Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:25]
Reactant: C[Si](C)(C)CCOCN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[Si](C)(C)CCOCN1CCNCC1=O

Procedure:
3-Oxo-4-(2-trimethylsilanyl-ethoxymethyl)-piperazine-1-carboxylic acid benzyl ester (3.00 g, 8.22 mmol) was dissolved in THF (30 ml) and MeOH (30 ml), and vigorously stirred on 20% Pd(OH)2/C under a hydrogen atmosphere (1 atm) for 14 h. After N2 was purged, Pd(OH)2/C was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH=95/5 to 90/10) to obtain the intended compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:22])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:22][C:4]1[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=[C:2]([S:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Sc4ccccc4)cc3c2C1
Temperature: 110 °C
Yield: 102.5 %

Procedure:
A mixture of tert-butyl 8-bromo-6-chloro-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (1.00 g, 2.58 mmol), benzenethiol (0.40 mL, 3.87 mmol), di-palladium-tris(dibenzylideneacetone) (118 mg, 0.13 mmol), N,N-diisopropylethylamine (0.9 mL, 5.16 mmol) and xantphos (149 mg, 0.26 mmol) were suspended in anhydrous dioxane (10 mL). The reaction flask was purged with argon and the mixture heated to 110° C. for 14 h. After cooling, the reaction mixture was diluted with dichloromethane and filtered through a celite bed. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-(phenylthio)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (1.10 g, 91%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.47-7.38 (m, 1H), 7.34 (d, J=1.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.26-7.25 (m, 2H), 7.24-7.19 (m, 2H), 4.50 (s, 2H), 3.86-3.79 (m, 2H), 2.92-2.87 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:17][CH2:18]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH2:17][CH2:18][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: OCCC1CCCCC1
Product: CC(=O)c1ccc(CCC2CCCCC2)cc1

Procedure:
This compound was synthesized from 4′-hydroxyacetophenone and 2-cyclohexylethanol according to general method 5 described earlier.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30]([CH3:31])=[O:41])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
{4-[3-(2-Methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 47 supra) (150 mg, 0.323 mmol) was dissolved in dichloromethane (20 mL), then m-CPBA (134 mg, 0.659 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 2 hours. The solvent was removed under reduced pressure and the solid was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 20:1) to afford {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 110 mg, 70.8%). LC-MS: [M+H]+ 472.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCCOc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(OCCCCCOc2ccc(N)cc2)cc1
Yield: 90 %

Procedure:
A mixture of 1,5-bis(4-nitrophenoxy)pentane (32.7 grams, 94.4 mmol; prepared as described in Part A of this Example) and Pd/C 10% (1.00 gram, obtained from Aldrich Chemical Co.) was stirred for 20 hours in tetrahydrofuran (400 milliliters) under 200 pounds per square inch of hydrogen gas. The mixture was then filtered over CELITE, and the solvent was removed by evaporation under reduced pressure. The resulting crude solid was recrystallized from ethanol to afford pure 1,5-bis(4-aminophenoxy)pentane (24.4 grams, 85.1 mmol, 90 percent yield) as small colorless crystals: mp 78–79° C.; IR (KBr) 3433, 3353, 3217, 2949, 2868, 1856, 1632, 1511, 1473, 1396, 1228, 1031, 1002, 825, 517 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.76 (d, 4H, 3J=8.8 Hz), 6.64 (d, 4H, 3J=8.8 Hz), 3.92 (td, 4H, 3J=6.4 Hz, 4J=1.4 Hz), 3.40 (s, 4H), 1.82 (q, 4H, 3J=6.8 Hz), 1.62 (q, 2H, 3J=6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 151.31, 140.06, 116.51, 115.78, 68.58, 29.32, 22.83; MS (FAB, 3-nitrobenzyl alcohol) m/e 286.7; Anal. Calcd for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.11; H, 8.22; N, 9.85.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[Mg].II.[N:13]([P:18](Cl)Cl)([CH2:16][CH3:17])[CH2:14][CH3:15]>CCOCC.C1COCC1>[CH2:14]([N:13]([P:18]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])[CH2:16][CH3:17])[CH3:15]
Reactant: Cc1ccc(Br)c(C)c1
Reactant: CCN(CC)P(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)P(c1ccc(C)cc1C)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.92 ml (21.61 mmol) of 4-bromo-1,3-dimethylbenzene in 3 ml of Et2O were added at 0° C. to a suspension of 0.5 g (20.56 mmol) of magnesium turnings in 7 ml of THF and 7 ml of Et2O and also a crystal of iodine. The mixture was heated to room temperature, stirred further overnight and slowly added dropwise at 0° C. to a solution of 1.5 ml (10.31 mmol) of Et2NPCl2 in 8 ml of THF. The mixture was heated to 5–10° C., stirred for a further 2 hours and the solvent was subsequently removed under reduced pressure. After adding 60 ml of hexane, the mixture was filtered through Celite under argon and the solvent was subsequently removed under reduced pressure. Yield: 1.37 g (59% of theory). 1H NMR (400 MHz, CDCl3) δ, 6.9 (m, 6H), 3.03 (m, 4H, CH2), 2.20 (s, 12H, CH3), 0.81 (t, 3J=7.0 Hz, 6H, CH3) 31P NMR (161.9 MHz, CDCl3) δ, 47.8.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:24]Br.O>CO>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH2:13][Br:24])[CH2:3]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12

Procedure:
To a flask containing a solution of 3α-hydroxy-5β-pregnan-20-one (5.15 g, 16.5 mmol)in methanol (100 mL) was added a solution of bromine (1.1 mL) in methanol (30 mL) dropwise in such a rate to maintain the brown color of the bromine until this color was persistent. Then water (200 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined extracts were dried over Na2SO4. Removal of the solvent resulted in the product as a foamy white solid (6.63 g). Other 21-bromo-pregnan-20-ones (3β-ethynyl-3α-hydroxy-21-bromo-5β-pregnan-20-one, 3β-methyl-3α-hydroxy-21-bromo-5α-pregnan-20-one and 3α-hydroxy-3β-trifluoromethyl-12-bromo-5β-19-norpregnan-20-one) were synthesized using the same method.
Reaction SMILES: [N:1]1([C:7](=[S:11])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:8]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[S:11])[C:9]#[N:10])=[CH:14][CH:15]=1
Reactant: N#CCC(=S)N1CCOCC1
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C(C#N)C(=S)N2CCOCC2)cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A solution of 3-morpholin-4-yl-3-thioxopropanenitrile (0.122 g, 0.72 mmol) and p-anisaldehyde (0.1 mL, 0.86 mmol) in 10% piperidine/ethanol (5.5 mL) was allowed to stir at 50° C. under nitrogen for 3.5 h. The reaction mixture was concentrated and the residue was diluted with 10% citric acid solution and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give 3-(4-methoxyphenyl)-2-(morpholin-4-ylcarbonothioyl)acrylonitrile. The crude product was a mixture of stereoisomers and was used directly in the next step. LCMS: (AA) ES+ 289.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2>O1CCCC1>[F:15][C:2]([F:1])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Solvent: C1CCOC1
Product: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-trifluoromethyl-1H-indole-5-carbonitrile (Intermediate 3, 0.16 g, 0.761 mmol) in tetrahydrofuran (5 ml) cooled in an ice-water bath, was treated with a 1M solution of borane tetrahydrofuran complex (3.05 ml, 3.05 mmol) dropwise via syringe. The reaction mixture was then left to stir under argon for 18 hrs while allowing it to warm to room temperature. The reaction mixture was then quenched with methanol (10 mL) and stirred at room temperature for 10 min. The reaction mixture was then poured onto a SCX cartridge (10 g) and washed well with methanol. The desired product was then eluted using 2M ammonia/methanol solution. Evaporation to dryness gave the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:17])[CH:5]=1.[N:19]([O-])=O.[Na+]>Cl.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH:17][NH2:19])[CH:5]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(NN)cc(-c2ccc(C)cn2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 174.9 %

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (1.0 g, 4 mmol) was suspended in 16 mL concentrated aqueous HCl, and the mixture was cooled to 0° C. A solution of sodium nitrite (0.30 g) in water (3 mL) was added, and the mixture was stirred at 0° C. for 45 minutes. A solution of SnCl2 hydrate (2.34 g) in 5 mL concentrated aqueous HCl was then added. The reaction mixture was stirred for one hour at room temperature, then filtered. The collected solid was washed with water and dried to give 1.80 g of 3-hydrazino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as a white powder.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17]I)[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][NH:22][CH3:23].C[O-].[Na+]>CN(C)C=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:22]([CH3:23])[CH3:21])[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCCN1CCN(N=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A stirred solution of 1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone (prepared as described in Example B, Part II) (7.0 g, 0.0189 mole), dimethylformamide (125 ml), and dimethylamine hydrochloride (6.15 g, 0.075 mole) is heated on a steam bath. Sodium methoxide (4.05 g, 0.075 mole) is added portionwise over approximately 2 hours while heating. After addition, heating is continued 2 hours, then the mixture is cooled to ambient temperature. The mixture is concentrated under reduced pressure to an oily residue. This residue is suspended in saturated NaHCO3 solution. (300 ml) and extracted with CH2Cl2 (3×100 ml). The CH2 Cl2 extract is washed with H2O (2×100 ml), then dried over MgSO4. The filtered solution is concentrated under reduced pressure to an oily-liquid residue, which is triturated in hexane (2×100 ml), decanted, then dried in vacuo, giving 4.6 g (0.016 mole) of 1-phenylmethyleneamino-3-[4-(dimethylamino)butyl]-2-imidazolidinone, as a solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1([CH3:29])[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=2OC)=[N:13]1.O>O1CCCC1>[CH3:26][O:25][C:19]1[C:18]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:17]([C:14]2[O:15][CH2:16][C:12]([CH3:11])([CH3:29])[N:13]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1OC
Reactant: Br[Mg]CCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)(C)CO2)c(CCc2ccccc2)c1OC
Reaction time: 16 h

Procedure:
A solution of phenylethyl magnesium bromide (1M in tetrahydrofuran (40 ml) was added to a stirred solution of 4,5-dihydro 4,4-dimethyl-2-(2,3,4-trimethoxyphenyl)oxazole (5.3 g 0.02M) in dry tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred at 20° for 16 hours. Water (200 ml) was added and the aqueous phase thoroughly extracted with diethyl ether (3×200 ml). The organic solution was dried over magnesium sulphate, filtered and evaporated to leave an oil which was purified by column chromatography on SiO2 eluting with ether/petroleum ether (50/50) to give a colourless oil (6.2 g); MS m/e 339.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:4][N:3]=1>COCCN>[CH3:36][O:35][CH2:34][CH2:33][NH:32][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[CH2:16][N:15]([C:30]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccnc(Cl)c3)no2)C1
Agent: COCCN
Product: COCCNc1cc(-c2noc(C3CC(c4ccc(OC(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)ccn1

Procedure:
69 mg (0.13 mmol) of 4-({3-[3-(2-chloropyridin-4-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)phenyl]piperidin-1-yl}carbonyl)morpholine (Example 88) were reacted in 1.2 ml of 2-methoxyethylamine according to the General Method 3. Yield: 31 mg (43% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=[O:13])=[CH:6]2.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])=[CH:6]2
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Reactant: Br[Mg]c1ccccc1
Product: COc1ccc2[nH]c(C(=O)c3ccccc3)cc2c1
Yield: 91 %

Procedure:
Reaction of 5-methoxy-1H-indole-2-carbaldehyde with phenylmagnesium bromide using the procedure described in example 404 gave (805) (91%), mp 159–161° C. 1H NMR δ [(CD3)2SO] 11.86 (s, 1H), 7.94–7.91 (m, 2H), 7.71–7.66 (m, 1H), 7.61–7.57 (m, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.03 (s, 1H), 6.99 (dd, J=8.9, 2.4 Hz, 1H), 3.77 (s, 3H). Found: C, 76.28; H, 5.21; N, 5.42. C16H13NO2 requires: C, 76.48; H, 5.21; N, 5.57.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl.[N:26]([O-])=[O:27].[Na+]>O.C(OCC)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([N:26]=[O:27])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(OCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=NN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 82.8 %

Procedure:
To a solution of 1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]piperazine (1 g) in 1N-hydrochloric acid (3 ml) was added 1N-hydrochloric acid in order to adjust pH to 4. The mixture was stirred at 70°-75° C. and therein a solution of sodium nitrite (0.31 g) in water (0.5 ml) was added dropwise. The mixture was stirred at 70°-75° C. for one hour, cooled, and diluted with a mixture of diethyl ether and aqueous sodium bicarbonate solution. The organic layer was washed withbrine, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with chloroform to yield 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-nitrosopiperazine (0.9 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][C@H:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32][OH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:33][CH2:32][C@H:31]([NH:30][C:27]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[C@H:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]1)=[O:29])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)C[C@@H](N)CO
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](CO)NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d, (R)-2-amino-4-methyl-pentan-1-ol (35.16 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethyl-3-methyl-butyl)-amide (26.2 mg, 24.7%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([NH:1][CH:2]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:33])=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (311 mg, 1.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg, 2.43 mmol) and 1-hydroxy-1H-benzotriazole (250 mg, 1.64 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted-with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (558 mg, 76%).
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]2=[O:19])=[CH:6][CH:5]=1.IC.[CH3:22]COC(C)=O>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C:12]([CH3:22])([C:15]([O:17][CH3:18])=[O:16])[C:11]2=[O:19])=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
LiH (13.8 mg, 1.737 mmol) was added to the solution of methyl 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylate (0.206 g, 0.868 mmol) in DMF (5 mL) at 0° C. After 30 minutes stirring, iodomethane (0.16 mL, 2.61 mmol) was added to the reaction mixture at 0° C., and then the reaction was warmed to room temperature. The reaction mixture was stirred for 17 hours and heated at 40° C. for 3 hours. After cooling to room temperature, the mixture was treated with EtOAc, quenched with ice water, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to give the crude material that was purified by silica gel flash column chromatography (19:1=CH2Cl2:EtOAc) to afford 0.149 g (68%) of the desired product. LRMS (ESI pos) m/e 252.1 (M+1). 1H-NMR (400 MHz, CDCl3) δ 7.61 (m, 2H), 7.07 (m, 2H), 3.94 (m, 1H), 3.78 (m, 1H), 3.75 (s, 3H), 2.68 (m, 1H), 2.06 (m, 1H), 1.55 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −117.6.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12]Br>>[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: CC(C)=CCBr
Reactant: Oc1ccccc1S
Product: CC(C)=CCSc1ccccc1O
Yield: 99 %

Procedure:
This compound was prepared in 99% yield from 2-mercaptophenol and 3-methyl-2-butenylbromide according to the general procedure for 16p in Example VII. Colorless Oil; 1H NMR (CDCl3): δ 1.29 (s, 3H), 1.66 (s, 3H), 3.30 (d, J=8.00 Hz, 2H), 5.21-5.26 (m, 1H), 6.82 (s, 1H), 6.84 (dt, J=1.35 Hz, J=7.40 Hz, 1H), 6.96 (dd, J=1.10 Hz, J=8.25 Hz, 1H), 7.26 (dt, J=1.65 Hz, J=7.70 Hz, 1H), 7.43 (dd, J=1.95 Hz, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 17.25, 25.70, 34.79, 114.56, 118.66, 119.14, 120.53, 131.31, 136.87, 137.25, 157.44; HRMS (FAB): 194.07654 calcd for C11H14OS [M]+ 194.0771 (2.9 ppm, 0.6 mmu).