Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:16]([F:19])([F:18])[F:17])[OH:15])[N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:16]([F:19])([F:18])[F:17])[OH:15])[N:3]=1
Reactant: Cc1ccc2c(N=C(c3ccccc3)C(O)(c3ccccc3)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(NC(c3ccccc3)C(O)(c3ccccc3)C(F)(F)F)cccc2n1
Reaction time: 2 h
Yield: 6.6 %

Procedure:
484 mg (2 mmol) Diethyl(phenyloxomethyl)phosphonate and 2,2,2-trifluoroacetophenone are stirred in 3 ml DMF together with 14 mg (0.22 mmol) potassium cyanide for 3 hours (Demir et al. J. Org. Chem. 2005, 70, 10584-87). Direct chromatographic purification on silica gel (ethyl acetate in hexane 33%) yields 580 mg phosphoric acid(1-benzoyl-2,2,2-trifluoro-1-phenylethyl)diethyl ester. 250 mg (0.6 mmol) of the phosphoric acid ester are stirred for 18 hours in 10 ml diethyl amine and 1 ml water. Evaporation and flash chromatography on silica gel (ethyl acetate in hexane 33%) yield 80 mg 3,3,3-trifluoro-2-hydroxy-1,2-diphenylpropan-1-one. 80 mg (0.29 mmol) 3,3,3-trifluoro-2-hydroxy-1,2-diphenylpropan-1-one, 0.2 ml tetra t.-butyl othotitanate and 45 mg (0.29 mmol) 5-amino-2-methylquinolin are refluxed for 18 hours in 3 ml toluene and 0.1 ml acetic acid. The reaction mixture is poured into water after cooling and filtrated through a path of cellites after stirring for 15 minutes and diluting with ethyl acetate. The phases were separated and the aqueous layer was extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated to yield 90 mg of raw β-[(2-methylquinolin-5-yl)imino]-α-phenyl-α-(trifluoromethyl)benzeneethanol. To 30 mg of the raw imine in 2 ml methanol and 0.5 ml THF are added 20 mg sodium borohydride in two portions. The mixture is stirred over 2 hours, after that period quenched by addition of acetone and saturated ammonium chloride solution and diluted with ethyl acetate. The phases are separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Preparative thin layer chromatography on silica gel (ethyl acetate in hexane 50%) yields 2 mg of the title compound and 8 mg of the starting material.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH2:57])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:65])([F:64])[F:63])[CH:42]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH:57][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][N:2]([CH3:9])[CH3:1])[CH2:55][CH2:56]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:63])([F:64])[F:65])[CH:42]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: CN(C)CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)CCCN(C)C)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.44 mg (11 μMol) 4-dimethylamino-butyric acid was dissolved in 100 μL DMF, 3.5 μL (24.95 μMol) triethylamine and 3.37 mg (10.5 μMol) TBTU in 100 μL DMF were added and the mixture was stirred for 10 min at RT. Then 3.80 mg (10 μMol) 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide in 100 μL DMF was added and the mixture was shaken for 3 days at ambient temperature. Filtered through Alox B, washed with DMF/MeOH=9/1 and the filtrate was evaporated down.
Reaction SMILES: COP([CH2:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH:11]=[CH2:12])(OC)=O.[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[CH:26][C:25]=1[N+:35]([O-:37])=[O:36])=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCO>[C:16]([O:15][C:14]([NH:13][C@@H:9]([CH2:10][CH:11]=[CH2:12])[C:8](=[O:21])/[CH:7]=[CH:22]/[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[CH:26][C:25]=1[N+:35]([O-:37])=[O:36])=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)/C=C/c1ccc(NC(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90 %

Procedure:
To a vigorously stirred solution of 5E (4.47 g, 13.92 mmol) and 5D (2.6 g, 11.60 mmol) in THF (anhydrous) (115 mL) and EtOH (absolute) (1.148 mL) under nitrogen was added portion wise K2CO3 (anhydrous) (2.56 g, 18.56 mmol) at 0° C. The reaction mixture was allowed to raise to rt and then the mixture was heated at 55° C. The reaction mixture was then filtered with the aid of EtOAc and the filtrate evaporated to a residue which was dissolved in a small amount of methylene chloride and purified by normal phase chromatography to give 5F (4.38 g, 90%) as yellow solid. MS (ESI) m/z: 420.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.83-7.73 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.02 (d, J=15.9 Hz, 1H), 5.77 (ddt, J=17.0, 10.2, 6.7 Hz, 1H), 5.16-5.01 (m, 2H), 4.32 (td, J=8.5, 4.9 Hz, 1H), 3.71 (s, 3H), 2.34-2.23 (m, 1H), 1.36 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1SCCCO
Product: Cc1c(C(=O)Nc2ccc(SCCCO)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 25.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (3.9 g) and 5-amino-2-(3-hydroxypropylthio)benzonitrile (2.9 g), the title compound (1.5 g) was obtained, melting point: 165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37].CCCCCC>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:11]([C:12]#[N:13])([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:37][C:36]([O:39][CH2:40][CH3:41])=[O:38])[CH3:35]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(CC#N)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)c(OC)c1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Combine 3,4-dimethoxyphenylacetonitrile (20 g, 113 mmol) and anhydrous tetrahydrofuran (100 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of sodium bis(trimethylsilyl)amide (226 mL, 1 M in THF, 226 mmol). When the addition is complete warm the reaction mixture to 10° C. and allow to stir for 15 minutes. Cool in a dry-ice/acetone bath, add dropwise ethyl bromoacetate (37.7 g, 226 mmol). When the addition of ethyl bromoacetate is complete, warm the reaction mixture to ambient temperature. After 18 hours, partition the reaction mixture between diethyl ether and water. Extract the organic layer with water and saturated aqueous solution of ammonium chloride. Separate the organic layer, dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 33% ethyl acetate/hexane. Remove residual solvent in vacuo at 82° C. to give the title compound: Rf=0.37 (silica gel, 33% ethyl acetate/hexane). Elemental Analysis calculated for C18H23NO6: C 61.88; H 6.64; N 4.01; Found: C 61.79; H 6.62; N 3.91.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][S:12][CH2:13][CH3:14])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(=O)([O-])[O-].[K+].[K+].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:40]([N:42]1[C:46](=[O:47])[CH:45]=[CH:44][NH:43]1)[CH3:41]>C(O)(CC)(C)C>[Cl:1][C:2]1[C:10]([CH2:11][S:12][CH2:13][CH3:14])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([C:45]1[CH:44]=[N:43][N:42]([CH2:40][CH3:41])[C:46]=1[OH:47])=[O:6]
Reactant: CCn1[nH]ccc1=O
Reactant: CCSCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCSCc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(CC)c2O)c1Cl
Reaction time: 4 h

Procedure:
3 g of 2-chloro-3-ethylthiomethyl-4-methanesulfonylbenzoic acid, 0.72 g of potassium carbonate, 50 ml of t-amyl alcohol, 1.95 g of N,N'-dicyclohexylcarbodiimide and 4.5 g of a 25% t-amyl alcohol solution of 1-ethyl-5-pyrazolone were mixed and heated under stirring for 4 hours at a temperature of from 70° to 80° C. After cooling, the mixture was distilled under reduced pressure, and 200 ml of water was added to the residue. After filtering off the insolubles, the filtrate was washed with chloroform. Hydrochloric acid was added to the aqueous layer, and the mixture was extracted with chloroform. The extract was dried, and the solvent was distilled off to obtain the desired product as a crude product. The crude product was recrystallized from ethanol to obtain 1.88 g of the purified product. (Melting pont: 142°-145° C.)
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)[CH2:2][C:3]#[CH:4].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C(N(CC)CC)C.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]#[C:3][CH2:2][CH2:1][C:5]2[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[CH:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCCc1ccc(CO)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Under an N2 atmosphere 130 mg (0.67 mmol) CuI and 300 mg (0.42 mmol) Pd(PPh3)2Cl2 are added to a solution of 2.0 g (12.48 mmol) (4-but-3-ynyl-phenyl)-methanol and 3.2 g (13.1 mmol) 2,5-dibromopyridine in 80 mL triethylamine and the reaction mixture is stirred for 1.5 h at 50° C. The solvent is eliminated in vacuo, the residue dissolved in a little DCM and purified by chromatography on silica gel (gradient: cyc/EtOAc 4:1 to cyc/EtOAc 3:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([CH3:24])[CH:15]=3)[CH2:12][O:11]C(=O)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Li+]>O>[NH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[C:16]([CH3:24])[CH:15]=1)[CH2:12][OH:11]
Reactant: Cc1cc(C2(c3cccc(Br)c3)COC(=O)N2)ccc1OC(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(N)(CO)c2cccc(Br)c2)ccc1OC(F)F
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A solution of 4-(3-bromo-phenyl)-4-(4-difluoromethoxy-3-methyl-phenyl)-oxazolidin-2-one (intermediate XVII-2) (5.1 g, 1 eq) in a 9:1-mixture of ethanol and water (50 ml) was added lithium hydroxide (9.2 g, 30 eq). The reaction was stirred at reflux for 3 hours. Then the mixture was allowed to cool to room temperature and concentrated at reduced pressure. The residue was extracted with ethyl acetate (3×20 ml), the combined organic layers were collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel using a 5:1-mixture of cyclohexane and ethyl acetate as the eluent. There were obtained 4.8 g (93% of theory) of the (RS)-2-amino-2-(3-bromo-phenyl)-2-(4-difluoromethoxy-3-methyl-phenyl)-ethanol as a white solid.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:23][S:24][C:25]1[S:29][C:28]([C:30]([OH:32])=O)=[C:27]2[CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:26]=12.C(N(C(C)C)CC)(C)C.[C:47]([O:51][C:52]([N:54]([CH2:62][C:63]1[CH:64]=[C:65]([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH:66]=[CH:67][CH:68]=1)[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[O:53])([CH3:50])([CH3:49])[CH3:48]>CN(C)C=O>[C:58]([O:57][C:55]([N:54]([CH2:62][C:63]1[CH:64]=[C:65]([CH:69]2[CH2:70][CH2:71][N:72]([C:30]([C:28]3[S:29][C:25]([S:24][CH3:23])=[C:26]4[C:36](=[O:37])[CH2:35][CH2:34][CH2:33][C:27]=34)=[O:32])[CH2:73][CH2:74]2)[CH:66]=[CH:67][CH:68]=1)[C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])=[O:56])([CH3:59])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCNCC2)c1)C(=O)OC(C)(C)C
Reactant: CSc1sc(C(=O)O)c2c1C(=O)CCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1sc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (120 mg, 0.38 mmol) was added to a room temperature solution of 3-methylsulfanyl-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (88 mg, 0.36 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) in dimethylformamide (2 mL), under nitrogen. The reaction mixture was stirred for 10 minutes at room temperature before adding a solution of 4-[3-(N,N-di-tert-butoxycarbonylaminomethyl)phenyl]piperidine (140 mg, 0.36 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) in dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 16 hours, concentrated to dryness in vacuo, and subjected to dry flash column chromatography on silica with 50:50, dichloromethane:ethyl acetate. 1-{1-[4-(3-(N,N-di-tert -butoxycarbonylaminomethyl)phenyl)-piperidin-1-yl]-methanoyl}-3-methylsulfanyl-6,7-dihydro-5H-benzo[c]thiophen-4-one was isolated as a colorless oil (177 mg). The intermediate was dissolved in dichloromethane (20 mL), cooled at 0° C., and treated with trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, and concentrated to dryness in vacuo. The residue was dissolved in 20% acetonitrile/water [containing 0.1% trifluoroacetic acid] (9 mL) and purified by preparative reverse-phase HPLC (C-18, 10 micron reverse-phase column), eluting with 10% to 100% acetonitrile/water (containing 0.1% trifluoroacetic acid). The product fractions were combined and the acetonitrile removed in vacuo. The aqueous residue was frozen and lyophilized to give the title compound as an amorphous white solid (122 mg, 64%). 1H NMR [(CD3)2SO]: δ 8.16 (br s, 3H, NH3+); 7.41-7.24 (m, 4H); 4.21 (br d, 2H); 4.03 (q, 2H); 3.18-3.02 (m, 2H); 2.91-2.72 (m, 3H); 2.59 (s, 3H); 2.53-2.41 (m, 2H); 1.98-1.90 (m, 2H); 1.90-1.79 (m, 2H); 1.68-1.50 (m, 2H). MS(Ion spray): 415 (M++1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH:15]=O.[Si](C#N)(C)(C)C.[N:29]1([C:34](N2C=CN=C2)=[O:35])C=CN=[CH:30]1>[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:15]([C:14]4[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:13]=4[O:12][CH3:11])[CH2:30][NH:29][C:34]3=[O:35])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Product: COc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)c(OC)c1
Yield: 30 %

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.400 g, 3 mmol), 2,4-dimethoxybenzaldehyde (0.5 g, 3 mmol), TMSCN (0.375 mL, 3 mmol), Pd/C (10%, 0.02 g), TEA 1.05 mL, 7.5 mmol), di-(imidazol-1-yl)methanone (0.730 g, 4.5 mmol) as described in method 2 to give 1-(1H-benzo[d]imidazol-5-yl)-5-(2,4-dimethoxyphenyl)imidazolidin-2-one (yield: 0.305 g, 0.9 mmol, 30%). Treating with borontribromide (0.512 mL, 5.41 mmol) as described for Example 151 gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH3:21])[N:14]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1.CCN(CC)CC.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH3:21])[N:14]([CH:15]4[CH2:20][CH2:19][N:18]([C:32]([CH:29]5[CH2:31][CH2:30]5)=[O:33])[CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1
Reactant: Cc1nc2cnc3ccc(Cl)nc3c2n1C1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2cnc3ccc(Cl)nc3c2n1C1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 8-chloro-2-methyl-1-(piperidin-4-yl)-1H-imidazo[4,5-c][1,5]naphthyridine (110 mg, 0.364 mmol) and Et3N (101 μL, 0.728 mmol) in THF (15 mL) was added cyclopropanecarbonyl chloride (36 μL, 0.401 mmol) while cooling with an ice-water bath. The reaction mixture was stirred at r.t. for 3 h, and was then concentrated under vacuum. The residue was dissolved in a mixture of CH2Cl2 (10 mL) and H2O (10 mL). The resulting solution was then extracted with EA (2×10 mL). The combined organic layers were concentrated to give crude (4-(8-chloro-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl) piperidin-1-yl)(cyclopropyl)methanone as a yellow solid (105 mg, yield 80%) which was used in the next step without further purification. MS (m/z): 370 (M+H)+.
Reaction SMILES: [OH:1][C:2]1C=[C:4]([CH:8]=[CH:9][CH:10]=1)C(O)=O.[Br:11]Br.[C:13]([OH:16])(=[O:15])[CH3:14]>S(=O)(=O)(O)O.O>[Br:11][C:9]1[CH:8]=[CH:4][C:14]([C:13]([OH:16])=[O:15])=[C:2]([OH:1])[CH:10]=1
Reactant: CC(=O)O
Reactant: O=C(O)c1cccc(O)c1
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(Br)cc1O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of 3-hydroxybenzoic acid (14.480 mmol, 2 g) in acetic acid (14.5 mL) and sulfuric acid (1.5 mL) at 50° C., a solution of bromine (15.204 mmol, 0.780 mL) in acetic acid (7.2 mL) was added and stirred 30 minutes at 100° C. The reaction was allowed to cool to RT and diluted with water. The aqueous layer was extracted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give the 4-bromo-2-hydroxy-benzoic acid. Yield: 100%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](NC(C)C)(C)[CH3:13].[Li]CCCC.BrCCBr>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: [Li]CCCC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C1Nc2cc(Br)ccc2C12CC2
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 6-bromoindolin-2-one (2 g, 9.43 mmol) and diisopropylamine (2.00 g, 2.82 ml, 19.8 mmol) in tetrahydrofuran (16 ml) was cooled to −25° C. and a solution of nBuLi (1.6 M in hexane, 23.6 ml, 37.7 mmol) was added dropwise. The reaction mixture was warmed to 0° C. and a solution of 1,2-dibromoethane (5.32 g, 2.44 ml, 28.3 mmol) in tetrahydrofuran (2 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 20 hours and carefully quenched with brine (2 ml) and conc. HCl (2 ml, ice bath). The reaction mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as red crystals (1.11 g).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH3:22][C:23]([CH3:43])([O:25][C:26]([NH:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:27])[CH3:24].O>ClCCl>[CH3:43][C:23]([CH3:22])([O:25][C:26]([NH:28][C@@H:29]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[CH:40][CH:41]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:27])[CH3:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 100 %

Procedure:
Under nitrogen atmosphere, pyridine(130.3 g) and trifluoromethanesulfonic anhydride (170.4 g) were added dropwise to a solution of ethyl (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-4-hydroxybenzenepropionate (170.0 g) in dichloromethane (1.7 L) at 10° C. or below. After stirring for 1 hour at the same temperature, water (850 ml) was added dropwise to the mixture and the mixture was stirred for 2 hours at the same temperature. The organic layer was washed with 10% aqueous citric acid solution and aqueous saturated sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-4-(trifluoromethanesulfonyloxy)benzenepropionate (242.5 g) as oil.
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.O.P([O-])(O)(O)=[O:25].[Na+]>ClCCl>[CH2:1]([O:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[O:25][CH2:22]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: C=CCCCCCCCCCOCc1ccc2c(c1)OCO2
Reactant: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C(=COCc1ccc2c(c1)OCO2)CCCCCCCC1CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 11.0 g. (0.036 mole) of 10-undecenyl piperonyl ether and 5.0 g. (0.036 mole) of sodium dihydrogen phosphate monohydrate in 100 ml. of dichloromethane, was added 7.6 g. (0.036 mole) of m-chloroperbenzoic and dissolved in 200 ml. of dichloromethane. After stirring at ambient temperature for 24 hours, the mixture was filtered and washed with an aqueous sodium bicarbonate solution. After drying the dichloromethane solvent was removed by evaporation. The crude product obtained in this way was purified by passing through a silica gel chromatographic column using first a 5% ether in hexane eluent and then a 50% ether in hexane eluent to recover the 10,11-epoxyundecenyl piperonyl ether which weighed 5 g. An infrared spectra had strong adsorption peaks at 3.4, 3.5, 6.7, 6.95, 7.9-8.0, 9.1, 9.6, 10.8 and 12.4 microns.