Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]=[C:8]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO.C(O)C>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1cc2ccccc2s1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1cc2ccccc2s1

Procedure:
To a stirred suspension of 10% palladium on carbon (45 mg) in methanol (5 mL) was added a solution of 3-(benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acid tert-butyl ester 29-7b (220 mg) in ethanol (5 mL) and the mixture was subjected to an atmosphere of hydrogen for 48 hours. The reaction mixture was filtered through Celite and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with 9:1 ethyl acetate/methanol to give 29-8b as a colorless oil.
Reaction SMILES: O[CH:2]([C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:15]([NH:17][C:18]1([C:27]([OH:29])=[O:28])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:16])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.Cl.[H][H]>C(O)C.CO.[Pd]>[CH3:34][O:33][C:32]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]2([C:27]([OH:29])=[O:28])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26]2)=[O:16])=[CH:13][C:12]=1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(O)COc1cccc(C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1CCOc1cccc(C)c1

Procedure:
The compound of example 114 (20 mg, 0.043 mmol) was dissolved in ethanol (2 ml), a 0.5 M solution of hydrogen chloride in methanol (0.2 ml) was added and the mixture was hydrogenated overnight in the presence of palladium on charcoal (10%) at room temperature at a hydrogen pressure of 5 bar (complete conversion of the starting compound). After filtration over a small plug of silica gel and evaporation, the residue was purified by preparative RP HPLC (water/ACN gradient).
Reaction SMILES: [Cl-].[CH2:2]([P+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:4][CH3:5].COC1C=CC(O)=CC=1.[C:28]([Cl:33])(=[O:32])[C:29]([CH3:31])=[CH2:30]>C(#N)C>[Cl-:33].[CH2:11]([P+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][O:10][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC[P+](CCCC)(CCCC)CCCO
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCCC[P+](CCCC)(CCCC)CCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-butyl(3-hydroxypropyl)phosphonium chloride dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 75.8 g (0.725 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature as above. The absence of an unreacted substance was confirmed using FT-IR, and the reaction solution was concentrated and dried with a vacuum pump to give 290.3 g of a slightly yellow liquid. The titration purity was 94.6% and the yield was 100.0%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.CCN(CC)CC>O1CCOCC1>[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: c1ccc2c(c1)CCN2
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: ClCCCN1CCc2ccccc21
Temperature: 70 °C
Reaction time: 15 h
Yield: 45.4 %

Procedure:
To a solution of 1-bromo-3-chloropropane (1.98 g, 12.6 mmol) and indoline (500 mg, 4.20 mmol) in 1,4-dioxane (6.0 mL) was added Et3N (2.12 g, 21.0 mmol) at 20° C. The reaction mixture was then stirred for 15 h at 70° C. The reaction mixture was cooled to 20° C. and quenched by addition of H2O. The product was extracted with Et2O. The organic solution was then washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. 1-(3-Chloro-1-propyl)indoline (373 mg, 45%) was isolated by flash chromatography on a silica gel column by elution with EtOAc/Hexanes a pale yellow oil. 1H NMR (CDCl3, 300 MHz) δ2.07 (qu, 2H, J=6.2 Hz), 2.97 (t, 2H, J=8.2 Hz), 3.24 (t, 2H, J=6.6 Hz), 3.35 (t, 2H, J=8.3 Hz), 3.68 (t, 2H, J=6.2 Hz), 6.50-6.56 (m, 1H), 6.66 (t, 1H, J=6.6 Hz), 7.04-7.10 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:4]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([C:4]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)nc1C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)c(C(C)=O)n1
Reaction time: 1.5 h

Procedure:
Ethyl 2-acetyl-6-methoxynicotinate (0.92 g, 4.13 mmol) in 20 ml of methanol is stirred with lithium hydroxide monohydrate (0.18 g, 4.20 mmol) in 3 ml of water. After 1.5 hours, the water and methanol are removed by rotoevaporation The residue is dissolved in chloroform and 3N hydrochloric acid. The aqueous phase is extracted with chloroform and the combined organic extracts are washed with brine and dried and the solvent is removed to give 2-acetyl-6-methoxynicotinic acid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+]>CCO.O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:22])=[O:3])[CH2:7][CH2:8]2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (11.7 g, 38 mmol, 1 eq.) in 154 mL of EtOH was added a solution of NaOH (3.07 g, 77 mmol, 2 eq.) in 154 mL of H2O. The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and treated with 1 N HCl to pH 5. The resulting mixture was freeze dried using lyophilizer to remove H2O. The resulting yellow solids were washed with dichloromethane/methanol and filtered off NaCl. The filtrate was concentrated to give the title compound as a white solid (11 g, 38 mmol). Exact mass calculated for C15H20N1O4 278.1. MS (ESI) m/z 278.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]2[N:7]=[C:20]([OH:21])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:15]([OH:16])[N:4]2[CH:3]=1
Reactant: Cc1cnc(N)[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1cn2c(O)c(-c3ccccc3)c(O)nc2n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
18 g (135 mmol) 5-Methyl-1H-imidazol-2-ylamine are dissolved in 155 mL DMF and 31.8 g (135 mmol) diethyl phenylmalonate are added. After dropwise addition of 61.5 g (404 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. for 16 h. The DMF has been removed and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (250 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (10.2 g=31%), which is used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C([O-])(O)=O.[Na+].[CH2:15]([N:19]([CH2:34][CH2:35][CH2:36][CH3:37])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[C:25]2[S:30](Cl)(=[O:32])=[O:31])[CH2:16][CH2:17][CH3:18]>O.CC(C)=O>[CH2:15]([N:19]([CH2:34][CH2:35][CH2:36][CH3:37])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[C:25]2[S:30]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:32])=[O:31])[CH2:16][CH2:17][CH3:18]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CCCCN(CCCC)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCN(CCCC)c1cccc2c(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)O)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two mmoles of aspartic acid and 4 mmoles of NaHCO3 were dissolved in 5 ml of water. A solution containing 1 mmol of 5-dibutylamino-naphthalene-1-sulfonyl chloride (Bansyl chloride, Purchased from TCI) in acetone was slowly added. More acetone was added until the solution was clear. The mixture was stirred overnight at room temperature and protected from light. Acetone was removed by flash evaporation and the remaining water solution was acidified to a of pH=4.5 to 5 by adding 2M citric acid. Then, NaCl was added until saturation and the solution was extracted with three portions of ethyl acetate (20 ml each). Extracts were combined, dried over MgSO4 and the solution was filtered. The solvent was removed and the residue was purified by liquid chromatography on a silica gel. A gradient of 0 to 5% methanol in dichloromethane was used as eluent. Fractions containing the desired product were combined and solvents removed. The residue was triturated in 1:1 ether: petroleum ether. The precipitate was filtered out and dried in vacuum overnight thus affording 5-dibutylamino-naphthalene-1-sulfonyl)-L-aspartic acid (NST705).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25](OCC)=[O:26]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][CH:25]=[O:26])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reactant: CCOC=O
Solvent: CN(C)C=O
Product: O=CN[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 90 °C

Procedure:
A mixture of trans-N1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (50 mg, 0.146 mmol) and ethyl formate (0.37 mL) in DMF (1.2 mL) was heated at 90° C. for 6 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo and purified b prep-HPLC to give EX. 8-83 (22 mg, 41%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl-].CS(O[CH2:21][CH2:22][NH+:23]([CH3:25])[CH3:24])(=O)=O.C(O)(=O)C>COCCOC>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: C[NH+](C)CCOS(C)(=O)=O
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
20 g (0.12 mol) of ethyl 4-hydroxybenzoate were dissolved in 300 mL of ethylene glycol dimethyl ether in a nitrogen atmosphere. 11.6 g (0.29 mol) of 60% sodium hydroxide were added in portions over the course of 25 minutes while stirring at room temperature followed by heating to 50° C. and stirring for 1 hour. Moreover, 29.4 g (0.14 mol) of [2-(methanesulfonyloxy)ethyl]dimethylammonium chloride were added in portions over the course of 1 hour at the same temperature followed by additionally stirring for 2 hours. After adding 4 mL of acetic acid while cooling with ice, the precipitate that formed was filtered out. The filtrate was concentrated and ethyl acetate was added to the residue followed by extraction with 3% sulfuric acid. After washing the aqueous phase with ethyl acetate, potassium hydrogen carbonate was added to bring to pH8 followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate followed by distilling off the solvent to obtain 26.3 g of the target substance (yield: 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.CSC.Cl[Si](C)(C)C.[O:24]=[C:25]([CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:26]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:28]([CH3:30])([CH3:29])[CH2:27][C:25](=[O:24])[CH3:26])[CH:7]=1
Reactant: CC(=O)C=C(C)C
Reactant: COc1ccc(F)cc1Br
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc(F)cc1C(C)(C)CC(C)=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a stirred solution of 2-bromo-4-fluoro anisole (3.24 mL, 25 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under argon was added n-butyl lithium (17.2 mL of 1.6 M solution in hexanes, 27.5 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with a solution of cuprous iodide in dimethyl sulfide (4.76 g in 15 mL, 25 mmol) and stirred for 15 minutes at −78° C. Then chlorotrimethylsilane (6.4 mL, 50 mmol) was added, followed by a solution of mesityl oxide (2.9 mL, 25 mmol) in anhydrous THF (5 mL). The reaction was stirred at −78° C. to −60° C. for 4 hours and then quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. The combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a light brown liquid (85% yield) which was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:23]1[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccncc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-pyridinylboronic acid to give (6-methoxy-1-pyridin-4-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 318(MH+).
Reaction SMILES: [O:1]=[C:2]1[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[NH:3]1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:27]([N:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:2]1=[O:1])[CH3:28]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-n3c(=O)[nH]c4cccnc43)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2ncccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A mixture of tert-butyl 5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (900 mg), ethyl iodide (418 mg) and cesium carbonate (1.25 g) in DMF (10 mL) was stirred at 50° C. for 12 h, treated with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give tert-butyl 5-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (830 mg) as an amorphous solid.
Reaction SMILES: C(O)(=O)CCCC.NC1C=CNC(=O)C=1N(C1C=CC(C2C=CC=CC=2C2NN=NN=2)=CC=1)C.[NH2:35][C:36]1[C:37](=[O:50])[NH:38][CH:39]=[CH:40][C:41]=1[NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Br[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]#[N:66])=[CH:55][CH:54]=1>>[CH2:43]([NH:42][C:41]1[CH:40]=[CH:39][NH:38][C:37](=[O:50])[C:36]=1[NH:35][CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]#[N:66])=[CH:57][CH:58]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: Nc1c(NCc2ccccc2)cc[nH]c1=O
Agent: CN(c1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1c(N)cc[nH]c1=O
Solvent: CCCCC(=O)O
Product: N#Cc1ccccc1-c1ccc(CNc2c(NCc3ccccc3)cc[nH]c2=O)cc1

Procedure:
A mixture of 1.02 g of valeric acid, 3.59 g of 4-amino-2-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-yl-methylamino]-1,2-dihydropyridine (obtainable by reacting 3-amino-4-benzylamino-1,2-dihydro-2-oxopyridine with 4-bromomethyl-2'-cyanobiphenyl to give 4-benzylamino-3-(2'-cyanobiphenyl-4-ylmethylamino)-1,2-dihydro-2-oxopyridine, reacting the latter with trimethyltin azide according to Example 13 to give 4-benzylamino-3-[2'-(tetrazol-5-yl) biphenyl-4-ylmethylamino]-1,2-dihydro-2-oxopyridine, and removing the benzyl group by hydro-genolysis! and 50 g of polyphosphoric acid is heated at 140° for 5 hours. 4-amino-2-oxo-3-[N-2'-(tetrazol-5-yl)biphenyl-4-ylmethyl-N-valerylamino]-1,2-dihydro-pyridine and 2-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-ylmethylamino]-4-valerylamino-1,2-dihydropyridine are formed in situ as intermediates. The mixture is cooled, poured on to ice, rendered alkaline with sodium hydroxide solution and worked up in conventional manner to give 2-butyl-4-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]-4,5-dihydro-3H-imidazo[4,5-c]pyridine, m.p. 167°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[C:15]([CH3:20])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[C:15]([CH3:20])[CH:14]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)ccc1I
Product: Cc1cc(Br)ccc1-c1ccc(CO)cc1
Yield: 7.1 %

Procedure:
In accordance with Example 4-(2), but using [4-(hydroxymethyl)phenyl]boronic acid instead of (4-bromophenyl)boronic acid, and 4-bromo-1-iodo-2-methylbenzene instead of tert-butyl[2-(4-iodophenyl)ethoxy]dimethylsilane, the title compound (yield 7.1%) was afforded as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1)[CH3:8].[C:21](O)(=[O:24])[CH:22]=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)CCl>[CH:16]([C:11]1[C:12]2[O:15][C:22](=[O:23])[CH:21]([OH:24])[C:13]=2[CH:14]=[C:9]([C:7]([CH3:19])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:20])[CH:10]=1)([CH3:17])[CH3:18]
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)c(C(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCCC(C)(C)c1cc(C(C)C)c2c(c1)C(O)C(=O)O2
Temperature: 25 °C

Procedure:
5-Methyl-5-(4-hydroxy-3-isopropyl phenyl)-hexanoic acid methyl ester (10.0 g), glyoxylic acid (6.4 g of the 50% solution in water) and p-toluene sulphonic acid (40 mg) are heated in 40 ml of ethylene chloride under nitrogen at reflux in an apparatus designed for the removal of water. After 5 hours the reaction mixture is cooled to room temperature, washed two times with 25 ml water, dried over magnesium sulphate and evaporated under reduced pressure to give 13 g of 7-isopropyl-5-(4-methoxycarbonyl-1,1-dimethylbutyl)-3-hydroxy-3H-benzofuran-2-one as a yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[N:8][CH:7]=1)=[O:5].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:2]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=2)=[N:8][CH:7]=1)[CH3:1]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Ethyl 6-chloro nicotinate (5.00 g, 26.9 mmol), 4-(trifluoromethoxy)phenol (5.28 g, 29.6 mmol), potassium carbonate (4.84 g, 35.0 mmol) and N,N-dimethylformamide (50 ml) were mixed and stirred at 100 to 110° C. overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→70:30) to afford the title compound as a colorless oil (7.48 g, 85%).
Reaction SMILES: [Mg].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.BrC(Br)C.[CH2:22]1[O:24][CH2:23]1.O1CCCC1>O1CCCC1.O>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:22][CH2:23][OH:24])=[CH:13][CH:12]=1
Reactant: C1CO1
Reactant: Brc1ccc(CCOC2CCCCO2)cc1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(CCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
Magnesium (1.31 g, 53.90 mmol) was added to a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene (14.00 g, 49.09 mmol) in tetrahydrofuran (20 ml). Then dibromoethane (0.1 ml) was added under an atmosphere of nitrogen gas, and the mixture was stirred under room temperature for 1 hour. After cooling to ice-cooling temperature, 2M-ethylene oxide/tetrahydrofuran solution (49.09 ml, 98.18 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl alcohol (6.00 g, 42%) .