[C:18]=2[OH:24])=[O:14])=[CH:8][CH:7]=1
Reactant: Oc1cccc(F)c1F
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(F)c(F)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of aluminium chloride (7.66 g, 57.4 mmol, 1.5 eq.) and (4-chlorophenyl)acetyl chloride (8.7 g, 46 mmol, 1.2 eq.) in 1,2-dichloroethane (75 ml) is stirred at 0° C. for 30 min. A solution of 2,3-difluorophenol (5 g, 38.4 mmol) in 1,2-dichloroethane (25 ml) is added to the reaction mixture, which is heated in an oil bath at 90° C. overnight. The reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo to afford a brown solid. This is triturated with hexane/ethyl acetate (9:1), filtered and dried to afford the title compound as a pale brown fine solid which is 87% pure by HPLC analysis.
Reaction SMILES: BrC(Br)(Br)Br.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([I:17])=[CH:14][CH2:15]O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C.[SH:46][C:47]1[CH:59]=[CH:58][C:50]([O:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[C:49]([CH3:60])[CH:48]=1>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[I:17])=[CH:14]/[CH2:15][S:46][C:47]2[CH:59]=[CH:58][C:50]([O:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[C:49]([CH3:60])[CH:48]=2)=[CH:9][CH:8]=1
Reactant: OCC=C(I)c1ccc(Br)cc1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(SC/C=C(\I)c2ccc(Br)cc2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A solution of tetrabromomethane (2.1 g, 6.6 mmol) in dry methylene chloride (20 mL) was added dropwise to an ice-cooled solution of 3-(4-bromophenyl)-3-iodoprop-2-en-1-ol (1.5 g, 4.4 mmol) and triphenylphosphine (2.4 g, 9.0 mmol) in dry methylene chloride (50 mL). The reaction mixture was stirred at room temperature for 2 h and the solvent was evaporated in vacuo. Under nitrogen atmosphere, N,N-diisopropylethylamine (1.2 g, 9.0 mmol) and ethyl (4-mercapto-2-methylphenoxy)acetate (1.5 g, 6.6 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517) were added to the residue. The reaction mixture was stirred for 3 h, filtered through a short path of silica gel and the filtrate was evaporated in vacuo. The residue was purified by column chromatography (silica gel Merck 60, hexane/ethyl acetate 1:0–9:1) giving 0.80 g of the ester. Yield: 0.80 g (40%).