Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(F)cc2)c[nH]1
Temperature: 0 °C
Yield: 53.6 %

Procedure:
Ethylpyrrole-2-carboxylate (2.0589 g, 14.80 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (3.9913 g, 29.93 mmol) and 4-fluorophenylacetyl chloride (5.1338 g, 29.75 mmol) in dichloroethane (22 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 3.5 h. 20.6195 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for ˜60 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered and concentrated. When 6.5 mL of 80:20 Hexanes: EtOAc were added, the organic liquid turned yellow, leaving behind a tan solid. The solid was removed by filtration, rinsed with 80:20 Hexanes: EtOAc, and dried to obtain pure 71 (2.1838 g, 53.6%). 1H (CDCl3, 400 MHz): δ 10.03 (1H, broad s), 7.54 (1H, s), 7.32 (1H, s), 7.23 (2H, dd, J=8.6, 5.3 Hz), 6.99 (2H, t, J=8.6 Hz), 4.35 (2H, q, J=7.1 Hz), 4.04 (2H, s), 1.37 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 192.81, 161.84 (d, J=244 Hz), 160.95, 130.89 (d, J=7.8 Hz), 130.37 (d, J=3.2 Hz), 126.72, 126.36, 124.30, 115.40 (d, J=21.4 Hz), 114.96, 61.02, 45.63, 14.29 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.29; CH2 carbons: 61.02, 45.63; CH carbons: 130.89 (d, J=7.8 Hz), 126.72, 115.40 (d, J=21.4 Hz), 114.96 ppm. HPLC: 9.689 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:5][CH:4]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=1
Reactant: CNOC
Reactant: O=C(Cl)CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a mixture of 3.034 g (13 mmol) 3-(4-Trifluoromethyl-phenyl)-propionyl chloride (CAS: 539855-79-3) and 1.4 g (14.1 mmol) N,O-Dimethylhydroxylamine hydrochloride in 55 mLl chloroform, under argon, was added dropwise 2.28 mL (28 mmol) pyridine at 0° C. The solution was allowed to warm to RT and was stirred for 2 hour. The mixture was washed with 1N HCl (50 mL). The organic layer was washed once with 1N NaOH. The organic phases was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified with flash column chromatography on silica gel eluting with a gradient formed from heptane and ethylacetate to provide 2.1 g (63%) of title compound as colorless oil. MS (m/e): 262.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2ccc3c(c2)C(C)(C)CC3=O)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-acetylphenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 279.2; HRMS: calcd for C19H18O2+H+, 279.13796; found (ESI, [M+H]+), 279.1395.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH2Cl2(50 mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) portionwise. The mixture was allowed to slowly warm to RT (3 hrs). The reaction mixture was diluted with CH2Cl2 then neutralized with NaHCO3(sat.). The aqueous phase was extracted three times with CH2Cl2 then the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-10% CH2Cl2:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline (1.37 g, 94% yield) as a off-white foam. MH+=284.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][OH:14])[N:6]=[CH:5]2.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:6]=[CH:5]2
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCn1ncc2cc(Br)ccc21
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCn1ncc2cc(Br)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Crude 3-(5-Bromoindazol-1-yl)-propan-1-ol (2s) (2.1 mmol) and imidzaole (0.22 g, 3.2 mmol) were dissolved in 10 mL CH2Cl2. tert-Butyldiphenylsilyl chloride (0.58 g, 2.1 mmol) was added to the solution and the reaction was stirred at room temperature for 4 hours. Additional amounts of imidazole (0.07 g, 1.0 mmol) and tert-butyldiphenylsilyl chloride (0.16 g, 0.63 mmol) were added and the reaction was stirred at room temperature overnight. The mixture was diluted with Et2O and washed sequentially with an aqueous 3% HCl solution and brine. The aqueous phases were extracted once with Et2O. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel with 1:6 Et2O/hexane to afford (3s) (1.0 g, 96% over two steps) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.86 (s, 1H), 7.61 (d, J=7.8 Hz, 4H), 7.44-7.42 (m, 3H), 7.36-7.33 (m, 5H), 4.53 (t, J=10.2 Hz, 2H), 3.63 (t, J=9.0 Hz, 2H), 2.16-10 (m, 2H), 1.08 (s, 9H); HPLC (5 to 95%) 4.72 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]([N:17]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH2:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(F)c(Br)c1)N=C(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reaction time: 8 h
Yield: 124.8 %

Procedure:
A solution of (S)-2-(benzhydrylidene-amino)-3-(3-bromo-4-fluoro-phenyl)-propionic acid tert-butyl ester (300 mg, 0.622 mmol) in THF (3 mL) was treated with 10% citric acid (3 mL). The mixture was stirred overnight, diluted with water, and extracted with Et2O (2×). The aqueous layer was basified to pH=10 with satd. aq. K2CO3 and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated to give the title compound (247 mg, 64%). MS (ESI+): mass calcd. for C13H17BrFNO2, 318.18; m/z found, 262.2 [M-t-Bu]+. 1H NMR (400 MHz, CDCl3): 7.42 (dd, J=6.6, 2.1 Hz, 1H), 7.16-7.11 (m, 1H), 7.08-7.02 (m, 1H), 3.56 (dd, J=7.3, 5.9 Hz, 1H), 2.85-2.78 (m, 1H), 2.99-2.92 (m, 1H), 1.43 (m, 9H).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[O:19][C:18](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:18]1[O:19][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccc([N+](=O)[O-])o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccc([N+](=O)[O-])o1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(5-nitro-2-furyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 293 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]1[N:10]=[N:11][C:12]([O:18][CH2:19][CH3:20])=[CH:13][C:14]=1[O:15][CH2:16][CH3:17].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[N:23]=1>CN(C=O)C>[CH2:16]([O:15][C:14]1[CH:13]=[C:12]([O:18][CH2:19][CH3:20])[N:11]=[N:10][C:9]=1[CH2:8][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[N:23]=1)[CH3:17]
Reactant: CCOc1cc(OCC)c(CCl)nn1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)c(Cn2ccnc2-c2cccc(F)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Excess K2CO3 is added to a stirred solution of 3-chloromethyl-4,6-diethoxy-pyridazine (70 mg, 0.32 mmol) and 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (52 mg, 0.32 mmol) in DMF (6 mL). The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and water (5 mL) and EtOAc (8 mL) are added. The layers are separated and the aqueous layer is extracted with EtOAc (8 mL). The combined extracts is washed with brine (10 mL) and dried (Na2SO4) and evaporated. Preparative TLC purification of the residue (5% MeOH in CH2Cl2) provides the title compound as a light yellow oil. H1 NMR δ (CDCl3) 8.07–8.10 (m, 1H), 7.82 (q, 1H, J=7.8 Hz), 7.14 (s, 2H), 6.80–6.84 (m, 1H), 6.22 (s, 1H), 6.11 (s, 2H), 4.50 (q, 2H, J=7.2 Hz), 3.95 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz), 1.18 (t, 3H, J=7.2 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH2:6][C:5]([CH3:10])([CH3:9])[C:4]=1[CH3:11]>C(O)C.[Ni]>[OH:1][CH2:2][CH:3]1[CH:8]=[CH:7][CH2:6][C:5]([CH3:10])([CH3:9])[CH:4]1[CH3:11]
Reactant: CC1=C(CO)C=CCC1(C)C
Agent: [Ni]
Solvent: CCO
Product: CC1C(CO)C=CCC1(C)C
Yield: 91.6 %

Procedure:
30.4 g of 1-hydroxymethyl-2,3,3-trimethyl-cyclohexa-1,5-diene were hydrogenated at 10°-12° in the presence of 1 g of Raney-nickel in 300 ml of ethanol. 3.95 l of hydrogen were thus absorbed within 2.5 h. A filtration followed by evaporation and distillation gave 28.2 g of 1-hydroxymethyl-2,3,3-trimethyl-cyclohex-5-ene. nD =1.4862, d20 =0.9447.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[S:20][N:19]=[C:18]([CH3:21])[CH:17]=1>>[CH3:21][C:18]1[CH:17]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[S:20][N:19]=1
Reactant: Cc1cc(Br)sn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: Cc1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)sn1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611) and 5-bromo-3-methylisothiazole, prepared as described in (U.S. Pat. No. 3,840,665) were coupled according to the procedure described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCC(O)c2cccc(Cl)c2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a stirring solution of 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde (1.08 g, 3.90 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.50 g, 4.29 mmol) and piperidine (0.42 mL, 4.3 mmol), and the resulting solution was heated to reflux and then stirred overnight at room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in EtOAc. This solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed eluting with 10-20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.31 g (89%) of the product as a light yellow solid. MS (ESI+) for C18H14ClNO4S m/z 375.0 (M+H)+. MS (ESI−) for C18H14ClNO4S m/z 374.1 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(Nc2ccc(OC)cc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1
Yield: 85 %

Procedure:
A mixture of 3-(4-methoxyphenylamino)phthalic acid dimethyl ester (0.80 g, 2.5 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 90 minutes. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.61 g in 85% yield: 1H NMR (DMSO-d6) δ 3.74 (s, 3H), 6.89-6.99 (m, 3H), 7.03-7.12 (m, 3H), 7.29 (t, J=8.0 Hz, 1H), 8.01 (br, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)([O:12][CH2:13][CH3:14])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].O.O.Cl[Sn]Cl>CCO>[CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([O:12][CH2:13][CH3:14])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC([PH2]=O)(c1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC([PH2]=O)(c1ccc(N)cc1)P(=O)(OCC)OCC
Temperature: 70 °C
Reaction time: 0.73 h
Yield: 76.2 %

Procedure:
A mixture of [(4-nitro-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (940 mg, 2.57 mmol) and SnCl2.2H2O (2.9 g, 12.9 mmol) in EtOH (˜10 mL) was stirred at 70° C. for 44 min and then concentrated at ambient temperature. The residue was taken up in CH2Cl2 and washed with half saturated aq NaHCO3 (40 mL), H2O (40 mL) and brine (40 mL). The aqueous washes were reextracted once with CH2Cl2, and the combined extracts were dried over K2CO3 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 20:1 CHCl3—MeOH followed by 15:1 CHCl3—MeOH afforded 657 mg of product.
Reaction SMILES: ClC1C=C(C=CC=1Cl)C([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:44]([C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH:49]=O)([O-:46])=[O:45].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[N+:44]([C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49][NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:9]1)([O-:46])=[O:45]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1NCc1ccccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A solution of Intermediate 3 (50 mg) and sodium (triacetoxy)borohydride (106 mg) in dichloromethane (6 ml) and acetic acid (1 ml) was treated with 2-nitro-benzaldehyde (45 mg). The resulting mixture was stirred under nitrogen for 18 h. Saturated sodium bicarbonate solution was carefully added, and the mixture extracted with dichloromethane. The organic layer was passed through a hydrophobic frit, and evaporated. The residue was then purified on a silica gel SPE cartridge. Gradient elution with 10-18% ethyl acetate in petrol gave the title compound as a colourless solid (33 mg) LC/MS RT=4.83 min Found ES+=387
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1.[CH3:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Br)=[CH:47][CH:46]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:44][C:45]2[CH:52]=[CH:51][C:48]([CH3:49])=[CH:47][CH:46]=2)=[CH:11][N:10]=1
Reactant: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(O)cn5)c(Cl)c4)CC3)cc2)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(CCOc6ccc(C)cc6)cc5)CC4)cc3Cl)nc2)cc1
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a DMF (5 mL) solution of (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methylphenyl}-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (479 mg) and 4-methylbenzyl bromide (155 mg) was added sodium hydride (60% w/w in oil, 42 mg) at 0° C., and stirred for 1 hour. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (10 mL), and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (AcOEt/MeOH=1/0 to 9/1) to afford (E)-3-[3-chloro-5-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (480 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=4)[NH:18]3)[CH:14]=[N:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:38][S:35]([CH:32]5[CH2:34][CH2:33]5)(=[O:37])=[O:36])=[O:30])[CH:23]=4)[NH:18]3)[CH:14]=[N:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)NS(=O)(=O)C5CC5)ccc4N3)c2)cc1
Yield: 20.1 %

Procedure:
A mixture of 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.48 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (130 mg, 0.72 mmol), 4-dimethylaminopyridine (88 mg, 0.72 mmol), cyclopropane sulfonic acid amide (170 mg, 1.44 mmol) in dichloromethane (20 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid {2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (50 mg, 20%) as a light yellow solid: MS (ESI) M+1=518.3.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[Br:27][CH2:28][C:29](Br)=[O:30]>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[C:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]([C:29](=[O:30])[CH2:28][Br:27])[CH2:4][CH2:3]1
Reactant: O=C(Br)CBr
Reactant: CN1CCNc2c(C(=O)c3ccccc3F)cccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN(C(=O)CBr)c2c(C(=O)c3ccccc3F)cccc21

Procedure:
To a solution of 1-methyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline (11.99 g) and pyridine (4.04 g) in methylene chloride (200 ml) was dropwise added a solution of bromoacetyl bromide (5.09 ml) in methylene chloride (10 ml) under stirring at a temperature below 10° C. and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was washed with water twice and dried. Removal of the solvent afforded viscous oil. The viscous oil was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried to give 1-methyl-4-bromoacetyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline (17.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br-].[C:31]1([P:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C1C=CC=CC=1>[Br-:1].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][P+:37]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1c(Br)cccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Br-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: Brc1cccc(Br)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
Bromination of 2,6-dibromotoluene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 3 h, gave the phosphonium salt (516) (95%) as a cream powder, mp (CH2Cl2/benzene) 241–243° C. 1H NMR (CDCl3) δ 7.78 (m, 9H), 7.64 (m, 6H), 7.40 (br d, J=7.9 Hz, 2H), 6.99 (td, J=8.0, 2.5 Hz, 1H), 5.58 (d, J=14.1 Hz, 2H). Found: C, 47.06; H, 3.37. C25H20Br3P.3/4 CH2Cl2 requires C, 47.23; H, 3.31.