Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>>[CH3:26][O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][N:10]1[C:9](=[O:27])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCCC(=O)O)ncc3c2=O)c(OC)c1
Yield: 48.2 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.068 mmol), β-alanine (801 mg, 9.0 mmol) and NaOMe solution (13.5 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl to pH about 1, and the resulting precipitate was isolated by filtration. The crude solid was further purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 14 mg of the title compound as a light yellow solid. MS: (+) m/z 428.31 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:19][O:20][CH2:21][C@H:22]([NH2:25])[CH2:23][CH3:24]>CCO>[Cl:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C@@H:22]([CH2:21][O:20][CH3:19])[CH2:23][CH3:24])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: CC[C@@H](N)COC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[C@H](COC)Nc1nccc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 155.4 %

Procedure:
2,4-Dichloro-3-nitropyridine (1.0 g, 5,18 mmol) was dissolved in EtOH (20 mL), followed by the addition of Et3N (1.05 g, 10.4 mmol) and (R)-1-methoxymethyl-propylamine (0.72 g, 5.18 mmol) and the reaction was heated at 60° C. for 3 h. The reaction was concentrated in vacuo to yield 2.09 g of (R)-(4-chloro-3-nitro-pyridin-2-yl)-(1-methoxymethyl-propyl)-amine as a crude viscous oil: MS (AP) m/z 259.69 [(M+H)+, 97].
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[NH:4][CH:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[N:4]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: Clc1ccnc2[nH]cc(Br)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ccnc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 71 %

Procedure:
3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (2.32 g) was dissolved in anhydrous THF and cooled to 0° C., the NaH (60%, 1.2 g) was added slowly and the mixture stirred at 0° C. for 40 min. The benzenesulfonyl chloride was added, and the mixture was allowed to warm to room temperature and stirred at room temperature for 3 h. The reaction mixture was quenched with H2O, and extracted with EtOAc. The organic layer was dried over Na2SO4. Ater the solvent evaporated under reduced pressure, the residue was purified with chromatography on silica gel to give 3-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine: (2.63 g), yield: 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2.Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.C(N(CC)C(C)C)(C)C.Cl.O>C(O)C.CO>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH:14][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2
Reactant: CC(N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of the single enantiomer of 1-[5-chloro-8-(3-fluorophenyl)cinnolin-7-yl]ethanamine (0.52 g, 1.7 mmol) from Step B, 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.73 g, 2.6 mmol), and N,N-diisopropylethylamine (0.90 mL, 5.1 mmol) in ethanol (9 mL) was heated at 90° C. for 21 hours. The reaction mixture was concentrated to give the crude THP-purine intermediate which was used without further purification. A solution of this material in methanol (10 mL) was treated with 1 M hydrogen chloride in water (15 mL, 15 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was concentrated and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/minute). The pure fractions were neutralized with ammonium hydroxide to pH˜7 and concentrated to remove all of the acetonitrile and most of the water. The solid that precipitated was filtered, washed with water, and dried to give the desired product (0.44 g, 62%). % ee>99.9. LCMS for C21H16ClFN7 (M+H)+: m/z=420.1; Found: 419.9. 1H NMR (300 MHz, DMSO-d6): δ 12.9 (br s, 1 H), 9.47 (d, J=5.9 Hz, 1 H), 8.50-8.38 (m, 2H), 8.26 (d, J=5.9 Hz, 1 H), 8.14 (br s, 1 H), 8.06 (d, J=10.8 Hz, 1 H), 7.64-7.52 (m, 2H), 7.37-7.22 (m, 2H), 5.36 (br s, 1H), 1.48 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([Sn:13](Cl)([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-:39].[Na+]>CO>[OH-:39].[CH2:26]([Sn+:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCC[Sn](Cl)(CCCCCCCCCCCC)CCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCC[Sn+](CCCCCCCCCCCC)CCCCCCCCCCCC

Procedure:
The tri-n-dodecyltin chloride was treated with a 20% aqueous methanol solution of sodium hydroxide to afford tri-n-dodecyltin hydroxide having a melting point of 58° to 61° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:53][O:54][CH2:55][CH2:56]O>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:56][CH2:55][O:54][CH3:53])[CH:26]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: COCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 61F (0.100 g, 0.227 mmoles), polystyrene supported triphenylphosphine (0.151 g, 0.454 mmoles, 3 mmoles P/g resin), and di-t-butylazodicarboxylate (0.079 g, 0.341 mmoles) in THF (2 mL) were treated with 2-methoxyethanol (0.022 g, 0.284 mmoles). The reaction mixture was shaken overnight at room temperature. The mixture was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[CH3:15][C:16](=[CH2:18])[CH3:17].S(=O)(=O)(O)O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:10])=[CH:7][CH:6]=1
Reactant: C=C(C)C
Reactant: COC(=O)Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-methoxy-2-oxoethyl)benzoic acid (0.87 g, 4.48 mmol) in methylene chloride (5 mL) was condensed isobutylene (approximately 20 mL) at −78° C. The solution was treated with 0.5 mL concentrated sulfuric acid and the solution was sealed in a stainless steel bomb and allowed to warm to ambient temperature for 6 hours. The solution was recooled to −78° C. and opened. The reaction was partitioned between 0.1M sodium hydroxide solution and diethyl ether. The organics were dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography (0-35% ethyl acetate/hexanes) gave tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate as a clear oil. 1H NMR (600 MHz, DMSO-d6) δ 7.81 (d, J=8.21 Hz, 2H), 7.35 (d, J=8.51 Hz, 2H), 3.75 (s, 2H), 3.56 (s, 3H), 1.51 (s, 9H); ESIMS calcd 251.1 (M++H), found 251.0 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:23][S:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: CSc1cccc(N=C=O)c1
Product: CSc1cccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)c1
Yield: 46.9 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and 3-(methylthio)phenyl isocyanate (0.0105 mL, 0.076 mmol) were reacted to give the title compound as an off-white solid (14.8 mg, 47%). 1H NMR (DMSO-d6) δ: 10.68 (s, 1H), 8.69 (s, 1H), 8.66 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.41-7.47 (m, 4H), 7.19-7.26 (m, 3H), 7.13-7.15 (m, 1H), 7.06 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.84-6.87 (m, 1H), 4.22 (dt, J=12.7, 3.0 Hz, 1H), 3.70-3.75 (m, 1H), 3.51-3.59 (m, 2H), 2.93-2.99 (m, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]1.[CH3:16][N:17]([CH:19](N(C)C)N(C)C)[CH3:18]>>[CH3:16][N:17](/[CH:19]=[C:8]1\[CH2:7][CH2:6][C:5]2[C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3][N:2]([CH3:1])[C:10]=2[C:9]\1=[O:11])[CH3:18]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: COC(=O)c1cn(C)c2c1CCCC2=O
Product: COC(=O)c1cn(C)c2c1CC/C(=C\N(C)C)C2=O
Temperature: 90 °C
Reaction time: 10 h

Procedure:
Methyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (288 mg, 1.39 mmol) was treated with tris(dimethylamino)methane (2.4 mL, 13.9 mmol) and the reaction mixture was stirred at 90° C. for 10 h. Volatiles were removed under reduced pressure and the residue used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[CH2:10][S:11][CH3:12])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[CH2:10][S:11]([CH3:12])=[O:19])=[CH:4][N:3]=1
Reactant: CSCC(C)Cc1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(Cc1ccc(Cl)nc1)CS(C)=O
Yield: 91.8 %

Procedure:
To a stirred solution of 2-chloro-5-[2-methyl-3-(methylthio)propyl]-pyridine (2.60 g, 12.5 mmol) in CH2Cl2 (35 mL) cooled to −15° C. in an ice-salt bath was added m-chloroperoxybenzoic acid (mCPBA, ˜85%, 2.54 g, ˜12.5 mmol) portion wise at such a rate that the temperature never rose above −10° C. After the addition was over, TLC showed that a single product plus a small amount of starting material was present in the solution. To avoid any sulfone formation, the reaction was quenched at this point by the addition of saturated NaHCO3 (50 mL). The organic layer was separated and the aqueous phase washed with CH2Cl2 (25 mL). The combined organic layers were dried over MgSO4 and the solvent was evaporated to give 2.66 g of crude product as a yellow oil. The oil was triturated with hot hexane (50 mL) and the hexane decanted after cooling. This procedure removed most of the starting material and the resulting product (a mixture of two diastereomers) was directly used for the following step without further purification. [M+H]+=232, 234; δ 1.09 (overlapping d, 3H), 2.57, 2.59 (2 s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1-Chloro-2,5-difluorobenzene (31.7 g, 0.21 mol) was dissolved in sulfuric acid (110 ml) at −40° C., then a solution of sulfuric acid (20 ml) and nitric acid (30 ml) was added dropwise. The mixture was stirred for 1 hr while temperature slowly raised to 20° C. The product was forced to crystallize by mixing the reaction mixture with ice-water (500 ml), the yellow crystals were filtered, washed with cold water and dried in fume hood overnight. (38.0 g). 1H NMR (CDCl3, 300 MHz) 7.46 (1H, dd, J=9.8, 9.9 Hz), 7.96 (1H, dd, J=7.9, 7.9 Hz) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17](N(OC)C)=[O:18])=[CH:11]2.N.ClCCl>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH:17]=[O:18])=[CH:11]2
Reactant: CON(C)C(=O)c1cc2cc(F)ccc2[nH]1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cc2cc(F)ccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
Lithium aluminium hydride (0.094 g, 2.488 mmol) was added to a solution of 5-fluoro-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.691 g, 3.11 mmol) in tetrahydrofuran (10 ml) at 0° C. and stirred for 1 hour. The reaction mixture was cooled to 0° C. and 25% ammonia solution was added dropwise to the reaction mixture until lithium aluminium hydride color turn gray to white. Then dichloromethane and cerite was added to the reaction mixture and stirred for 30 min. The mixture was filtered through a pad of Celite and concentrated in vacuo to give 523 mg of the crude title compound. This was used for the next step without further purification:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:14])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[CH:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:14])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[CH:2]1
Reactant: CCCCOC(=O)C(O)c1ccoc1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: c1ccccc1
Product: CCCCOC(=O)C(=O)c1ccoc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 39.6 g of butyl fur-3-yl-glycolate and 8.6 g of lead tetraacetate in 400 ml of absolute benzene is refluxed for 8 hours. After cooling to room temperature, the salts are filtered off and washed with benzene, and the combined benzene phases are shaken with a 10% strength sodium bicarbonate solution and a saturated sodium chloride solution. After drying over sodium sulphate, filtering off and concentrating, the oily residue is distilled in vacuo. 32.7 g (83%) of an oil, boiling point 80° C. (0.3 Torr), nD20 =1.477, are obtained.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.C(C1CN(CC2C=CC(OC)=CC=2)C(=O)N1)C.[CH3:41][C:42]1[C:43]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[CH:67]([CH2:68][CH3:69])[CH2:66][N:65](CC5C=CC(OC)=CC=5)[C:64]4=[O:79])=[N:61][CH:62]=3)=[O:56])[CH2:51][CH2:50]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>>[CH3:41][C:42]1[C:43]([N:49]2[CH2:50][CH2:51][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[CH:67]([CH2:68][CH3:69])[CH2:66][NH:65][C:64]4=[O:79])=[N:61][CH:62]=3)=[O:56])[CH2:53][CH2:54]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: CCC1CN(Cc2ccc(OC)cc2)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1
Agent: CCC1CN(Cc2ccc(OC)cc2)C(=O)N1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCC1CNC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 127 and 4-ethyl-1-(4-methoxybenzyl)imidazolidin-2-one (140 mg) described in Preparation Example 208 and by the reaction and treatment in the same manner as in Example 505, the title compound (96 mg) was obtained via 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-4-ethyl-1-(4-methoxybenzyl)imidazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([F:28])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)cc(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2cc(Cl)cc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(3,5-dichlorophenyl)-3-hydroxypyrrolidin-1-carboxylate (0.88 g, 2.65 mmol) in dichloromethane (50 mL) was added dropwise diethylaminosulphurtrifluoride (0.35 mL, 2.65 mmol) dissolved in dichloromethane (20 mL) and the mixture was stirred at 0° C. for 20 minutes and at ambient temperature for 10 minutes. Aqueous sodium carbonate (10%, 50 mL) was added and the phases separated. The aqueous phase was extracted with dichloromethane (2×50 mL) and the pooled organic phase was dried (Na2SO4) and evaporated. Purification by flash column chromatography gave the title compound (0.45 g). MS m/z (rel. intensity, 70 eV) 334 (M+, 1), 278 (8), 277 (6), 260 (8), 57 (bp).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]([C:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[C:5]=1[C:10]([NH:1][C:4]1[CH:14]=[CH:13][CH:12]=[CH:6][CH:5]=1)=[O:11])([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1C(=O)Nc1ccccc1

Procedure:
50 g (259 mmol) 3-nitro-phtalic anhydride and 24.7 g (24.1 mL, 266 mmol) aniline in 710 mL acetic acid were heated to reflux for 3 hours under an argon atmosphere. Acetic acid was removed under reduced pressure and the residue was treated with 150 mL ethanol at 0° C. The precipitated 3-nitro-phtalanilide was isolated by filtration, washed with a small amount of cold ethanol and dried. 59.1 g (58%) 3-nitro-phtalanilide was isolated (m.p. 139-141° C.).
Reaction SMILES: [Cl-].[Li+].[I-].[Sm+2].[I-].[C:6]1(=[O:10])[CH2:9][CH2:8][CH2:7]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[C:6]1([OH:10])([C:6]2([OH:10])[CH2:9][CH2:8][CH2:7]2)[CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCC1
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Product: OC1(C2(O)CCC2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
To a solution of lithium chloride (2.12 g) in tetrahydrofuran (60 mL) was added samarium(II) iodide (5.0 g) under argon atmosphere, followed by stirring the mixture at room temperature for 15 minutes. To this reaction mixture was added dropwise a solution of cyclobutanone (825 mg) in tetrahydrofuran (5 mL), followed by stirring the mixture at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium thiosulfate solution under ice-cooling, followed by extraction with diethyl ether three times. The organic layers were combined, washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:19 to 3:2) to give bicyclobutyl-1,1′-diol (399 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C(C)=CC=CC=1C.[C:17](Cl)(=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:26])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cccc(Br)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 3-bromoaniline (13.1 mL, 120 mmol) in dichloromethane (100 mL) and 2,6-lutidine (21 mL, 180 mmol) at 0° C. was added a solution of cinnamoylchloride (20 g, 120 mmol) in dichloromethane (50 mL) dropwise. The reaction mixture was allowed to reach room temperature and was stirred for 2 hours. It was quenched with potassium phosphate buffer (100 mL, 1M, pH 7) and stirred for 15 minutes. Dichloromethane was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic phase was washed with phosphate buffer (200 mL), dried over sodium sulfate and concentrated to dryness. The residue was crystallized from toluene/hexanes to give the product as colorless solid (33.4 g, 92%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=2)[NH:3]1.CCN(C(C)C)C(C)C.[C:37]1([CH2:43][C:44](Br)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[NH4+].[Cl-]>C(Cl)Cl.CCOCC>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:26][CH3:27])([C:12]([F:15])([F:14])[F:13])[C:16]([F:17])([F:18])[F:19])[CH:8]=2)[N:3]1[C:44](=[O:45])[CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Br)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2C(=O)Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A solution of 101 mg (0.24 mmol) of 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole (example 51.2) in CH2Cl2 was treated with 0.05 mL (0.3 mmol) of DIPEA and then with 0.03 mL (0.24 mmol) of phenylacetylbromide at 0° C. The mixture was stirred at RT for 3 hrs and then distributed between Et2O a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated to yield 120 mg of 1-[2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-yl]-2-phenyl-ethanone. This crude was dissolved in 2 mL of THF and treated with 0.9 mL of a 1M BH3 soution in THF. After stirring for 10 hrs at RT the mixture was distributed between Et2O and a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated to yield 135 mg of 2-methyl-1-phenethyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole, of which 30 mg were dissolved in 1 mL of THF and treated with 0.07 mL of 1M TBAF in THF. Stirring for 30 min, evaporation, and column chromatography on silica gel with n-heptane/EtOAc (4:1) yielded 12 mg (51%) of 1,1,1,3,3,3-hexafluoro-2-(2-methyl-1-phenethyl-2,3-dihydro-1H-indol-5-yl)-propan-2-ol, colorless waxy solid, MS: 404 (MH+).