Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:23])[C@H:4]([OH:22])[C@@H:5]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C@@H:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C@@H:4]([OH:22])[C:3]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]
Reactant: COC(=O)[C@H](O)[C@@H](Sc1ccccc1N)c1ccc(OC)cc1
Reactant: Nc1ccccc1
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(=O)Nc2ccccc2)cc1

Procedure:
(2S,3S)-3-(2-Aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-propionic acid methyl ester and aniline are treated in the same manner as in Reference Example 5 to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-phenylpropionamide.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=[CH:6]2
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
To a cooled (−78° C.) solution of 1-[2-(6-methoxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (4.2 g, 12 mmol) in methylene chloride (45 mL), was added, dropwise, 1 N boron tribromide in methylene chloride (25 mL, 25 mmol). The reaction mixture was stirred at room temperature for 3 hours, 45 minutes. The mixture was cooled to −11° C. and quenched, dropwise, with methanol (25 mL), then poured into excess water, and diluted with additional methylene chloride. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and solvent evaporated. The residue was purified by flash chromatography (Biotage apparatus) using 5-20% ethyl acetate in hexane as an eluant to afford 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone as a yellow solid (3.09 g), mp 148-149° C. Mass spectrum (+EI, M+) m/z 344; 1HNMR (400 MHz, DMSO-d6): δ10.1 (d, 1H, J=4.0 Hz), 8.3 (d, 1H, J=1.1 Hz), 8.0-8.05 (m, 1H), 7.95 (d, 1H, J=8.8 Hz), 7.85 (d, 1H, J=8.6 Hz), 7.7-7.75 (m, 2H), 7.35-7.45 (m, 2H), 7.15-7.25 (m, 2H), 2.75 (t, 2H, J=7.4 Hz), 1.5-1.55 (m, 2H), 1.1-1.15 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C23H20O3: Calculated: C, 80.21; H, 5.85; N, 0.00. Found: C, 79.92; H, 5.81; N, 0.12.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(Br)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1)n1ccnc1
Temperature: 50 °C

Procedure:
To a stirred solution of 1H-imidazole (13 mg, 0.19 mmol) in DMF (2 mL) was added 2-(1-bromoethyl)-5-(4-nitrophenyl)pyridine (50 mg, 0.1 mmol) and K2CO3. The reaction was heated at 50° C. for about 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 100-200μ) using 2% methanol in DCM eluent to afford 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-nitrophenyl)pyridine as off white solid (50 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.31 (d, 2H), 8.22 (dd, 1H), 8.01 (d, 2H), 7.82 (s, 1H), 7.30 (t, 2H), 6.91 (s, 1H), 5.71-5.65 (m, 1H), 1.84 (d, 3H), LC-MS m/z calcd for [M+H]+ 295.11. found 295.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:24]3[CH2:27][C@H:26]([CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:40][NH:41][CH3:42].C1COCC1>CO>[CH3:40][N:41]([CH2:28][C@@H:26]1[CH2:27][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:25]1)[CH3:42]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C[C@H]1C[C@@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Temperature: 60 °C

Procedure:
A mixture of cis-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (30.0 mg, 0.0555 mmol), 2 M of dimethylamine in MeOH (2 mL) and THF (5 mL, 0.06 mol) was heated to 60° C. overnight in a sealed tube. The material was concentrated in vacuo, redissolved in minimal MeOH/DCM, and loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH)/DCM. The band containing the pure product was collected, and the product was filtered off using 1:1 MeOH/DCM. The filtrate was concentrated in vacuo, and hexanes was added. The mixture was sonicated until a white precipitate crashed out. The solid was filtered off, washing several times with hexanes, to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=2.23 (s, 6H), 2.26-2.33 (m, 2H), 2.42 (d, J=6.3 Hz, 2H), 2.57-2.70 (m, 3H), 3.60-3.71 (m, 1H), 5.03 (s, 2H), 7.03-7.17 (m, 7H), 7.34-7.41 (m, 2H), 7.61-7.65 (m, 2H). MS (ES+): m/z 414.19 (100) [MH+]. HPLC: tR=1.98 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:34])=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 3-chlorobenzenesulfonamide. MS (ESI) m/z 509 [M+H]+, 507 [M−H]−, 1H-NMR (CDCl3)δ1.22 (3H, t, J=7.5 Hz), 2.68 (2H, q, J=7.5 Hz), 2.86 (2H, t, J=6.6 Hz), 3.47-3.56 (2H, m), 6.44 (1H, br), 7.23-7.28 (5H, m), 7.36 (2H, t, J=7.3 Hz), 7.45 (2H, t, J=8.1 Hz), 7.58 (2H, d, J=8.1 Hz), 7.73-7.78 (2H, m), 7.87 (1H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C.[H][H]>[Pd].C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: CCOc1cnc(-c2ccc(C=CCCCO)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cnc(-c2ccc(CCCCCO)cc2)nc1
Yield: 70.3 %

Procedure:
A mixture of 12 g of 2-[4-(5-hydroxy-1-pentenyl)phenyl]-5-(ethoxy)pyrimidine, 2 g of palladium on active charcoal (10 w/w %) and 150 ml of ethyl acetate was hydrogenated at normal pressure and room temperature until one molar equivalent of hydrogen had been taken up. The inorganic material was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel with hexane/ethyl acetate (vol. 8:2). Recrystallization from ethyl alcohol gave 8.5 g of pure 2-[4-(5-hydroxy-1-pentyl)phenyl]-5-(ethoxy)pyrimidine.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:12])=[C:5](Cl)[C:6]=1[C:7](=[O:10])[CH2:8][Cl:9].[Cl:13]C1SC(Cl)=CC=1.ClCC(Cl)=O>>[Cl:9][CH2:8][C:7]([C:6]1[CH:5]=[C:4]([Cl:12])[S:3][C:2]=1[Cl:13])=[O:10]
Reactant: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Reactant: Clc1ccc(Cl)s1
Agent: O=C(Cl)CCl
Product: O=C(CCl)c1cc(Cl)sc1Cl
Yield: 91 %

Procedure:
General procedure described for compounds 1 and 2 starting from 2,5-dichlorothiophene and chloroacetyl chloride. Purified by column chromatography column (hexane:ethyl acetate 12:1), yield 91%, m.p.: 43-44° C. (ethanol), 1H-NMR (CDCl3): δ7.1 (s, 1H, CH-Aromat), 4.6 (s, 2H, CH2); 13C-NMR (CDCl3): 186.6 (CO), 136.9 (C—Cl), 136.0 (C—CO), 130.2 (C—Cl), 129.4 (CH—Ar), 50.6 (CH2); M/z (EI): 234, 232, 230, 228 (M+, 1, 6, 16, 16%), 183, 181, 179 (M-CH2Cl, 18, 79, 100%), 155, 153, 151 (M-COCH2Cl, 3, 13, 19%), 118, 116 (M-COCH2Cl2, 5, 13%); HPLC: Delta Pak Column C18, 5 μm, 300 A, (150×3.9 mm), Purity 99%, r.t.=6.16 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[Cl:16][CH2:17][C:18](Cl)=[O:19]>O1CCOCC1>[Cl:16][CH2:17][C:18]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:19]
Reactant: CCOCCNc1ncccc1[N+](=O)[O-]
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Product: CCOCCN(C(=O)CCl)c1ncccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 42.24 parts of N-(2-ethoxyethyl)-3-nitro-2-pyridinamine in 309 parts of 1,4-dioxane were added 49.7 parts of 2-chloroacetyl chloride. The reaction mixture was stirred for 4 hours at reflux temperature. The whole was evaporated and the residue was taken up in methylbenzene. The organic layer was evaporated again, yielding 57.5 parts (100%) of 2-chloro-N-(2-ethoxyethyl)-N-(3-nitro-2-pyridinyl)acetamide as a residue (int. 1).
Reaction SMILES: CO[C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)=[O:14]>I.CC(O)=O.O>[OH:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[O:14][C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[CH:12][C:11]2=[O:23]
Reactant: COc1ccc(C(=O)CC(=O)c2cccc(OC)c2OC)cc1
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(O)cc2)oc2c(O)cccc12
Temperature: 110 °C
Yield: 51.9 %

Procedure:
1-(2,3-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (3.1 g, 9.86 mmol) was dissolved in mixture of HI (10 mL) and AcOH (10 mL) and heated at 110° C. for 4 days. The reaction mixture was cooled to rt, diluted with water and solids were filtered. The solid product was washed with water, dried and purified by column chromatography, using 30% EtOAc in dichloromethane to give 1.3 g (52%) of 8-hydroxy-2-(4-hydroxy-phenyl)-4H-chromen-4-one. MS (ES) m/z: 255.08 (M+1), and 154.15.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=1.[P:14]([O-:21])(OCC)OCC.Cl>O1CCCC1.C1(C)C=CC=CC=1.O>[CH3:10][N:9]([CH3:11])[C:8]1[CH:12]=[CH:13][C:5]([PH:14](=[O:21])[C:5]2[CH:13]=[CH:12][C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=2)=[CH:6][CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: CN(C)c1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc([PH](=O)c2ccc(N(C)C)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Under an argon atmosphere, a solution of magnesium (3.0 g, 1.0 equivalent) and a small amount of iodine in tetrahydrofuran (30 mL) was stirred at room temperature for 1 hr. After addition of 4-bromo-N,N-dimethylaniline (25 g, 0.125 moL) at 45° C., the mixture was stirred at 5° C. for 1 hr. After addition of diethyl phosphite (8.63 g, 0.50 equivalent) at 5° C., the mixture was stirred at 5° C. for 1 hr. Water (30 mL) was added to the mixture at 3° C., and toluene (60 mL) and 6M hydrochloric acid (30 mL) were added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the aqueous layer was neutralized with sodium hydroxide and extracted with tetrahydrofuran (30 mL). Then, the combined organic layer was dried over anhydrous magnesium sulfate and filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether to give the title compound (9.53 g, slightly brown white crystals). yield 52.9%. melting point 152.1° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[C:32]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:35])[CH2:33][CH3:34]
Reactant: CCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16](=[S:18])=S.[C:19]([O:22][C:23]1[C:24]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:25][C:26]2[O:30][C:29]([CH2:32][NH2:33])([CH3:31])[CH2:28][C:27]=2[C:34]=1[C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:21])[CH3:20]>O1CCCC1>[C:19]([O:22][C:23]1[C:24]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:25][C:26]2[O:30][C:29]([CH2:32][N:33]=[C:16]=[S:18])([CH3:31])[CH2:28][C:27]=2[C:34]=1[C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:21])[CH3:20]
Reactant: S=C=S
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CN)O2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CN=C=S)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To an ice-cooled suspension of 4.56 g of dicyclohexylcarbodiimide and 8 ml of carbon disulfide in 20 ml of tetrahydrofuran was added dropwise a solution of 6.18 g of 5-acetoxy-2-aminomethyl-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 70-5) in 20 ml of tetrahydrofuran. The mixture was stirred at 0° C. for 2 hours and then stirred at room temperature for 24 hours. After reaction, carbon disulfide and tetrahydrofuran were removed using an evaporator and the precipitated dicyclohexylthiourea was filtered off. Then, water was added to the filtrate and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 10% ethyl acetate to give 5.15 g of (5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl isothiocyanate (rotamer mixture) as a colorless oil (yield 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Li]CCCC.CN(CCN(C)C)C.[I:26]I>C1COCC1>[F:1][C:2]1[C:3]([O:8][C:9]([F:11])([F:10])[F:12])=[CH:4][CH:5]=[CH:6][C:7]=1[I:26]
Reactant: II
Reactant: Fc1ccccc1OC(F)(F)F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1c(I)cccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-fluoro-2-(trifluoromethoxy)benzene [2106-18-5] (20.0 g, 111 mmol) in dry THF (200 mL), cooled to −78° C., was added dropwise n-BuLi (2.5 M solution in n-hexane; 65 mL, 160 mmol) and subsequently TMEDA (60 mL). The reaction mixture was stirred for additional 60 min at −78° C., followed by addition of a solution of iodine (30.2 g, 120 mmol) in dry THF (50 mL). The resulting mixture was stirred for 1 h and then quenched by addition of a saturated aqueous NH4Cl solution (20 mL). The organic layer was washed with 1N HCl, water and brine, and dried over MgSO4. Volatiles were removed in vacuo to afford the title compound as yellow oil. The product was used in the next reaction step without further purification. MS (LC/MS): 306.0 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:18][CH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:19]1([NH:18][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: NC1CCc2ccccc21
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc2c(c1)CCC2NC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 1-aminoindan (67 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (17 mg) and a syn-form compound (18 mg).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1

Procedure:
A tetrahydro-β-carboline (II) is reacted with benzoyl chloride to provide a 2-benzoyl-1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole (III). Then compound (III) is reduced to give a 2-benzyl-1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole (IV). Thereafter, compound (IV) is transformed by t-butyl hypochlorite into a chloroindolenine derivative (V) which is immediately treated with a metal dialkylmalonate such as thallium t-butyl methyl malonate to give a dialkyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino-(4,5-b)-indole-5,5-dicarboxylate (VI). Compound (VI) is then partly decarboxylated into a alkyl 3-benzyl-1,2,3,4,5,6-hexahydro-(4,5-b) indole-5-carboxylate (VII). Compound (VII) is hydrogenated to give an alkyl 1,2,3,4,5,6-hexahydroazepino-(4,5-b)-indole 5-carboxylate (VIII). In an alternative embodiment, compound (VI) can be hydrogenated to the corresponding dialkyl 1,2,3,4,5,6-hexahydroazepino-(4,5-b)-indole-5,5-dicarboxylate which is then decarboxylated into compound (VIII). Compound (VIII) is condensed with a functionalised aldehyde, typically a epoxy aldehyde or a haloaldehyde such as 1-bromo-4-formylhexane, to give vincadifformine or similar pentacyclic derivatives.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Nc1ccccc1C1CC(C)(C)c2cc(C(F)(F)F)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg) and pyridine (200 μL) in dichloromethane (3 mL) was added ethanesulfonylchloride (44 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give ethanesulfonic acid [2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide. LC/MS m/e obsd. (ESI+) [(M+H)+] 412.9.
Reaction SMILES: [C:1]1([NH:7][C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]1C=CC=CC=1.[OH-].[Na+].COS(OC)(=O)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:23][O:22][CH2:21][C:8]1([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: c1ccccc1
Reactant: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 32 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinemethanol in 90 parts of benzene are added 0.2 parts of N,N,N-triethylbenzenemethanaminium chloride and 150 parts of a sodium hydroxide solution 60%. After stirring vigourously, there are added dropwise 10.9 parts of dimethylsulfate at a temperature below 30° C. Upon completion, stirring is continued at room temperature, first for 2 h. 30 and further, after the addition of a second portion of 2.6 parts of dimethyl sulfate, for 1 h. 30. The reaction mixture is cooled in ice-water and 200 parts of water are added. The organic phase is separated and the aqueous phase is extracted with benzene. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 3% of methanol, saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 24.8 parts of 4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine as a residue.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:31][C:16]([F:15])([F:30])[C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:22][CH2:21]1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: O=CCCc1cc(-c2cccs2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN1CCN(CCCc2cc(-c3cccs3)no2)CC1
Yield: 60.2 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (10.0, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 17 hr and followed the same processes as in Example 1 to obtain 13.1 mg (62.7%) of the target compound.