Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:34][C:33]([F:36])([F:35])[C:29]1[N:30]=[C:31]([N:10]2[CH2:11][CH2:12][CH:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH2:3]3)[CH2:8][CH2:9]2)[CH:32]=[CH:27][N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: FC(F)(F)c1nccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccnc(C(F)(F)F)n3)CC2)CC1
Temperature: 70 °C

Procedure:
The tert-butyl 4,4′-bipiperidine-1-carboxylate (28.5 mg, 0.11 mmol) and cesium carbonate (106 mg, 0.32 mmol) were stirred in NMP (0.5 ml) and the 4-bromo-2-(trifluoromethyl)pyrimidine (12 mg, 0.053 mmol) was added. The mixture was heated at 70° C. for 2 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[OH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>CN(C)C=O>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:18][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)CCCC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCC(C)CCCC(C)C)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
Under an argon atmosphere, potassium carbonate (12.5 g, 90.3 mmol) was suspended in anhydrous N,N-dimethylformamide (100 ml), 1-bromo-3,7-dimethyloctane (13.3 g, 60.1 mmol) and methyl (4-hydroxy)benzoate (8.74 g, 57.4 mmol) were added, and the mixture was stirred at 70° C. for 16 hr. The reaction mixture was filtered to remove potassium carbonate. Water (50 ml) was added and the mixture was extracted with hexane (250 ml). The extract was washed successively with 1.0 mol/l aqueous hydrochloric acid solution (100 ml), aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml). The obtained organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (16.1 g, 95.7%) as a colorless oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1.O>CS(C)=O>[C:1]([CH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1)#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(OC)nc(CCl)n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)nc(CC#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
16.7 g of dried sodium cyanide was dissolved in 850 ml of dimethyl sulfoxide at 90° C. under N2 protective gas. At this temperature, 52.8 g of 2-chloromethyl-4,6-dimethoxypyrimidine, dissolved in 280 ml of dimethyl sulfoxide, are added dropwise over the course of 2 hours. Stirring is continued for 1 hour at 90° C., and the mixture is cooled to room temperature and poured into 300 ml of water. The aqueous phase is extracted seven times using ether, and the combined organic phases are washed using saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in a rotary evaporator. This gives 29.1 g of crude product, from which 2-cyanomethyl-4,6-dimethoxypyrimidines of melting point 65°-67° C. are obtained after column chromatography (SiO2 ; CH2Cl2 /CH3OH; 98.5/1.5).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [Na+]
Solvent: O
Solvent: CC#N
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F

Procedure:
Prepared according to Procedure A using 2,8-dichloroquinoline 3-carbaldehyde (1.0 g, 4.42 mmol), 2-trifluoromethylphenyl boronic acid (0.924 g, 4.87 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.256 g, 0.221 mmol, 0.05 eq), and sodium carbonate (2.34 g, 22.1 mmol, 5 eq) in acetonitrile (30 mL) and water (10 mL). After purification, 2-(2-trifluoromethylphenyl)-8-chloroquinoline-3-carbaldehyde was obtained as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.95 (1 H, s), 9.19 (1 H, s), 8.33 (1 H, dd, J=8.5, 1.2 Hz), 8.20 (1 H, dd, J=7.3, 1.2 Hz), 7.95 (1 H, d, J=7.3 Hz), 7.74-7.87 (2 H, m), 7.63 (1 H, d, J=7.3 Hz) Mass Spectrum (ESI) m/e=336.1 and 338.0 (M+1)
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([NH:8][C:9](=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([C:28]([O:30]C)=[O:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[OH-].[Li+]>>[CH2:1]([C:3]1[O:7][N:6]=[C:5]([NH:8][C:9](=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(C(=O)OC)cc34)cc2)no1
Agent: [Li+]
Agent: [OH-]
Product: CCc1cc(NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(C(=O)O)cc34)cc2)no1
Yield: 78 %

Procedure:
Using an analogous procedure to that described in Example 8, N-(5-ethylisoxazol-3-yl)-2-[4-(7-methoxy-6-methoxycarbonylquinolin-4-yloxy)phenyl]acetamide was reacted with lithium hydroxide to give the title compound in 78% yield; 1H NMR: (DMSOd6) 1.2 (t, 3H), 2.68-2.78 (m, 2H), 3.76 (s, 2H), 3.99 (s, 3H), 6.5 (d, 1H), 6.64 (s, 1H), 7.29 (d, 2H), 7.47 (d, 2H), 7.51 (s, 1H), 8.56 (s, 1H), 8.68 (d, 1H), 11.22 (br s, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[F:39].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=3[F:39])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])cc3F)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 77 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (402 mg, 1 mmol), 1,2-difluoro-4-nitrobenzene (318 mg, 2 mmol) and potassium carbonate (414 mg, 3 mmol) in 1,2-dimethoxyethane (20 mL) and water (5 mL) was heated at 100° C. for 48 hours. The solution was cooled to room temperature and concentrated, diluted with ethyl acetate (50 mL) and washed with water. The organic layer was dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 5-cyclopropyl-6-(N-(2-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (420 mg, 0.77 mmol, 77% yield) as a yellow solid. LCMS (m/z, ES+)=542 (M+H+)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(F)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4 b]indole (5.0 g, 16.33 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (0.98 g, 24.5 mmole). After 10 min, 4-fluorobenzyl bromide 3,40 g, 18.0 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (6.42 g, 95%) as a white solid: MS (ES) m/e 415 (M+H)+.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[CH:15]1([NH:14][CH2:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC(CNC3CC3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: C1CC(CNC2CC2)CN1
Yield: 76.1 %

Procedure:
A mixture of 13.6 g (59.0 mmole) of 1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinemethanamine, 0.5 g of 20% palladium on carbon and 140 mL of methanol was shaken in an atmosphere of hydrogen at about 4.5×105Pa at room temperature for 24 hours. The catalyst was removed by filtering through Celite, the filtrate concentrated and distilled in vacuo to give 6.3 g of N-cyclopropyl-3-pyrrolidinemethanamine, bp 88°-90°/13 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:6][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)NC(C)(C)Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)NC(C)(C)Cc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 98 %

Procedure:
An ice-cooled solution of 3.3 g (12 mmol) of N-[2-(4-bromophenyl)-1,1-dimethylethyl]-acetamide in 3 ml of concentrated sulfuric acid was treated dropwise with a mixture of 3 ml of concentrated sulfuric acid and 6 ml of 90% nitric acid. After 1 hour the mixture was cautiously added to 200 ml of ice/water and the precipitated product extracted with 150 ml of dichloromethane. The organic solution was dried over magnesium sulfate, filtered and evaporated to give 3.7 g (98%) of N-[2-(4-bromo-3-nitrophenyl)-1,1-dimethyl-ethyl]acetamide as a white solid. [Mass spectrum (ESI) MH+ =315].
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].Cl.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO>[NH2:8][C:7]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: CC(C)(C#N)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C#N)c1cc(N)n(-c2ccccc2)n1
Temperature: 60 °C
Yield: 53.9 %

Procedure:
To a solution of 2,2-dimethyl-3-oxopentanedinitrile (500 mg, 3.7 mmol) prepared as described in Example 125A Step 1, in anhydrous EtOH (33 ml) was added phenylhydrazine hydrochloride (763 mg, 3.7 mmol) and the reaction mixture was heated at 60° C. for 2 h. The solvent was removed under reduced pressure and the residue taken in EtOAc, washed with water and brine and the organics combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 1:1) to afford 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (451 mg, 54%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.76 (s, 6H), 3.84 (brs, 2H), 5.69 (s, 1H), 7.26-7.57 (m, 5H); LC-MS (ESI) m/z 227 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCSc1ccc(C(=O)OC)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCCO
Product: CCSc1ccc(C(=O)OC)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 85 %

Procedure:
Using a procedure analogous to Example 1-D, methyl 2-hydroxy-4-(ethylthio)benzoate and 3-t-butoxycarbonylamino-propanol gave the title compound as a solid (10.41 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:3]=1[F:23].O1CCCC1>CO>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:3]=1[F:23]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1C
Yield: 96.4 %

Procedure:
To a mixture comprised of methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate (2.52 g, 0.00789 mol), tetrahydrofuran (50 ml), methanol (50 ml) and washed Raney nickel (0.5 g) was initially applied 48.6 psi of hydrogen gas at 30.2° C. in a shaker for 4 hours 48 minutes. The mixture was filtered and the filtrate concentrated in vacuo to afford 2.20 g of a salmon-colored amorphous solid; 96% yield; 1H-NMR (400 MHz; DMSO) δ 7.84 (s, 1H), 7.04 (d, 1H, J=7.1 Hz), 6.98 (d, 1H, J=1.2 Hz), 6.95–6.91 (m, 1H), 6.68–6.64 (m, 1H), 6.40–6.36 (m, 1H), 5.39 (s, 2H), 4.73 (s 2H), 3.66 (s, 3H), 2.21 (s, 3H); 19F-NMR (376 MHz; DMSO) δ −139.66 (s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][CH2:15][CH2:14]2)[N:5]=[C:4]([NH:23][CH2:24][C:25]([CH3:37])([CH3:36])[CH2:26][CH2:27][CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][CH2:29]2)[N:3]=1.[CH2:38]([NH:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:38]([N:41]([CH2:42][CH2:43][CH3:44])[C:2]1[N:3]=[C:4]([NH:23][CH2:24][C:25]([CH3:37])([CH3:36])[CH2:26][CH2:27][CH:28]2[CH2:33][C:32]([CH3:34])([CH3:35])[NH:31][CH2:30][CH2:29]2)[N:5]=[C:6]([NH:8][CH2:9][C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][CH2:15][CH2:14]2)[N:7]=1)[CH2:39][CH3:40]
Reactant: CC(C)(CCC1CCNC(C)(C)C1)CNc1nc(Cl)nc(NCC(C)(C)CCC2CCNC(C)(C)C2)n1
Reactant: CCCNCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCN(CCC)c1nc(NCC(C)(C)CCC2CCNC(C)(C)C2)nc(NCC(C)(C)CCC2CCNC(C)(C)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
53.6 g of 2-chloro-4,6-bis-(2,2,6,6-tetramethyl-4-piperidylbutylamino)-1,3,5-triazine, together with 15.0 g of dipropylamine in 250 ml of xylene, are stirred under reflux for 16 hours. After cooling to room temperature, 100 ml of 2N sodium hydroxide solution are added, the mixture is stirred vigorously for 15 minutes and the aqueous phase is then separated off. The xylene solution is dried over sodium sulfate and evaporated in vacuo. Crystallisation of the resulting residue from acetonitrile gives 2-dipropylamino-4,6-bis-(2,2,6,6-tetramethyl-4-piperidylbutylamino)-1,3,5-triazine, melting point 95°-96° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[CH:14]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:22]=[CH2:23])[CH:21]=3)[N:12]=[CH:11][C:10]=2[CH:9]=[N:8]1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:22]([C:20]1[CH:21]=[C:16]([C:13]2[N:12]=[CH:11][C:10]3[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:24])([CH3:1])[CH3:25])[C:15]=3[CH:14]=2)[CH:17]=[N:18][CH:19]=1)[CH3:23]
Reactant: C=Cc1cncc(-c2cc3c(cn2)cnn3COCC[Si](C)(C)C)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1cncc(-c2cc3c(cn2)cnn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
To a solution of trimethyl-[2-[[6-(5-vinyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl]silane (543.4 mg) in Ethanol (50 mL) in a 250 mL round bottom flask was added Pearlman's catalyst (0.1850 mmol; 129.9 mg). The flask was vacuumed and connected with a balloon of Hydrogen. The mixture was stirred at room temperature overnight. The mixture was filtered through Celite. The filtrate was concentrated. The residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford 2-[[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (87 mg, 27%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:22]([OH:24])=O)[CH3:3].C(N1C=CN=C1)([N:27]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.O>[CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:22]([NH2:27])=[O:24])[CH3:3]
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(OCc3ccccc3)cc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1c(C(N)=O)oc2ccc(OCc3ccccc3)cc12
Yield: 51.9 %

Procedure:
A mixture of 3-(1-methylethoxy)-5-(phenylmethoxy)-2-benzofurancarboxylic acid (0.53 g, 1.6 mmol) and 1,1'-carbonyldiimidazole (0.29 g, 1.8 mmol) in 20 mL of tetrahydrofuran is stirred at reflux for 2 hours. The cooled reaction mixture is treated with 3.0 mL of ammonium hydroxide solution and stirred at room temperature for an additional 2 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous magnesium sulfate), and evaporated. Purification of the residue by flash chromatography (silica gel, 50% ethyl acetate in hexane elution) gives 0.27 g (53%) of product; mp=158°-160° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K]>CN(C)C=O>[C:37]1(=[O:47])[N:41]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=2[C:11]([NH:13][C:14]2[CH:32]=[CH:31][C:17]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.6 %

Procedure:
A mixture of 1-{4-[2-(6-bromohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (4.00 g), potassium phthalimide (2.02 g) and dimethylformamide (100 ml) is stirred at 100° C. for 5 hours. The reaction mixture is filtered and the filtrate is distilled off. The resulting residue is extracted with ethyl acetate and the organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane), and recrystallized from methanol/diethyl ether to give 1-{4-[2-(6-phthalimidohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (4.06 g) as white powder, m.p. 145-146.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@@H:10]1[C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc([C@H]2CCCN2C(=O)OC(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 16A (2.8 g) in THF (20 mL) was added lithium hydroxide monohydrate (500 mg) in water (5 mL). The mixture stirred at ambient temperature overnight and partitioned between ethyl acetate and 0.5 M hydrochloric acid. The extract was washed with water, dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[CH2:12]([SH:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH2:12]([S:14][CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: CCS
Reactant: O=C(O)CC(Br)C(=O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSC(CC(=O)O)C(=O)C(=O)O

Procedure:
To a suspension of 1.00 g of 3-bromo-2-oxoglutaric acid in 20 ml of dichloromethane was added 0.33 ml of ethane thiol while stirring under ice-cooling, followed by addition of 1.83 ml of triehtylamine. The reaction mixture was stirred at room temperature for 3 hours, then the solvent was distilled off. The residue was distributed to ethyl acetate and 1N-HCl. The ethyl acetate layer was separated, washed with water and dried (Na2SO4), followed by distilling off the solvent to give 0.82 g of 3-ethylthio-2-oxoglutaric acid as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH:19]1([C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH:19]1([C:22]2[N:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=3[C:10]#[C:11][C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=3)=[CH:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
Reactant: OB(O)c1ccc(C2CC2)nc1
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: COCCOC
Solvent: O
Product: CCc1nccc(-c2ccc(C3CC3)nc2)c1C#Cc1ccc(N)nc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 150 mg (0.58 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 142 mg (0.87 mmoL) 2-cyclopropyl-pyrid-5-yl boronic acid, 4.5 mg (0.03 mmol) Pd(PPh3)4 and 154 mg (1.11 mmol) K2CO3 in a mixture of 6.0 mL DME and 1.5 mL water. The reaction mixture is stirred twice under microwave irradiation at 150° C. for 120 min. The reaction mixture is concentrated in vaccuo and the crude product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 68 mg (34%).