Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[O:30][CH2:31][CH2:32]Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:16]=3[O:30][CH2:31][CH2:32]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccccc3)cc2OCCCl)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCOc3cc(S(=O)(=O)c4ccccc4)ccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a solution of 4-[4-benzenesulfonyl-2-(2-chloro-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.175 g, 0.354 mmol) in 0.500 mL anhydrous DMF was added sodium iodide (2.0 mg, cat) followed by sodium hydride (17 mg. of a 60% dispersion in mineral oil, 0.424 mmol) in 3 portions. The reaction mixture was stirred at room temperature for 2 hours, added to 50 mL water, and then extracted twice with 50 mL ethyl acetate. The organic fraction was washed with 50 mL brine, dried over sodium sulfate, then concentrated in vacuo. The resulting crude oil was purified by flash chromatography (10%-40% ethyl acetate in hexanes) to give 0.111 g (0.242 mmol, 68%) of 4-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.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>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1Cl
Reaction time: 3 h

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (15 g, 57.9 mmol) in toluene (120 mL) and water (30 mL) under nitrogen was added 2-chlorophenylboronic acid (19.9 g, 127.4 mmol), followed by potassium carbonate (16 g, 115.8 mmol) and Pd(PPh3)4 (3.34 g, 2.8 mmol). After 3 hours at 100° C., the reaction mixture was diluted with EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), water (2×100 mL) and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, pet ether/EtOAc) to afford of the title compound as a pale yellow oil. LC/MS, M+(ESI): 291.0. 1H NMR (CDCl3, 400 MHz) δ 8.21 (1H, s), 8.01 (1H, d), 7.48 (1H, m), 7.34 (2H, m), 7.26 (2H, m), 4.33 (1H, dd), 4.20 (1H, dd), 3.94 (3H, s), 3.27 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]2[OH:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCCC[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCC[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of (1S,2R)-2-(hydroxymethyl)cyclohexanol (0.44 g, 3.85 mmol) and N,N-dimethylaminopyridine (DMAP) (0.485 g, 3.97 mmol) in anhydrous CH2Cl2 (10 mL) was added a solution of p-toluenesulfonyl chloride (0.767 g, 4.02 mmol) in anhydrous CH2Cl2 (5 mL) under argon at room temperature. The reaction mixture was stirred at room temperature for 22 hrs and triethylamine (0.5 mL) was added. The mixture was stirred for additional 100 min, concentrated under reduced pressure, water was added and the product was extracted with EtOAc twice. Combined organic layers were washed with brine, concentrated under reduced pressure and purified by flash chromatography (20% to 70% EtOAc/hexanes gradient) to give ((1R,2S)-2-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield (0.732 g, 71%). 1H NMR (400 MHz, DMSO-d6) δ 7.72-7.76 (m, 2H), 7.42-7.47 (m, 2H), 4.60 (d, J=5.5 Hz, 1H), 4.12 (dd, J=3.1, 9.2 Hz, 1H), 3.90 (dd, J=7.2, 9.2 Hz, 1H), 3.00-3.10 (m, 1H), 2.40 (s, 3H), 1.73-1.80 (m, 1H), 1.46-1.65 (m, 3H), 1.34-1.42 (m, 1H), 0.85-1.16 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-:30].[Ca+2].[OH-:32]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:32])(=[O:30])[C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2
Reaction time: 24 h

Procedure:
400 Mg. 8-chloro-3-cyanodibenzo[b,f]-thiepin is dissolved in 30 cc. chloroform and 2 g. m-chloroperbenzoic acid added, and the solution stirred for 24 hours. 5 G. calcium hydroxide is added, the mixture stirred for five minutes and filtered through celite. The organic filtrate is evaporated to dryness and the residue chromatographed on silica gel and eluted with 5% ethyl acetate/benzene mixture to yield 339 mg. (76%) pure sulfone, m.p. 228°-230° C.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[CH2:17](O)C>[Pd]>[NH2:8][C:5]1[C:4]([CH3:17])=[C:3]([S:11]([N:14]([CH3:15])[CH3:16])(=[O:12])=[O:13])[CH:2]=[CH:7][CH:6]=1
Reactant: CCO
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Agent: [Pd]
Product: Cc1c(N)cccc1S(=O)(=O)N(C)C
Reaction time: 16 h
Yield: 98 %

Procedure:
A suspension of 2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (2.0 g, 8.20 mmol) and Pd/C (0.30 g) in ethanol (40 mL) was stirred under an H2 balloon for 16 h. The suspension was filtered through Celite and washed with methylene chloride. The filtrate was concentrated to provide 3-amino-2-methyl(N,N-dimethyl) benzenesulfonamide (1.72 g, 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][NH:36][CH3:37])[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][N:36]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH3:37])[CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CNCCc1cccc(OCc2ccccc2)c1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Product: CN(CCc1cccc(OCc2ccccc2)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and 1-[3-(benzyloxy)phenyl]-2-(methylamino)ethane was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a pale yellow crystal having a melting point of 78 to 78.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]([C:9]#[CH:10])[CH3:8].O1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([Li])CCC.BrCC1CC1>CCOCC.O.CN(C)P(=O)(N(C)C)N(C)C>[CH:14]1([CH2:15][C:10]#[C:9][CH:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:8])[CH2:12][CH2:13]1
Reactant: C#CC(C)C1CCCCO1
Reactant: C1CCOC1
Agent: BrCC1CC1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C#CCC1CC1)C1CCCCO1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-tetrahydropyranyl-but-3-yne (1.14 parts) in 15 parts by volume of tetrahydrofuran are cooled to -20° C. and 4.63 parts by volume of 1.6N n-butyl lithium are added. The reaction mixture is allowed to warm to 0° C. and again cooled to -20° C. and then 1 part of bromomethylcyclopropane in 3 parts by volume of tetrahydrofuran are added. The reaction mixture is allowed to warm to room temperature and 15 parts by volume of hexamethylphosphoric triamide is added and the reaction is stirred over three hours. The reaction mixture is poured into ether/water and extracted several times with ethyl acetate. The extracts are washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed by evaporation at reduced pressure and the residual oil is chromotographed with 10% ethyl acetate/hexane to provide 5-cyclopropyl-2-tetrahydropyranyl-pent-3-yne. This material is dissolved in a solution of 25 parts by volume of tetrahydrofuran, 25 parts by volume methanol, and 25 parts by volume of 1N HCl and stirred at room temperature for 1 hour. The reaction mixture is poured into a mixture of ether and water. The aqueous layer is extracted with ethyl acetate and the extracts are combined and washed with water and saturated sodium chloride. The organic layer is dried over anhydrous sodium sulfate and chromatographed with 15% ethyl acetate/hexane to provide 5-cyclopropyl-pent-3-yne-2-ol. 1.5 parts of this alcohol is reacted with 3.25 parts of pyridinium chlorochromate in 35 parts by volume of methylene chloride. The reaction mixture is stirred for three hours at room temperature, 100 parts by volume of ether is added and the mixture is stirred for 1 hour then filtered through Florisil. The solvent is removed by evaporation at reduced pressure. The residue is dissolved in hexane and again filtered. The solvent is evaporated under reduced pressure to provide 5-cyclopropyl pent-3-yne-2-one.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCN1Cc1ccccc1
Product: O=C1C(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
Prepare by the method of Example 17.2 using 1-benzyl-2-oxopyrrolidine and benzyl bromide to give the title compound: Rf=0.46 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: C1C=CC=CC=1.[NH2:7][CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][C:29]([CH3:31])=O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>O>[Cl:17][C:13]1[CH:12]=[C:11]([C@@H:9]([OH:10])[CH2:8][NH:7][C@H:29]([CH3:31])[CH2:28][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: NC[C@H](O)c1cccc(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2cccc(Cl)c2)cc1OC
Reaction time: 24 h
Yield: 81 %

Procedure:
To 40 ml benzene solution of (R)-2-amino-1-(3-chlorophenyl)ethanol (0.304 g), was added 0.344 g of methyl 3,4-dimethoxyphenylmethyl ketone. The mixture was refluxed in an apparatus equipped with a water-trap for one hour and the water produced was removed from the reaction system. After cooling the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was dissolved into 10 ml of methanol. To the mixture was added platinum oxide, and the reducing reaction was conducted at room temperature at 1 atm pressure under hydrogen atmosphere for 24 hours. After removing off platinum oxide by filtration, the solvent was distilled off under reduced pressure to give 0.501 g of white oil of (R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol (yield 81.0%). The optical purity of the (R,R)-isomer was 80%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([Cl:12])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(#N)C>[Cl:12][C:5]1[CH:4]=[C:3]([CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:8]=[CH:7][C:6]=1[C:9](=[O:11])[CH3:10]
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(CN2CCOCC2)cc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
A mixture of 1-(4-(bromomethyl)-2-chlorophenyl)ethanone (1.65 g, 6.65 mmol) (preparation 16) and acetonitrile (25 ml) was prepared at room temperature and stirred under nitrogen. Potassium carbonate (1.10 g 7.98 mmol) was then added followed by morpholine (0.695 ml, 7.98 mmol) and the mixture stirred at room temperature. After 2 h, TLC indicated the presence of both product and starting material. The mixture was then heated under nitrogen to 40° C. for 16 h, then allowed to cool to room temperature, filtered to remove excess carbonate and filtrate concentrated under reduced pressure. The mixture was then diluted in DCM (30 ml), washed with water (2×10 ml), filtered through a phase separator and the filtrate concentrated under reduced pressure. The crude mixture was purified by column chromatography (40-100% EtOAc/hexane) to afford 1-(2-chloro-4-(morpholinomethyl)phenyl)ethanone as a yellow oil (1.08 g, 4.25 mmol, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC1CCN(CCc2ccc(Cl)cc2)CC1
Product: O=[N+]([O-])c1ccc(OCC2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner similar to Preparation 2, react 1-[2-(4-chlorophenyl)ethyl]-4-piperidinemethanol with 1-fluoro4-nitrobenzene to obtain the title compound.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[NH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=2)[CH2:29]1.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:27][CH:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=3)[CH2:29]2)(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
In the same manner as described in Examples 50-(1), methyl (+)-(2-aminoindan-5-yl)acetate (+)-dibenzoyl-D-tartaric acid salt and 4-chlorophenylsulfonyl chloride are treated to give methyl (+)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate.
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:3][CH2:4][CH:5]=[C:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[OH-].[Na+].[H][H]>[C].[Pd].CO>[CH3:13][C:2]([N+:14]([O-:16])=[O:15])([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: [H][H]
Reactant: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CCCC1NC(=O)NC1=O)[N+](=O)[O-]
Yield: 72.8 %

Procedure:
Methanol (200 ml) was added to 5-(4-methyl-4-nitropentylidene)hydantoin (25.85 g, 114 mmol) and 27% aqueous sodium hydroxide solution was added to adjust the pH to 10 for dissolution. Palladium-carbon (1.1 g) and hydrogen were added for reduction. After the reaction, palladium-carbon was filtered off and methanol was evaporated by concentration under reduced pressure. Water (50 ml) was added and the pH was adjusted to 2 with concentrated hydrochloric acid. The precipitated crystals were separated and dried to give 5-(4-methyl-4-nitropentyl)hydantoin (19.02 g, 83 mmol, yield 72.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]([CH3:25])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:25])[CH:16]=[C:15]2[N:10]1[CH2:11][CH2:12][N:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cn1cc(Br)c2cc(Cl)ccc21
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cn(C)c3ccc(Cl)cc23)C1=O
Yield: 58.9 %

Procedure:
Using the same reaction conditions as in Example 15, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-114b: 150 mg, 0.8465 mmol) was reacted with 3-bromo-5-chloro-1-methyl-1H-indole (I-137a: 226.2 mg, 0.9311 mmol), 1,4-dioxane (20 mL), copper iodide (16.1 mg, 0.8465 mmol), trans-1,2-diamino cyclohexane (30.6 mL, 0.255 mmol) and potassium phosphate (441 mg, 2.077 mmol). The resulting mixture was heated to reflux for 16 hours. The reaction workup afforded 170 mg of 1-(5-Chloro-1-methyl-1H-indol-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (58.9% yield).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:12]([C:4]1[CH:3]=[C:2]([C:2]2[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=2)[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]=1[NH2:6])([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1N
Reaction time: 8 h
Yield: 100.4 %

Procedure:
Dry nitrogen gas was bubbled into a mixture of 4-bromo-2,6-diisopropylaniline (35.1 g, 137 mmol), potassium phosphate tribasic monohydrate (126 g, 548 mmol) and 2-dicyclo-hexylphosphino-2′,6′-dimethoxybiphenyl [S-Phos] (2.250 g, 5.48 mmol) in toluene:water (10:1, 1400 mL) at room temperature for a period of 40 minutes. Pd2(dba)3 (1.255 g, 1.370 mmol) was then added to the mixture above. The reaction was refluxed under a nitrogen atmosphere and monitored by GC-MS. The reaction was complete after overnight refluxing. The reaction mixture was cooled down and the organic layer was separated, washed with water (3×) and filtered through a bed of Celite®. Toluene was removed in vacuum to give a crude oil which was purified by silica gel column chromatography using hexane/AcOEt: 9/1 to 85/15 as eluants. Pure fractions were distilled to afford the title compound as an oil (17.43 g, 50% yield).
Reaction SMILES: C([O:8][C:9]1[CH:25]=[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)C1C=CC=CC=1>CCOC(C)=O.CN(C=O)C.[OH-].[OH-].[Pd+2]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH2:15][CH2:16][N:11]3[N:10]=[C:9]([OH:8])[CH:25]=[C:12]3[C:13]2=[O:24])=[CH:22][CH:21]=1
Reactant: O=C1c2cc(OCc3ccccc3)nn2CCN1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2cc(O)nn2CCN1c1ccc(F)cc1
Yield: 88.2 %

Procedure:
A solution of 2-(benzyloxy)-5-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.79 g, 2.34 mmol) in a mixture of AcOEt (30 mL) and DMF (30 mL) was hydrogenated in a H-Cube reactor (1.5 ml/min, 70 mm Pd(OH)2/C cartridge, full H2 mode, 80° C., 1 cycle). The solvents were evaporated in vacuo to yield 5-(4-fluorophenyl)-2-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.51 g, 88% yield) as a white solid, that was used in the next step without further purification.
Reaction SMILES: I[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])[O:5][N:4]=1.[O-:18][CH2:19][CH3:20].[Na+]>>[CH2:19]([O:18][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])[O:5][N:4]=1)[CH3:20]
Reactant: CC[O-]
Reactant: FC(F)(F)c1ccncc1-c1nc(CI)no1
Agent: [Na+]
Product: CCOCc1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-Iodomethyl-5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole (0.5 g) was dissolved in a freshly prepared solution of sodium ethoxide (30 mg of sodium in 7 ml of ethanol), and the mixture was stirred at room temperature for 6 hours.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.[H-].[Na+]>CN(C=O)C.[Cu]I>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1cccc2cccnc12
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccnc(Oc3cccc4cccnc34)c2)cc1

Procedure:
This material was prepared according to the method described in Example 413 using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.16 g, 0.6 mmol), 8-hydroxyquinoline (0.1 g, 0.7 mmol), sodium hydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06 mmol) in DMF (3 mL). Purification on a Biotage 40S column (3:1 hexanes:EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 367 (M+1). Anal. Calcd for C21H13F3N2O: C, 68.85; H, 3.58; N, 7.65. Found: C, 68.88; H, 3.59; N, 7.51.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:29][CH:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:27][CH:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:29]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 27) (1.32 g, 2.70 mmol) in dichloromethane (15 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The resulting mixture was stirred for 3 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×3) then dichloromethane to afford the title compound as a white foam (1.31 g).