Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH2:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:26]([C:25]([NH:24][C:17]1[CH:16]=[C:15]([CH:12]2[CH2:11][C:10]([CH3:22])([CH3:23])[C:9]3[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[CH:7][CH:8]=3)[NH:13]2)[CH:20]=[CH:19][CH:18]=1)([CH3:30])[CH3:29])([OH:28])=[O:27]
Reactant: CC(C)(N)C(=O)O
Reactant: COC(=O)c1cccc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cccc(C(=O)O)c3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (374 mg, 1.0 mmol), copper(I) iodide (57 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309 mg, 3.0 mmol) and potassium carbonate (415 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (95.3 mg, 25.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 383.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][NH:14][CH3:15].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:13][CH3:12])[CH3:15])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CNOC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
A mixture of 4-bromo-3-methyl-benzoic acid (15 g, 0.069 mol), O,N-dimethyl hydroxylamine (6.5 g, 0.1 mol) HATU (38 g, 0.1 mol), and triethylamine (20 g, 0.2 mol) dissolved in DMF (50 mL) was stirred at RT for 12 h, concentrated, and purified by silica gel chromatography (1:1 EtOAc:petroleum ether) to provide the title intermediate (11 g, 61% yield) 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.52 (m, 2H), 7.32 (m, 1H), 3.50 (s, 3H), 3.29 (m, 3H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 38976.4 %

Procedure:
A mixture of 2-chloronicotinic acid (20 g, 0.127 mmol) and oxalyl chloride (13.3 mL, 0.152 mmol) in 2 drops of DMF and 200 mL of methylene chloride was stirred at room temperature for approximately 14 hours. The mixture was stirred at reflux temperature for 1 hour. The solution was cooled and partitioned between 100 mL of ice-cold aqueous sodium bicarbonate and 300 mL of methylene chloride. The organic layer was washed with brine, dried (Na2SO4) and concentrated to give 2-chloronicotinic acid chloride (8.8 g, 49.5 mmol).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
The compound was prepared as in Example 5 from 1-(4-carbomethoxymethoxyphenyl)propan-2-one (2.22 g) and 2-hydroxy-2-(3-chlorophenyl) ethanamine (1.71 g) and crystallised from hexane m.p. 82°-87° as a 58:42 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH:27]=[CH2:28]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:28][CH:27]=[CH2:26])=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Br
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (200 mg, 0.507 mmol) in tetrahydrofuran (5 mL) was added dropwise allylmagnesium bromide (1 M solution in diethyl ether, 1.00 mL, 1.00 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the two title compounds as colorless solids.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].Cl.[N:31]1([CH2:38][C:39]2[CH:47]=[CH:46][C:42]([C:43](O)=O)=[CH:41][CH:40]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][C:39]2[CH:47]=[CH:46][C:42]([CH2:43][CH2:2][CH2:1][NH:3][C:4]3[C:5]([CH:13]4[CH2:22][CH2:21][C:20]5[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=5[CH2:14]4)=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)=[CH:41][CH:40]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Reactant: O=C(O)c1ccc(CN2CCCCCC2)cc1
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1cc3c(cc1NCCCc1ccc(CN4CCCCCC4)cc1)OCO3)C2
Yield: 27 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-azepan-1-ylmethylbenzoic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (14 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](/[CH:13]=[CH:14]/[C:15]2[N:16]=[C:17]3[C:22]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[N:19][N:18]3[C:29]=2[C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=2)=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](/[CH:13]=[CH:14]/[C:15]2[N:16]=[C:17]3[C:22]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=[N:19][N:18]3[C:29]=2[C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:41][CH:42]=2)=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc2ccccc2nc1/C=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ccccc2nc1/C=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 63a (212 mg, 1.22 mmol) in 3 mL of DCM at rt was added TFA (1.00 mL, 13.1 mmol). After stirring at rt for 0.5 h, the mixture was concentrated in vacuo and the residue was triturated with DCM to give a red solid. Recrystallization of the solid in 1:1 MeOH/DCM afforded the title compound 119 as a red solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.09-8.22 (m, 2H), 8.00 (s, 1H), 7.77-7.93 (m, 3H), 7.44-7.59 (m, 2H), 6.43 (d, J=5.6 Hz, 1H), 5.99 (d, J=6.1 Hz, 2H), 5.81 (s, 1H), 5.71 (s, 1H), 4.06 (br. s., 4H), 3.99 (s, 3H), 3.86 ppm (br. s., 4H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O4, 508.2 (M+H). found 508.5.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.I[Si](C)(C)C>C(#N)C>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][C:4]1([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[CH2:12][C:3]1=[O:2]
Reactant: COC(=O)C1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COC(=O)C1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of Example 178B (0.18 g, 0.6 mmol) in acetonitrile (2 mL) was added iodotrimethylsilane (TMSI) (0.13 mL, 0.9 mmol). The reaction solution was stirred at room temperature for 3 h. After which, additional 1.5 equivalents of TMSI (0.13 mL) were added and stirring was continued for 2 h. The solution was quenched with water (5 mL) and extracted with ethyl acetate (2× 5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (40%-80% ethyl acetate/hexane) afforded product as a white solid (0.11 g, 65%). 1H NMR (300 MHz, CDCl3) δ ppm 0.46 (m, 1H), 0.79 (m, 7H), 1.41 (m, 1H), 2.29 (m, 1H), 2.53 (m, 1H), 3.60 (s, 3H), 3.83 (m, 1H), 6.11 (s, 1H), 7.52 (m, 3H), 8.12 (d, J=7.72 Hz, 1H); MS m/z 289.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][OH:26])=[N:3]1.[H-].[Na+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>O1CCCC1.CN(C)C=O>[CH2:29]([O:31][CH2:32][O:26][CH2:25][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)[N:2]([CH3:1])[N:3]=1)[CH3:30]
Reactant: CCOCCl
Reactant: Cn1nc(CO)nc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOCOCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Temperature: 25 °C

Procedure:
A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol (3.6 g) in dry tetrahydrofuran (30 ml) and dry dimethylformamide (3 ml), was added to a suspension of an 80% dispersion of sodium hydride in mineral oil (0.31 g), in dry tetrahydrofuran (10 ml).The suspension was heated under reflux for 0.5 h. and cooled to room temperature. Chloromethyl ethyl ether (1.0 ml) was added dropwise, and thesuspension was heated at reflux for 1 h. The solvent was removed under reduced pressure, and the residual yellow oil was partitioned between aqueous sodium carbonate and ethyl acetate. The organic phase was chromatographed on silica using a mixture of dichloromethane:ethanol:0.880ammonia (100:8:1) to give an oil (0.7 g). This oil was distilled to give the title compound (0.44 g) as a pale yellow oil b.p. 220°/0.06 mm Hg.
Reaction SMILES: [Na].[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[SH:7].[C:25]([O:28][CH2:29][C:30]([CH2:32]Cl)=[O:31])(=[O:27])[CH3:26]>CN(C)C=O>[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:7][CH2:32][C:30](=[O:31])[CH2:29][O:28][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)OCC(=O)CCl
Reactant: CCOC(=O)C(C(=O)OCC)=C(S)Nc1ccc(F)c(F)c1F
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(F)c1F)SCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (5.3 g) was dissolved in N,N-dimethylformamide (70 ml) and thereto 1-acetoxy-3-chloroacetone (2.2 g) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered to remove insoluble materials. After the filtrate was evaporated to dryness under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to give the title compound (6.0 g) as pale yellow oil.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])=[CH:7][C:6]=1[O:16][CH3:17].[CH2:18](Br)[C:19]#[CH:20]>CO>[CH3:17][O:16][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:20][C:19]#[CH:18]
Reactant: C#CCBr
Reactant: COc1cc(CCNC=O)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#CCOc1ccc(CCNC=O)cc1OC

Procedure:
Sodium methoxide (32 ml of a 5.4 M solution in methanol, 0.17 mol) is added to a solution of N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide (32 g, 0.16 mol) in methanol (400 ml). Propargyl bromide (20 g, 0.17 mol) is added and the mixture is refluxed for 4 hours. After evaporation the residue is taken up in ethyl acetate (400 ml) and washed with water (2×200 ml). The organic layer is dried over magnesium sulfate and evaporated. The residue is submitted to flash-chromatography to give the N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide. 1H-NMR (300 MHz, CDCl3): 2.44 (t, 1H, C≡CH), 2.73 (t, 2H, CH2CH2), 3.51 (t, 2H, CH2CH2), 3.82 (s, 3H, OCH3), 4.69 (m, 2H, OCH2), 5.53 (bs, 1H, NH), 6.62-6.95 (m, 3H, CH arom.), 8.09 (s, 1H, CHO).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])/[CH:7]=[CH:8]/[CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[O:15]1[CH2:16][CH2:17][N:12]([CH2:9]/[CH:8]=[CH:7]/[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)/C=C/CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/CN1CCOCC1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 4-iodocrotonic acid tert-butyl ester (310 mg) synthesized according to the method described in Journal of Medicinal Chemistry, 2005, vol. 48, pp. 1107-1131 in tetrahydrofuran (3 mL), morpholine (200 μL) was added under ice cooling, and the mixture was stirred at room temperature for 13 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain (E)-tert-butyl 4-morpholino-2-butenoate (B14, 180 mg).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2][CH3:3].[C:13]1([C:19]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:20]2[C:24]([C:25]3[C:30]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=4)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:23][N:22]=[N:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>>[CH2:1]([C:4]1[N:12]([CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[N:20]([C:19]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:21]=[N:22][N:23]=3)=[CH:36][CH:35]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=1)[CH2:2][CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc2ncccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc2cccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
2-propyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 2-propylimidazo[4,5-b]pyridine (19 mg, 0.118 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (60 mg, 0.108 mmol), and NaH (0.236 mmol).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.75 (t, J=7.5 Hz, 3 H), 1.10-1.40 (m, 15 H), 1.93 (tdd, J=7.0, 7.0, 1.0 Hz, 2 H) 3.30-3.50 (m, 2 ), 4.37 (d, J=12.0 Hz, 1 H), 4.43 (d, J=12.0 Hz, 1 H), 5.20-5.40 (m, 1 H), 5.9 (dt, J=16.0, 1.1 Hz, 1 H), 7.0-7.40 (m, 4 H). FAB-MS: calculated for C23H30NOCl 372; found 372 (M+H, 100%). Rf=0.26 (10% ethyl acetate/n-hexane). mp 101-104° C.
Reaction SMILES: [CH2:1]1[CH:8]2[NH:9][CH:3]([CH2:4][C:5]([CH2:7]2)=O)[CH2:2]1.Cl.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CC(O)C.CO>[NH:9]1[CH:8]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:17][C:5]=3[CH2:4][CH:3]1[CH2:2][CH2:1]2
Reactant: NNc1ccccc1
Reactant: O=C1CC2CCC(C1)N2
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: c1ccc2c3c([nH]c2c1)CC1CCC3N1
Reaction time: 24 h
Yield: 68.4 %

Procedure:
Method A, A solution of nortropinone hydrochloride (10.0 g, 61.9 mmol) and phenylhydrazine (7.7 g, 71.2 mmol) in 175 mL of 2-propanol was refluxed for 30 minutes, then it was allowed to cool to room temperature, saturated with hydrogen chloride, and heated under reflux for an additional 10 hours. The resulting solution was concentrated under reduced pressure to give a dark residue which was dissolved in methanol. Amberlite IRA-400 resin (pre-washed with methanol) was added until the pH exceeded 10. The mixture was filtered and the filter cake was washed with hot methanol to complete removal of the product from the resin. After the filtrate was treated with decolorizing carbon, it was filtered through a pad a diatomaceous earth and concentrated in vacuo. The residue was suspended in 50 mL of methylene chloride and the mixture was held at -5° C. for 24 hours. Filtration afforded 8.4 g (69%) of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole which was converted into a hydrogen fumarate in ethanol, mp 208°-209° C. (dec); NMR (DMSO-d6) d 1.63 (1H, m), 1.90 (1H, m), 2.15-2.19 (2H, m), 2.68 (1H, d, J=16, 4 Hz), 3.31 (1H, dd, J=16.6, 4 7.28 (1H, d, J=8 Hz), 7.46 (1H, d, J=8 Hz), 11.10 (1H, s).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[N:17]=[CH:18][C:19]([C:21]4[C:22]([CH3:29])=[CH:23][C:24]([C:27]#[N:28])=[N:25][CH:26]=4)=[N:20][C:11]2=3)[CH2:5][CH2:4]1.FC(F)(F)C(O)=[O:33].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[N:17]=[CH:18][C:19]([C:21]4[C:22]([CH3:29])=[CH:23][C:24]([C:27]([NH2:28])=[O:33])=[N:25][CH:26]=4)=[N:20][C:11]2=3)[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Temperature: 65 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinonitrile (0.607 g, 1.55 mmol), trifluroacetic acid (2.0 mL, 26.0 mmol) and sulfuric acid (0.5 mL, 9.38 mmol) were combined and heated at 65° C. for 1 h. Reaction pH was adjusted to 10 with sodium carbonate and the resulting solution was extracted with ethyl acetate (3×15 mL). Organic layers were collected, dried over magnesium sulfate, concentrated and purified using reverse-phase preparatory HPLC (10-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined and condensed under reduced pressure and dried under high vacuum to afford the title compound as a yellow solid (0.425 g, 1.04 mmol, 67% yield). MS (ESI) m/z 411.5 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]3[NH:20][C:21]([C:23]([C:25]4[CH:30]=[CH:29][N:28]=[C:27](Br)[CH:26]=4)=[O:24])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37]([N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]3[NH:20][C:21]([C:23]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:42]5[C:41]([CH3:54])=[N:40][N:39]([C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[C:43]=5[CH3:44])[CH:26]=4)=[O:24])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3n2)CC1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(C(=O)OC(C)(C)C)c(C)c1-c1cc(C(=O)c2nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3[nH]2)ccn1
Temperature: 120 °C
Yield: 97.1 %

Procedure:
The mixture of [4-[2-(2-bromo-pyridine-4-carbonyl)-3H-imidazo[4,5-b]pyridine-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (Example 164) (100 mg, 0.205 mmole), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (Example 167) (66 mg, 0.205 mmole), Pd(Ph3)4 (23 mg, 0.021 mmole), 2 molar of K3PO4 aqueous (0.21 ml, 0.41 mmole), and dioxane (3.0 ml) was degassed and heated to 120° C. for 40 minutes in microwave. Reaction solution was diluted with water and extracted with EtOAc. EtOAc layer was concentrated to afford 120 mg of crude 4-{2-[2-(1-tert-butoxycarbonyl-3,5-dimethyl-1H-pyrazol-4-yl)-pyridine-4-carbonyl]-3H-imidazo[4,5-b]pyridin-5-yl}-piperazine-1-carboxylic acid tert-butyl ester, which was dissolved in 3 ml of 2 molar HCl ether solution. The acidic solution was stirred for 2 hours, then solvent was removed. Residue was washed with EtOAc and was purified by using HPLC, eluting with 10 to 20% of acetonitrile in water (0.1% of NH4OH) to yield [2-(3,5-Dimethyl-1H-pyrazol-4-yl)-pyridin-4-yl]-(5-piperazin-1-yl-3H-imidazo[4,5-b]pyridine-2-yl)-methanon (20 mg, 24%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 2.41 (s, 6H), 2.94 (m, 4H), 3.61 (m, 4H), 6.88 (d, J=9.03 Hz, 1H), 7.87 (d, J=9.03 Hz, 1H), 7.94 (d, J=5.02 Hz, 1H), 8.17 (s, 1H), 8.76 (d, J=5.02 Hz, 1H). HR-MS m/z 403.1981 (M+1).