Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21][N:20]=2)[CH2:15][CH2:14]1)([O-])=O.C(N(CC)CC)C>C1COCC1.[Ni]>[S:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH2:1])[CH2:14][CH2:15]2)=[N:20]1
Reactant: O=[N+]([O-])c1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
3-{4-[3-(2-Nitro-phenyl)-propyl]-piperazin-1-yl}-1,2-benzoisothiazole (3.25 g, 8.5 mmol) was dissolved in 100 mL of THF treated with triethylamine (0.3 ml) and with wet Raney nickel (1.02 g). The resulting mixture was placed on a shaker type hydrogenator, purged with hydrogen, pressurized (29.8 psig) and shaken at room temperature for 16 hours. The resulting mixture was filtered to remove the catalyst then filtered a second time over celite before the filtrate was concentrated. The resultant solid was dried in vacuo (2.33 g, 6.61 mmol). Yield 78%; MS (APCI): 352 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.B.O1CCCC1>O1CCCC1.O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1=O
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@H]1O
Yield: 92.2 %

Procedure:
(S)-(−)-CBS-oxazaborolidine (1.0 M in tetrahydrofuran, 1.06 mL, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (53.1 mL, distilled from sodium/benzophenone ketyl). To this solution was simultaneously added a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(2-methyl-3-oxo-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 4 (2.18 g, 5.31 mmol) in anhydrous tetrahydrofuran (20 mL) via syringe pump (1.6 mL/min.) and borane-tetrahydrofuran (1.0 M in tetrahydrofuran, 3.19 mL, 3.19 mmol) at a rate such that enone addition was complete upon addition of approximately 2/3 of borane-tetrahydrofuran. Upon completion of borane-tetrahydrofuran addition, the reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide, 1N hydrochloric acid, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica, 50% ethyl acetate in hexane) to afford the title compound (2.02 g) as a white solid. Analytical HPLC (Chiralpak AD, 4.6×250 mm, 50% ethanol in hexane, 0.5 mL/min.) indicated an enantiomeric excess of 96.4%.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:26])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18]([OH:20])=O)[N:10]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:45]1([NH2:48])[CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([NH:48][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([C:14]3[C:13](=[O:26])[CH:12]=[CH:11][N:9]4[C:8]=3[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:2]=3[F:1])=[N:10]4)[CH:16]=2)[CH2:47][CH2:46]1
Reactant: COc1ccc(C(=O)O)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NC2CC2)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 1 in CH2Cl2 was added triethyl amine and ethylchloroformate at 0° C. The mixture was warmed to ambient temperature and stirred for 10 min. The reaction was complete by LCMS analysis and concentrated in vacuo to yield crude residue. To the crude residue was added CH2Cl2 and cyclopropyl amine, followed by stirring for ½ hr. LCMS indicated the reaction was complete. The reaction was diluted with CH2Cl2, washed with 0.5 N NaOH, H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2/MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:4]([N+:14]([O-])=O)[CH:3]=1.CCOC(C)=O.[Sn](Cl)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[C:4]([CH:3]=1)[NH2:14]
Reactant: O=[N+]([O-])c1cc(Br)ccc1N1CCOCC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: Nc1cc(Br)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(4-bromo-2-nitrophenyl)morpholine (13.2 g, 46 mmol) dissolved in EtOAc (200.00 mL, 2043 mmol) at rt was added all in one portion tin(II) chloride dehydrate (52 g, 230 mmol). An exotherm developed and the orange color faded to a faint yellow. The reaction was stirred at ambient temperature for 15 min then heated to reflux for 45 min. After 60 min TLC indicated no starting material remained and the reaction was equilibrated to rt. The reaction was washed with 200 mL 5N aq. Sodium hydroxide solution followed by 100 mL water and 50 mL brine. The organic separation was stirred over anhydrous magnesium sulfate, filtered and the filtrate concd under reduced pressure to afford a pale yellow solid. Mass Spectrum (ESI) m/e=257.0 & 259.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:23][C:24](=[O:41])[CH:25]([N:29](C(OCC2C=CC=CC=2)=O)[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:14](=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:23][C:24](=[O:41])[CH:25]([NH:29][CH3:30])[CH:26]([CH3:27])[CH3:28])[C:14](=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)C(C)C
Yield: 98.3 %

Procedure:
To a solution of 2-(N-benzyloxycarbonyl-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(2-pyridylcarbamoyl)ethylamide (1.74 g, 3.10 mmol) in methanol (50 ml), 10% palladium carbon (300 mg) was added and stirred in a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=5:0.1:100), giving the titled compound (1.30 g, 98%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[CH:2]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: CC(=O)Nc1cccc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc(C=O)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of N-(3-[1,3]Dioxolan-2-yl-phenyl)-acetamide (7.8 g, 0.037 mol) and pyridinium-p-toluenesulfonate (2.8 g, 0.011 mol) in acetone-water (4:1, 400 mL) was refluxed for 1 hr. The solution was then cooled to room temperature, and the bulk of the solvent (˜90%) removed under reduced pressure. The remaining solution was then extracted with EtOAc, and the combined extracts washed with saturated NaHCO3, brine, and dried with MgSO4. Evaporation of the solvent gave N-(3-Formyl-phenyl)-acetamide (5.98 g, 98%) as an orange oil. 1H NMR (CDCl3) δ 2.22 (s, 3H), 7.46 (t, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.89 (d, J=8 Hz, 1H), 8.07 (s, 1H), 8.69 (br s, 1H), 9.94 (s, 1H). 13C NMR (CDCl3) δ 193.9, 171.0, 140.8, 138.5, 131.2, 127.5, 127.1, 122.0, 26.0.
Reaction SMILES: Cl[CH:2]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[S:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3]([CH:2]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: ClC(c1csc2ccccc12)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(NC(c2csc3ccccc23)C2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a mixture of 3-[chloro(cyclohexyl)methyl]-1-benzothiophene (2.42 g) synthesized above, methyl 4-aminobenzoate (2.77 g), sodium iodide (2.74 g) and N,N-dimethylacetamide (50 mL) was added sodium carbonate (1.94 g), and the mixture was stirred under argon atmosphere at 100° C. overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3, volume ratio) to give a pale-yellow oil. To a mixture of the obtained oil, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred overnight with heating under reflux. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (40 mL), and 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (1.80 g, 54%) as a white solid.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][O:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH:15]12[CH2:16][NH:8][CH2:9][CH:10]1[NH:11][CH2:12][CH2:13][O:14]2
Reactant: c1ccc(CN2CC3NCCOC3C2)cc1
Agent: [Pd]
Solvent: CO
Product: C1COC2CNCC2N1

Procedure:
7.2 g (33 mmol) of 8-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane are hydrogenated in 400 ml of methanol with 2.5 g of palladium-on-active charcoal (10% of Pd) under 50 bar at 100° C. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:21][C:20]3[CH:19]=[N:18][N:17]([CH3:22])[C:16]=3[NH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH:37]=[O:38])[CH2:33][CH2:32]1)=[O:30].Cl>CO>[OH:38][CH2:37][CH:34]1[CH2:35][CH2:36][N:31]([C:29](=[O:30])[CH2:28][CH2:27][C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:21][C:20]4[CH:19]=[N:18][N:17]([CH3:22])[C:16]=4[NH:15][C:14]4[CH:23]=[CH:24][CH:25]=[CH:26][C:13]3=4)=[O:11])=[CH:9][C:4]=2[CH3:3])[CH2:32][CH2:33]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(C=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
Sodium borohydride (12 mg, 0.32 mmol) was added to a solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidine-4-carbaldehyde from Example E58.1 (74 mg, 0.15 mmol) in methanol (6 ml). The mixture was stirred for 1 h at room temperature, acidified with 1M HCl and concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was crystallised from chloroform and pet. ether to give a white powder identified as the title compound (28 mg, 38%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([N:16]1[C:25](=[O:26])[CH2:24][C:19]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:18][C:17]1=[O:27])[CH2:13][CH:14]=[CH2:15]>C(Cl)Cl>[O:9]1[CH2:15][CH:14]1[CH2:13][CH2:12][N:16]1[C:17](=[O:27])[CH2:18][C:19]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:24][C:25]1=[O:26]
Reactant: C=CCCN1C(=O)CC2(CCCC2)CC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CC2(CCCC2)CC(=O)N1CCC1CO1
Yield: 75 %

Procedure:
A solution of MCPBA (80%, 5.01 g, 1.13 equiv) in 50 mL of CH2Cl2 was added to a stirring solution of 8-(3-butenyl) -8-azaspiro[4.5]decane-7,9-dione (4.54 g, 1.00 equiv) in 0 mL of CH2Cl2. The resulting solution was stirred until TLC inspection indicated the absence of limiting reagent (δ15 h). The reaction was quenched with 40 mL of 2% Na2CO3 solution and transferred to a separatory funnel. The layers were separated and the organic phase was washed with 2% Na solution (3×20 mL). The combined aqueous layers were back-extracted with CH2Cl2 (40 mL). The combined organic layers were dried on anhydrous Na2SO4, filtered and the solvent removed in vacuo. Flash chromatography of the resulting residue in 25% EtOAc/hexane afforded the title compound (3.65 g, 75%) as a clear, viscous liquid.
Reaction SMILES: Br[C:2]1([F:20])[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH2:3]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].O>COCCOC>[F:20][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1Cc2ccccc2C1)C1=CCC(F)(Br)C=C1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(NC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2C1)c1ccc(F)cc1
Yield: 44.5 %

Procedure:
150 mg (0.45 mmoles) 4-bromo-N-indan-2-yl-4-fluoro-benzamide, 102 mg (0.54 mmoles) 3-trifluoromethylbenzeneboronic acid, 211 mg (0.67 mmoles) barium hydroxide octahydrate and 20 mg tetrakis-triphenylphosphine-palladium were suspended in 10 ml 1,2-dimethoxyethane and 10 ml water and heated to reflux for 7 h. Subsequently, the reaction mixture was evaporated to dryness, the residue taken up in methylenchloride and extracted twice with water. The oil remaining after evaporation of the organic phase was purified using prep. HPLC chromatography. (RP18, acetonitrile/water, 1% trifluoroacetic acid). 80 mg (45%) of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])=[C:9]([F:25])[CH:8]=1.[NH2:27][C:28]1[N:32]=[CH:31][NH:30][N:29]=1.C(N(CCCC)CCCC)CCC>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]2[C:20]([OH:21])=[N:27][C:28]3[N:29]([N:30]=[CH:31][N:32]=3)[C:15]=2[OH:16])=[C:9]([F:25])[CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(CCCCN(C)C)cc1F
Reactant: Nc1nc[nH]n1
Solvent: CCCCN(CCCC)CCCC
Product: CN(C)CCCCc1cc(F)c(-c2c(O)nc3ncnn3c2O)c(F)c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of diethyl 2-{4-[4-(dimethylamino)butyl]-2,6-difluorophenyl]malonate (1.0 g, 2.7 mmol), 3-amino-1,2,4-triazole (250 mg, 3.0 mmol), and tributylamine (0.71 mL, 3.0 mmol) is stirred under nitrogen atmosphere at 160° C. for 16 h and cooled to room temperature. The mixture is stirred with 20 ml of hexanes. The precipitates are collected by filtration, washed with hexanes to give 6-{4-[4-(dimethylamino)butyl]-2,6-difluorophenyl}[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diol as a white solid (795 mg). MS: m/z 362.1 (M−H).
Reaction SMILES: [C:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11][CH2:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)C1CCNCC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Temperature: 80 °C

Procedure:
A mixture of alpha-phenyl-4-piperidinemethanol (1.5 g, 7.8 mmol), 2-bromoethyl benzene (1.1 ml, 8.0 mmol) and potassium carbonate (1.1 g, 8.0 mmol) in dry DMF (20 ml) was heated at 80° C. over the weekend (60 h). The excess DMF was distilled off at reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was washed with H2O (3×100 ml), saturated aqueous NaCl (1×100 ml), dried (MgSO4), filtered and evaporated to give a pale yellow oil which eventually crystallized. After recrystallization from ethyl acetate-hexane, a white crystalline solid was obtained, mp 125°-128° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].O.Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>CC#N>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[C:9]([Cl:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cl)c1)OC
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(Cl)c1)OC
Temperature: 85 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
3-(3 Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (0.020 g, 0.077 mmol) was dissolved in CH3CN (3 mL) and 4-(3-bromo-propoxy)-biphenyl (Example 132, Step D), (0.025 g 0.085 mmol) and K2CO3 (0.032 g, 0.23 mmol) were added. The mixture was heated to 85° C. and stirred for 5 hours. After cooling, water (2 mL) was added. The mixture was extracted in EtOAc (3×10 mL), washed with H2O (2×5 mL) and brine (2×5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate 9:1) to produce 3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic acid ethyl ester (0.017 mg, 48%). 1H-NMR (200.15 MHz, CDCl3): δ 7.57–7.24 (m, 9H), 7.02–6.89 (m, 3H), 4.28–4.12 (m, 5H), 3.89 (dd, 1H, J=7.24, 5.62), 3.62 (t, 1H, J=6.44), 3.36 (s, 3H), 2.93 (dd, 2H, J=6.31, 2.42), 2.32 (qn, 2H, J=5.10), 1.25 (t, 3H, J=7.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]([CH2:22][C:23]([NH:25][NH2:26])=O)#[N:21]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][C:20]#[N:21])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: N#CCC(=O)NN
Solvent: CCCCO
Product: N#CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A mixture of 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione (5.72 g., 0.02 mole), cyanoacetic acid hydrazide (5.95 g., 0.06 mole) and n-butylalcohol (275 ml.) is refluxed for 7.5 hours with a slow stream of nitrogen bubbling through the mixture. The mixture is then concentrated in vacuo. The resulting residue is suspended in water and extracted with methylene chloride. The extract was dried and concentrated. The residue is chromatographed on silica gel (400 g.) with 2% methanol- 98% CHCl3. The product eluted from the column is crystallized from ethyl acetate-Skellysolve B hexanes to give 2.62 g. of 8-chloro-6-phenyl-4H-s-triazolo[4,3a][1,4]benzodiazepine-1-acetonitrile of melting point 198°-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[C:37]([NH2:41])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([NH:41][C:23](=[O:25])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)N
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NC(C)(C)C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with tert-butylamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[C:27]([F:43])[CH:26]=2)(C(OCC=C)=O)[C:12]([O:14]CC=C)=[O:13])=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH2:24][C:25]2[CH:26]=[C:27]([F:43])[C:28]([O:32][Si:33]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:40]([CH3:41])[CH3:42])=[C:29]([F:31])[CH:30]=2)[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C(CCc1ccc(C#N)cc1)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=CO
Product: CC(C)[Si](Oc1c(F)cc(CC(CCc2ccc(C#N)cc2)C(=O)O)cc1F)(C(C)C)C(C)C
Temperature: 100 °C

Procedure:
4720 mg (7.72 mmol) of diallyl 2-[2-(4-cyanophenyl)ethyl]-2-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)malonate, 34.6 mg (0.15 mmol) of palladium(II) acetate and 141.6 mg (0.54 mmol) of triphenylphosphine are stirred in 180 ml of dioxane under argon. Then a solution of 2576 mg (25.60 mmol) of triethylamine and 887.7 mg (19.29 mmol) of formic acid in 90 ml of dioxane is added dropwise, and the mixture is heated at 100° C. for 2 h. The cooled mixture is concentrated and the crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1→2:1→1:1). 3682 mg (97.9% of theory) of the title compound are obtained
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=3)[CH2:31][CH2:30][CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:40])([F:39])[F:41])[CH:36]=4)[CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccc(C(F)(F)F)cc32)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCCc2ccc(C(F)(F)F)cc21

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was subjected to preparative HPLC (66%). HPLC-MS m/z: 483.1 (M+1), Rt: 5.87 min.