Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:3]=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]3([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccccc2)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)n2)cc1
Temperature: 120 °C
Yield: 42.8 %

Procedure:
tert-butyl 4-(((6-chloro-4-(trifluoromethyl)pyridine-2yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100.0 mg, 0.21 mmol); 4-methoxyphenyl boronic acid (128.0 mg, 0.84 mmol), and tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.04 mmol) were combined in dry tetrahydrofuran (3 mL) in a sealed tube. The mixture was flushed with nitrogen then 0.75 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:2, 3 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. Concentration and preparative HPLC afforded 41.0 mg (34%) of the desired compound as its TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 7.99 (d, 2H, J=8.0 Hz), 7.86 (s, 1H), 7.31-7.49 (m, 5H), 7.24 (s, 1H), 7.01 (d, 2H, J=8.0 Hz), 4.61 (s, 2H), 3.84 (s, 3H), 3.34 (s, 2H), 3.32-3.60 (m, 2H), 2.85-2.97 (m, 2H), 2.53-2.57 (m, 2H), 2.20-2.26 (m, 2H). Mass spec.: 457.18 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([NH2:22])[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.ON1C2C=CC=CC=2N=N1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][CH2:11][C:12]2[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COc1ccc(CN)cc1OC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2ccc(Br)nc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a mixture consisting of 6-bromonicotinic acid (Sigma-Aldrich, 1.5 g), N,N-dicyclohexylcarbodiimide (1.60 g), and dichloromethane (10 mL) was added a solution consisting of veratrylamine (1.24 g) in dichloromethane (10 mL) followed by addition of 1-hydroxybenzotriazole (100 mg). The reaction mixture was stirred overnight at room temperature. The crude reaction mixture was diluted with added dichloromethane (200 mL) and the diluted mixture was washed twice with water (2×100 mL) and once with brine solution (100 mL). The organic phase was subsequently dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a white solid. The product was triturated in ethyl acetate and collected by filtration to afford the title intermediate as a white solid (2.22 g, 85% yield); Rf 0.35 with 3:2 v/v hexanes-ethyl acetate; MS (ESI−) m/z 349, 351.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][O:27][CH2:26]4)[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O>C1COCC1.CO>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][O:27][CH2:26]4)[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCOC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCOC2)c1
Yield: 97.1 %

Procedure:
Methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (3.75 g, 8.68 mmol) was dissolved in THF (40 mL), 1N sodium hydroxide (8.68 mL, 8.68 mmol) was added followed by water (40 mL) and methanol (1 drop) and the resultant solution stirred at RT for 3 hours. The organics were removed in vacuo, the aqueous solution filtered and extracted with ethyl acetate (30 mL). The aqueous layer was acidified with 2N hydrochloric acid, extracted with ethyl acetate (3×50 mL), and the organic extracts washed with water (10 mL), brine (10 mL) then evaporated to dryness to give the desired material as a white foam (3.53 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.CCOCC>CS(C)=O>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH2:15][C:1]#[N:2])[CH:17]=[CH:18][CH:19]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: ClCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cccc(OCc2ccccc2)c1

Procedure:
A solution of sodium cyanide (5.9 g.) in dimethyl sulphoxide (40 ml.) was treated with 3-benzyloxybenzyl chloride (23.2 g.) and the reaction mixture stirred and maintained at 60° for 1 hour. The mixture was poured into water and the product was isolated with ether in the usual manner to give 3-benzyloxyphenylacetonitrile, b.p. 162°-166°/0.55 mm.
Reaction SMILES: CC1C=CC=C(C#CC=C2CCN(C3C=CC=CC=3)CC2)N=1.[F:23][C:24]1[CH:25]=[C:26]([C:31]#[C:32][CH2:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:27]=[C:28]([F:30])[CH:29]=1.Br[C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[C:43]#[N:44]>>[F:23][C:24]1[CH:25]=[C:26]([C:31]#[C:32][CH2:33][CH:34]2[CH2:35][CH2:36][N:37]([C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=3[C:43]#[N:44])[CH2:38][CH2:39]2)[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: N#Cc1ccccc1Br
Reactant: Fc1cc(F)cc(C#CCC2CCNCC2)c1
Agent: Cc1cccc(C#CC=C2CCN(c3ccccc3)CC2)n1
Product: N#Cc1ccccc1N1CCC(CC#Cc2cc(F)cc(F)c2)CC1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 42, but using Compound 248a instead of the Compound of Example 3 and 2-bromobenzonitrile instead of bromobenzene. The crude was purified by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient, affording the title product as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=O)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16][CH3:17])=[CH:10][CH:9]=3.[Cl-].[OH:20][NH3+:21].C(OCC)(=O)C>C(O)C.O>[OH:20][N:21]=[C:7]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=O
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NO
Temperature: 0 °C
Yield: 85.4 %

Procedure:
4.7 g (0.0195 mol) of 3,6-dimethoxyfluoren-9-one and 2.7 g (0.039 mol) of hydroxylammonium chloride are heated at 90° C. in a mixture of 50 ml of ethanol and 20 ml of water. After five hours the solution is poured into ice/water and ethyl acetate is added. The resulting suspension is filtered and the product that has been filtered off is washed with water and dried in vacuo. 4.25 g (86%) of 9-hydroxyimino-3,6-dimethoxyfluorene are obtained in the form of a yellow solid having a melting point of 230-240° C. According to 1H-NMR, that crude product still contains amounts of 3,6-dimethoxyfluoren-9-one. The crude product is, however, used in the subsequent step without being further purified and 3,6-dimethoxyfluoren-9-one is not removed until the end product is purified. Elemental analysis: C15H13NO3 (255.27)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-chlorobenzoic acid (1.00 g, 4.25 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[C:8]([C:12]1[CH:13]=[C:14]([OH:18])C=[CH:16][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].C1N2CN3CN(C2)CN1C3>O>[C:8]([C:12]1[CH:13]=[C:14]([OH:18])[C:2](=[CH:16][CH:17]=1)[CH:3]=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 80 °C
Yield: 56 %

Procedure:
A five liter three-neck round bottom flask equipped with overhead mechanical stirrer and condenser was charged with trifluoroacetic acid (2.4 L). A mixture of 3-tert-butylphenol (412 g, 2.8 mole) and HMTA (424 g, 3.0 mole) was added portion-wise causing an exotherm. With cooling, the temperature was maintained under 80° C. The reaction was heated at 80° C. for one hour, then cooled, and water (2 L) added. After 0.5 hour additional water (4 L) was added and the mixture was extracted with ethyl acetate (6 L). The organic extract was washed with water and brine. The resulting organic phase was divided into 2 L volumes and each diluted with water (1 L), and solid NaHCO3 added until the mixture was neutralized. The organic phases were isolated and combined, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. This oil was distilled at 95° C. (0.8 mm) yielding the desired salicylaldehyde as an oil (272.9 g, 56%) which was of sufficient purity to be used without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH:21][NH2:22]>C(O)CCC>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[C:12](=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:21]([CH3:20])[N:22]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: CNN
Solvent: CCCCO
Product: CC(=O)N1CCC(c2nn(C)c3cc(F)ccc23)CC1
Yield: 108.7 %

Procedure:
A solution of 5.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine, 1.2 g of methylhydrazine and 50 ml of n-butanol was heated under reflux for 16 hrs. After cooling, the solvent was removed in vacuo and the residue was diluted with water. The aqueous mixture was made basic with ammonium hydroxide and extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to yield 5.6 g of 3-(1-acetyl-4-piperidinyl)-6-fluoro-1-methyl-1H-indazole as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:24]=[CH2:25].[OH-].[K+]>CN1C(=O)CCC1>[F:27][C:17]([F:16])([F:26])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH2:24][CH2:25][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnccc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnccc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C1(C)C=CC=CC=1.O>[CH2:25]([O:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1)OCc1ccccc1
Reaction time: 2 h

Procedure:
8 g of 1-[4-aminobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine are dissolved in 200 ml of dioxane. 8.7 g of chloroformic acid benzyl ester in the form of a 50% solution in toluene are added dropwise thereto at 15°. After 2 hours at room temperature, the reaction mixture is diluted with water, dioxane is distilled off and the aqueous phase is rendered alkaline with 2N sodium hydroxide solution and extracted by shaking with ethyl acetate. The oil obtained from the ethyl acetate is crystallised from alcohol and ether, yielding 1-[4-(N-benzyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 149°-150°.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH:34]=O)=[CH:28]3)[CH2:21][CH2:20][CH2:19][CH2:18]1.N1CCCCC1>C(O)C>[C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[CH:34][C:29]4[NH:30][C:31]5[C:27]([CH:28]=4)=[CH:26][C:25]([O:24][CH2:23][CH2:22][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:33][CH:32]=5)[C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 72.3 %

Procedure:
A mixture of 6-phenyl-2-oxindole (41 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (72%) of the title compound as a red solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][CH2:10][O:11][C:12]([CH2:14]P(OCC)(OCC)=O)=[O:13].[H-].[Na+]>C1C=CC=CC=1>[CH2:10]([O:11][C:12](=[O:13])[CH2:14][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH3:9]
Reactant: CN1CCC(=O)CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCN(C)CC1

Procedure:
2-(1-Methyl-piperid-4-yl)-ethanoic acid ethyl ester is prepared from 1-methyl-piperid4-one (1 equiv), triethyl phosphono acetate (1 equiv) and NaH (1.1 equiv) in benzene followed by reduction of the alkene bond according to the procedure of Cignarella etc. (J Heterocyclic Chem 1993, 30 (5), 1337-1340).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:34](=[CH:35][CH:36]=3)[CH2:33][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:32])[CH2:22]4)=[O:17])[C:13](=[O:37])[C:12]([CH3:39])([CH3:38])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:40]OS([O-])=O.[K+].O>CO>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:34](=[CH:35][CH:36]=3)[CH2:33][C@:23]3([C:31]5[C:26](=[N+:27]([O-:40])[CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:32])[CH2:22]4)=[O:17])[C:13](=[O:37])[C:12]([CH3:39])([CH3:38])[CH2:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3c2ccc[n+]3[O-])C1=O

Procedure:
A mixture of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (20.0 mg, 0.038 mmol, described in Example 49) and Oxone® (70.0 mg, 0.113 mmol) in MeOH (0.5 mL) and water (0.5 mL) was stirred at ambient temperature for 3 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].[CH3:30]I>>[CH3:30][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:12]1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Br:1])=[C:3]([O:26][CH2:27][C:28]#[N:29])[CH:4]=[CH:5]2
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)[nH]c2ccccc12
Reactant: CI
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)n(C)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.111 g, 69%) from {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using MeI and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.73 (t, J=7.4 Hz, 3H), 1.08-1.26 (m, 4H), 1.47-1.62 (m, 2H), 2.69 (t, J=8.2 Hz, 2H), 3.61 (s, 3H), 5.48 (s, 2H), 7.09 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.68-7.80 (m, 2H), 8.08 (s, 1H), 8.22 (d, J=8.9 Hz, 1H), 8.27 (d, J=8.9 Hz, 1H); mass spectrum [(+) ESI], m/z 461/463 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][CH2:6]O.CS(Cl)(=O)=O.O.[N:18]1C=CC=C[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][CH2:6][NH:18][CH3:19]
Reactant: OCCc1ccc(Cl)c(Cl)c1
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Product: CNCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A portion (1 g, 5.23 mmol) of the 3,4-dichlorophenethyl alcohol produced in (1) above was dissolved in pyridine (10 ml) and methanesulfonyl chloride (0.61 ml, 7.85 mmol) was slowly added dropwise, followed by stirring at room temperature for 1 h and pouring into water. The mixture was subjected to extraction with ethyl acetate and concentrated under vacuum; the residue was dissolved in 50 ml of a solution of 40% methylamine in methanol and the solution was stirred overnight at room temperature, followed by concentration under vacuum. The residue was subjected to column chromatography using a 9:1 solvent system of chloroform and methanol as an eluent to yield the end compound 3,4-dichlorophenethyl-N-methylamine (0.76 g).
Reaction SMILES: O[CH2:2][C@H:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)=[CH:23][C:22]=1[C:37]([F:40])([F:39])[F:38])#[N:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(N(C)C)=O.CCOC(C)=O>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:2][C@@H:3]3[CH2:4][N:5]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:6][CH2:7][N:8]3[C:28]2=[O:29])=[CH:23][C:22]=1[C:37]([F:38])([F:39])[F:40])#[N:20]
Reactant: N#Cc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCN[C@H](CO)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(N2C[C@@H]3CN(C(=O)OCc4ccccc4)CCN3C2=O)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
To (S)-benzyl 3-(hydroxymethyl)piperazine-1-carboxylate (256 mg, 1.02 mmol) in DMA (1 mL) was added phenyl 4-cyano-3-(trifluoromethyl)phenylcarbamate (250 mg, 0.82 mmol), and the mixture was heated to 40° C. for 5 h. The reaction was cooled to RT, and PPh3 (321 mg, 1.22 mmol) followed by DIAD (241 μL, 1.22 mmol) were added to the reaction. After stirring for 15 min at RT, the reaction was diluted with EtOAc (20 mL) and washed twice with 0.5 N NaOH (10 mL), then twice with sat'd brine (10 mL). The EtOAc was dried over MgSO4 then concentrated in vacuo. The residue was taken up in CH2Cl2 (5 mL) and cooled to −10° C., and Et2O (5 mL) was added. The resulting precipitate was collected by filtration and rinsed with cold 1:1 Et2O:CH2Cl2 to give Example 1, (R)-benzyl 2-(4-cyano-3-(trifluoromethyl)phenyl)-3-oxo-hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate 187 mg (52%). HPLC RT: 3.253 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm). (M+H)+:445.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4](=[O:14])[O:5]C(C1C=CC=CC=1)=O.[H][H].N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CCSC.CN1CCOCC1.ClC(OCC(C)C)=O>CO.Cl.[Pd].[C].C1COCC1.CN(C=O)C>[NH2:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4](=[O:5])[OH:14]
Reactant: [H][H]
Reactant: NC(=O)[C@H](CC(=O)OC(=O)c1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: CC(C)COC(=O)Cl
Agent: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)[C@@H](N)CC(=O)O
Temperature: -20 °C

Procedure:
12.47 g (0.035 mole) of Z-Asp(OBz)-NH2 (m.p. 118°-120° C. [α]D24 -2.6° (C=1, methanol). Anal. Calcd. (%) for C19H20N2O5 : C, 64.04; H, 5.66; N, 7.86. Found (%): C, 64.04, H, 5.73, N, 7.73) was dissolved in a mixture of 300 ml of methanol and 35 ml of 1N HCl and subjected to contact reduction with hydrogen (at room temperature for 6 hours) in the presence of 1.75 g of a 10% Pd-carbon catalyst. The catalyst was then filtered off, the solvent was distilled off, and the residue was dried in vacuo. On the other hand, 9.36 g (0.035 mole) of Boc-Met-OH wa dissolved in 50 ml of THF, the solution was cooled to -20° C., and 3.85 ml of N-methylmorpholine and 4.62 ml of isobutyl chloroformate were added. The resulting mixed anhydride was admixed with a solution of the above obtained H-Asp-NH2 in 50 ml of DMF (containing 4.90 ml of triethylamine). The mixture was stirred at 0° C. for 10 minutes, at 40° C. for 1 minute, and at room temperature for 20 minutes. The reaction mixture was treated in the same manner as in (1) of Example 1, giving 8.30 g of Boc-Met-Asp-NH2 ; yield 65.2%, m.p. 226°-229° C.