Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]3([C:16]([CH2:18][OH:19])=[O:17])[O:11][C:12]([CH3:15])(C)[O:13][C@@H:9]3[CH2:8][C@H:7]1[C@@H:6]1[CH2:20][CH2:21][C:22]3[C@@:28]([CH3:29])([C@H:5]1[C@@H:4]([OH:30])[CH2:3]2)[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3.[CH:31](=O)[CH2:32]CC.F>O>[CH3:31][CH2:32][CH2:15][CH:12]1[O:11][C@:10]2([C:16]([CH2:18][OH:19])=[O:17])[C@@H:9]([CH2:8][C@@H:7]3[C@:2]2([CH3:1])[CH2:3][C@H:4]([OH:30])[C@H:5]2[C@H:6]3[CH2:20][CH2:21][C:22]3[C@:28]2([CH3:29])[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3)[O:13]1
Reactant: CCCC=O
Reactant: CC1(C)O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Agent: F
Solvent: O
Product: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 Grams of desonide (16α-hydroxyprednisolone-16,17-acetonide) and immediately thereafter 12,5 ml of butyraldehyde were added to 500 ml of a 70% hydrofluoric acid solution, at -5° C. The mixture was stirred at 0° C. for one hour and then poured into 5 liters of demineralized water at 0° C. The precipitate was filtered, washed to neutrality with water and dried under vacuum to give 51 g of pure budesonide with an A/B epimer ratio of 9/91.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])(=[O:33])[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[C:31]([NH:34][C:35]1[CH:36]=[C:37]([NH:38][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)[CH:39]=[CH:40][CH:41]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(Nc3cccc4c3ccn4C)n2)c1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (60 mg, 0.15 mmol) in NMP (0.6 mL) was added 3-acetamidoaniline (25 mg, 0.165 mmol) and pTsOH.H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (20 mg). MS found for C22H21N7O2 as (M+H)+ 416.3. λ=211.3, 250.9.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[NH:14][C:13]2=S)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][CH2:31][CH2:32][OH:33].[Cl-]>C1COCC1>[CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[NH:14][C:13]2=[N:30][CH2:31][CH2:32][OH:33])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2NC1=S
Reactant: NCCO
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2NC1=NCCO
Temperature: 55 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A mixture of 3-cyclohexyl-N-(2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide (162 mg, 0.4 mmol), 2-aminoethanol (96 μL, 98 mg, 1.6 mmol) and mereuric chloride (141 mg, 0.52 mmol) in THF (5 mL) was stirred at 55° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc/Hexane. The solid was collected and dried in vacuo to give 3-cyclohexyl-N-[2,3-dihydro-2-(2-hydroxyethylimino)-5-phenyl-1H-1,4-benzodiazepin-3-yl)propanamide as a solid (120 mg, 69%). A sample (90 mg, 0.2 mmol) was dissolved in dichloromethane (7 mL), cooled to 0° C. and methanesulfonyl chloride (19 μL, 28 mg, 2.4 mmol) and diisopropylethylamine (75 μl, 56 mg, 0.43 mmol) were added. The mixture was stirred at 0° C. for 30 min., then at room temperature for 2 h. The solvent was evaporated under reduced pressure, toluene was added and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (98:2) to give 3-cyclohexyl-N-{2,4-dihydro-6-phenyl-1H-imidazo[1,2-a][1,4]benzodiazepin-4-yl}propanamide as a solid (40 mg, 48%), m.p. 202°-208.5° C.
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.Cl>C(O)C>[ClH:1].[CH3:2][S:3][C:4]1[C:5]2[NH:10][C:17]3[CH2:18][CH2:19][NH:14][CH2:15][C:16]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCNCC1
Reactant: CSc1ccccc1NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 91.3 %

Procedure:
1-[2-(methylsulfanyl)phenyl]hydrazine hydrochloride (27 g, 141.9 mmol) and 4-piperidone monohydrate hydrochloride (21.8 g, 141.9 mmol) were dissolved in ethanol (350 mL) and heated at reflux for 45 minutes. Concentrated HCl (30 mL) was added and heated at reflux for 12 h. The reaction was cooled to room temperature, filtered, washed with cold isopropyl alcohol (50 mL), and dried to give an off white solid, 6-(methylsulfanyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (33 g, 92%). 1H NMR (CD3OD, 300 MHz) δ 7.24 (d, 1H, J=8.7 Hz), 7.08 (dd, 1H, J=0.7, 7.3 Hz), 6.93 (t, 1H, J=7.7 Hz), 3.29-3.27 (m, 2H), 3.17 (t, 2H, J=5.85 Hz), 2.85 (t, 2H, J=5.65 Hz), 2.44 (s, 3H) ppm.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH2:16]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
A mixture of 19.33 g (0.1 mole) of 2-phenylindole, 13.92 g (0.11 mole) of benzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O, 2.5 g (2.5 mmoles) of PEG-1000, and 100 mL of toluene was stirred and heated at 55°-60° for 24 hours. After cooling to room temperature, 100 mL of H2O was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed with 2N HCl (2×50 mL), H2O (2×50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 32.3 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was elut4d with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 18-20 were combined giving 3.74 g (13%) of 1-benzyl-2-phenylindole as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: OCCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: OCCc1cccc(Nc2nc(Nc3cccc(O)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
A solution of 2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethanol (0.10 g, 0.35 mmol) and 3-aminophenol (58 mg, 0.53 mmol) in 1,4-dioxane (3.5 mL) was treated with p-toluenesulfonic acid monohydrate (54 mg, 0.28 mmol) and heated at 100° C. for 1 h. The reaction mixture was treated with additional 3-aminophenol (19 mg, 0.18 mmol) and heated at 100° C. for 1 h. The reaction mixture was poured into 10% potassium carbonate (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude brown oil. This material was purified by flash column chromatography to give the desired product (0.12 g, 96%) as a light brown solid. LCMS for C18H18ClN4O2 (M+H)+: m/z=357.0.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:39](=[O:40])[CH2:38][CH2:37][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(C(=O)OCC)cc3)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)OCC)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using ethyl 4-({4-[(4-butylphenyl)ethynyl]benzyl}amino)benzoate and 3-cyclopentylpropanoyl chloride as a yellow oil (79%). 1H NMR (CDCl3, 300 MHz) δ 8.01 (d, J=8.3 Hz, 2H), 7.41 (m, 4H), 7.14 (m, 4H), 7.04 (d, J=8.3 Hz, 2H), 4.89 (s, 2H), 4.39 (q, J=6.8 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.09 (m, 2H), 1.80-1.25 (m, 16H), 1.00-0.88 (m, 5H). M+ (ESI): 536.9. HPLC, Rt: 6.58 min (Purity: 98.7%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].O.[NH2:30][NH2:31]>CO.CC1C=CC(S(O)(=O)=O)=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][C:3]([NH:30][NH2:31])=[O:2])[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: COC(=O)CCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2C(CCC(=O)NN)CCC2c2ccc(F)cc2)cc1
Yield: 83.3 %

Procedure:
To a stirred solution of (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester (1.5 g, 3.7 mmol) in MeOH (15 ml) was added hydrazine hydrate (0.54 ml, 11.1 mmol) and p-TsOH (10 mg) and the reaction mixture was heated under reflux conditions for 24 h. Evaporation and purification by column chromatography on silica gel (dichloromethane/MeOH 19:1) yielded (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid hydrazide (1.25 g, 83%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12].[OH:15][C:16]12[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[C:20]1([NH:29][C:30](=[O:32])[CH3:31])[C:19]1[CH:33]=[CH:34][C:35]([CH:37]([CH3:39])[CH3:38])=[CH:36][C:18]=1[O:17]2>C1COCC1>[C:8]([O:17][C:18]1[CH:36]=[C:35]([CH:37]([CH3:38])[CH3:39])[CH:34]=[CH:33][C:19]=1[C:20]1([NH:29][C:30](=[O:32])[CH3:31])[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]1=[O:15])(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(=O)Cl
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.1 %

Procedure:
Triethylamine (0.24 ml, 1.77 mmol) and Valeroyl chloride (0.18 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.20 g, 32%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][CH:44]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:42])[CH:31]=2)=[CH:22][CH:21]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:19][C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[C:43]2[CH:44]=[CH:45][C:46]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]3)=[CH:47][CH:48]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:42])[CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#CCN1CCC(CO)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCC(CO)CC3)cc2)cc1C
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, (1-propargylpiperidin-4-yl)methanol (122 mg, 0.8 mmol) and diisopropylamine (370 mg, 0.56 mmol) were added to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (220 mg, 0.4 mmol; prepared as described in example 7) in tetrahydrofuran (15 mL). Subsequently, bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) and copper(I) iodide (15 mg, 0.075 mmol) were added; the reaction mixture was degassed again and then stirred under inert atmosphere at ambient temperature over night. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a paddle of silica gel. The paddle was thoroughly washed with ethyl acetate (4×20 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform/methanol 95:5) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-[4-(hydroxymethyl)piperidin-1-yl]propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[I-].[Na+].[H-].[Na+].Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:41])[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>CN(C=O)C>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[S:10]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[CH2:28][CH2:29]2)=[O:41])=[CH:39][CH:38]=1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCl)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
In an atmosphere of argon, N-(2-methoxyphenyl)-p-toluenesulfonamide (277 mg, 1.0 mmol) and a catalytically effective amount of sodium iodide were dissolved in DMF (3 ml) to which was subsequently added sodium hydride (44 mg, 60%, 1.1 mmol) at room temperature. After stirring at the same temperature for 30 minutes and then at 60° C. for 10 minutes, 1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine (324 mg, 1.2 mmol) which has been divided into 3 portions, each being dissolved in DMF (1 ml), was added to the reaction solution at 1 hour intervals at 60° C. After 1.5 hours of additional stirring at the same temperature, DMF was removed by evaporation. The thus obtained residue was diluted with water (10 ml) and extracted with ether. The resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a silica gel column chromatography (ether:hexane=2:1) to obtain 467 mg (91.5%) of the title compound in the form of colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]([N:18]([CH3:20])[CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:21]([O-])=O)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]([N:18]([CH3:20])[CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:21])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cc(-c2cccc(Cl)c2)nc2ccc([N+](=O)[O-])cc12
Reactant: CNC
Product: CN(C)c1cccc(-c2cc(N(C)C)c3cc(N)ccc3n2)c1

Procedure:
The title compound was prepared from N-[2-(3-chlorophenyl)-6-nitro-4-quinolinyl]-N,N-dimethylamine by the procedure of step D2 of Method D using dimethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[O:7]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6](=[O:12])[O:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)[CH3:22]
Reactant: CCOC(=O)CCCCBr
Reactant: O=c1ccc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCOc1cccc2oc(=O)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2.25 g (18.6 mmol) of 5-hydroxycoumarin, 4.2 g (20 mmol) of ethyl 5-bromovalerate, 7.0 g (50 mmol) of anhydrous, granular potassium carbonate, and 10 mL of dimethyl sulfoxide was stirred at room temperature for 24 hr. The resulting slurry was filtered with suction and the solids washed well with ethyl acetate. The filtrate and washes were combined and poured into water and the mixture was worked-up with ethyl acetate in the usual manner. The semi-solid residue was triturated and washed with hexane giving 2.36 g (44%) of 5-[(2-oxo-2H-1-benzopyran-5-yl)oxy]pentanoic acid ethyl ester as a tan solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[BH3-]C#N.[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>CO>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:3]
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CNCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
A suspension of glycine ethyl ester hydrochloride (10.0 g, 71.6 mmol) and NaBH3CN (5.00 g, 79.6 mmol) in MeOH (60 mL) was treated dropwise over 15 min with p-anisaldehyde (11.0 mL, 90.4 mmol). After stirring at room temperature overnight, the solvent was removed in vacuo. The residue was partitioned between CH2Cl2 (200 mL) and saturated aqueous NaHCO3 (300 mL). The aqueous layer was extracted with CH2Cl2 (2×200 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 90:10 to 50:50) gave the title compound (7.77 g, 49%) as a colorless liquid: MS (ESI) m/e 224 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].CC(C)([O-])C.[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1cc(Br)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 12.4 g (0.053 mol) of 2-hydroxy-5-bromo-phenylacetic acid in 125 ml of dimethylformamide is combined with 14 g (0.125 mol) of potassium tert.butoxide. After 15 minutes at ambient temperature 18.5 g (0.108 mol) of benzylbromide are added. The reaction solution is stirred for 3 hours at ambient temperature, poured onto ice water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is dissolved in 100 ml of ethanol and after the addition of 50 ml of 2N sodium hydroxide solution stirred for 3 hours at ambient temperature. The solvent is distilled off, the residue is adjusted to pH 4 with 2N hydrochloric acid. After extraction with ethyl acetate the organic phases are dried and evaporated down. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (8:2).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2O[CH:19]=[N:20][N:21]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.FC(F)(F)C(O)=O>C(O)CCC>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:26]([CH:23]3[CH2:25][CH2:24]3)[CH:19]=[N:20][N:21]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=C(Nc1cccc(-c2nnco2)c1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)OCc1ccccc1
Temperature: 110 °C
Yield: 30.8 %

Procedure:
A mixture of (3-[1,3,4]Oxadiazol-2-yl-phenyl)-carbamic acid benzyl ester (200 mg, 0.68 mmol), cyclopropylamine (0.5 mL, 7.2 mmol), trifluoroacetic acid (0.05 mL, 0.65 mmol) in anhydrous 1-butanol mL) was heated at 110° C. overnight in a sealed tube. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. Solvent was removed after drying with sodium sulfate and purified by silica gel chromatography (rf=0.26 in 20:1 ethyl acetate/methanol) to obtain [3-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-phenyl]-carbamic acid benzyl ester as a white powder (70 mg, 31%). M+1=335.1
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][CH:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.N1C2C=CC=C(CO)[C:34]=2N=N1.C(O)(C)(C)C.[I-].[I-].[Sm+2]>C1C=CC=CC=1>[CH3:16][O:15][C:13](=[O:14])[CH2:12][CH:11]1[CH2:10][CH:9]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=2)[N:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([C:2]([F:29])([F:30])[F:1])=[CH:4][CH:5]=2)[CH2:34]1
Reactant: COC(=O)/C=C/CC(NCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: OCc1cccc2[nH]nnc12
Agent: [I-]
Agent: [Sm+2]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)CC1CC(c2ccc(C(F)(F)F)cc2)N(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
The amine from Step 4 (400 mg, 0.9 mmol) was dissolved in benzene and benzotriazolemethanol (135 mg, 0.9 mmol) was added followed by powdered molecular sieves (470 mg). This was stirred overnight, the molecular sieves removed by filtration through Celite and the filtrate concentrated in vacuo. The residue was dissolved in THF (25 mL) and anhydrous t-butanol (0.17 mL, 0.9 mmol) was added. This solution was added dropwise via cannula onto a solution of samarium diiodide (27 mL, 2.7 mmol, 0.1M in THF) which was pre-cooled to −78° C. The mixture was stirred (−78° C. 0° C.) overnight then quenched with aq. K2CO3 and extracted with ethyl acetate. The organic extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified on silica using 30-50% CH2Cl2 in iso-hexane to elute isomer a (245 mg) and isomer b (100 mg).