Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:22][C:21]1[C:3]2[C:2](=[CH:20][CH:19]=[CH:18][C:4]=2[O:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12](=[O:13])[NH:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:7]2)[N:1]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)NC(=O)C1CCC(Oc2cccc(N)c2C#N)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCC(C(=O)NC(C)C)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 4-(3-amino-2-cyanophenoxy)-N-isopropylcyclohexanecarboxamide (Example 45b) and ethyl 3-oxobutanoate as a yellow solid (56%). MS 414 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[CH:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34](Cl)=[C:29]3[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34]([O:12][C:9]4[CH:10]=[CH:11][C:6]([C:3]5[CH:4]=[CH:5][S:1][CH:2]=5)=[CH:7][CH:8]=4)=[C:29]3[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(-c2ccsc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-c5ccsc5)cc4)ncnc32)CC1
Temperature: 160 °C
Yield: 23.5 %

Procedure:
A mixture of 4-thiophen-3-yl-phenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 16 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-thiophen-3-yl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 22%) as a white solid. Mass spectrum MH+=478.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]1[O:17][C@@H:16]1[CH2:18][OH:19]>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:15][C@H:16]([OH:17])[CH2:18][OH:19])[N:5]=1)([O-:3])=[O:2]
Reactant: OC[C@@H]1CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared as in Example 5, 3.00 g, 26.55 mmol) in N,N-dimethylformamide (15 mL) was treated with solid potassium carbonate (11.0 g, 79.65 mmol) and (R)-(+)-glycidol (3.93 g, 53.10 mmol) and placed in a sealed tube and heated at 100° C. for 1 h in an oil bath. After this time the N,N-dimethylformamide was removed in vacuo. Purification by AnaLogix Intelliflash system (80 g column, 0% to 10% methanol/dichloromethane) afforded (S)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (2.28 g, 46%) as a yellow oil: LR-ES-MS m/z calculated for C6H9N3O4 [M]+ 187, observed [M+H]+ 188.
Reaction SMILES: [CH3:1][P:2]([CH3:10])([CH:4]([OH:9])[C:5](OC)=[O:6])=[O:3].[NH3:11]>CO>[CH3:1][P:2]([CH3:10])([CH:4]([OH:9])[C:5]([NH2:11])=[O:6])=[O:3]
Reactant: COC(=O)C(O)P(C)(C)=O
Reactant: N
Solvent: CO
Product: CP(C)(=O)C(O)C(N)=O
Reaction time: 144 h
Yield: 82.2 %

Procedure:
16.6 g (0.1 mol) of methyl 2-(dimethylphosphinoyl)-2-hydroxyacetate are dissolved in 70 ml of methanol, which has first been gassed with NH3 gas for 10 minutes. After the mixture has been left to stand in a bomb tube at 25° for six days, it is filtered and concentrated and the oily residue is digested with ethyl acetate. 12.4 g (82.2%) of the amide of melting point 155° are obtained.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([OH:17])=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:18][C:19]1[C:20]([CH3:26])=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26])=[CH:13][C:12]([OH:17])=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(O)ccc1N
Reactant: CCCC(=O)c1cnc2ccc(O)cc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2ccc(O)cc2c1Nc1ccc(O)cc1C
Yield: 24.1 %

Procedure:
3-Butyryl-4-chloro-6-hydroxyquinoline (4.0 g) and 4-amino-m-cresol (2.0 g) were heated together under reflux in 1,4-dioxan (60 ml) for 2 hours. The solvent was evaporated and the residue was dissolved in chloroform and washed successively with 2M HCl, sodium hydrogen carbonate solution (×2) and brine. The organic solution was dried, filtered and evaporated to a brown oil. A quantity of solid material that appeared insoluble in chloroform was combined with the oil and the mixture was chromatographed (silica gel, 2-4% methanol in chloroform) to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-6-hydroxyquinoline (1.3 g, 24%) as orange crystals, m.p. 242°-244°.
Reaction SMILES: [OH-].[K+:2].O.[SH:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[O:7].C(CN(CC([O-])=O)CC(O)=O)N(CC(O)=O)CC([O-])=O.[Na+].[Na+]>O1CCCC1>[OH2:7].[K+:2].[SH:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[C:12]([NH:14][CH2:15][C:16]([O-:18])=[O:17])=[O:13])=[O:7]
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Temperature: 45 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
An aqueous solution of 4N potassium hydroxide (4.65 ml., 0.01 mole) and 4 ml. of water is slowly added to a suspension of N-[3-(mercaptoacetylamino)benzoyl]glycine (5 g., 0.0186 mole) with 5 mg. disodium edetate. Warming the mixture to 45° C. provides a clear solution which is first diluted with 200 ml. of tetrahydrofuran and then cooled in a dry ice-ethanol bath to promote crystallization. After stirring the mixture for a period of 16 hr. at 25° C., the precipitated solid is collected, washed with tetrahydrofuran and dried under vacuum over calcium chloride to provide 5.6 g. (93% yield) of N-[3-(mercaptoacetylamino)benzoyl]glycine potassium salt hydrate, m.p. 175° C. (dec.).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.ClCCl.[CH2:13](N(CC)CC)[CH3:14].C(OCC)(=O)C>CCO.O>[CH:13]([C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[CH2:14]
Reactant: N#Cc1ccc(Br)nc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C=Cc1ccc(C#N)cn1
Temperature: 25 °C

Procedure:
To a stirring solution of 6-bromopyridine-3-carbonitrile (2.0 g, 10.9 mmol), in EtOH (70 mL) were added bis[(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.892 mg, 0.10 mmol), potassium vinyl trifluoroborate (2.93 g, 21.9 mmol), triethylamine (3.0 mL, 21.9 mmol), and water (0.5 mL). The reaction mixture was heated to reflux. Upon completion as determined by reverse phase HPLC-MS (1-2 h) and TLC (eluent: 10% ethyl acetate in hexanes), the reaction was cooled to room temperature, and then was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The extracts were concentrated and chromatographed over a column of SiO2 (0-20% EtOAc hexanes as eluent). Evaporation of the solvent yielded 6-ethenylpyridine-3-carbonitrile.
Reaction SMILES: [C:1]1(=[N:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:9][S:10]([OH:13])(=[O:12])=[O:11].[O:14]=S(=O)=O>>[S:10]([OH:13])([OH:12])(=[O:11])=[O:9].[C:1]1(=[O:14])[NH:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)=O
Reactant: ON=C1CCCCC1
Agent: O=S(=O)(O)O
Product: O=C1CCCCCN1

Procedure:
The cyclohexanone oxime thus obtained was rearranged with oleum to give caprolactam sulfate. Caprolactam sulfate and excess sulfuric acid were neutralized with ammonia.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([Cl:23])=[CH:11][C:12]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=2)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C(C)=C)[CH2:27][CH2:28]C>CN(C=O)C.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>[Cl:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7]([C:27]([CH3:28])=[CH2:26])=[CH:8][N:9]=1
Reactant: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(C)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Reaction time: 5 h
Yield: 69.8 %

Procedure:
To a suspension of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (100 mg, 0.25 mmol) and tributyl(prop-1-en-2-yl)stannane (100 mg, 0.28 mmol) in DMF (2 mL) was added Pd(PPh3)4 (10 mg, 0.02 mmol) at 100° C. under N2, and the mixture was stirred for 5 hours. After concentrated in vacuum, the residue was suspended in H2O and extracted with EA. The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtrated and concentrated to give 2-(2-chloro-5-(prop-1-en-2-yl)pyridin-4-yl)-4-fluoro-1H-indole (50 mg, yield: 70%). 1H-NMR (CDCl3, 400 MHz) δ 8.96 (s, 1H), 8.14 (s, 1H), 7.47 (s, 1H), 7.08˜7.13 (m, 2H), 6.95 (s, 1H), 6.72˜6.76 (m, 1H), 5.39 (s, 1H), 5.23 (s, 1H), 1.77 (s, 3H). MS (M+H)+: 287/289.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([O-])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[Na+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:28])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([Cl:28])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2nnnc2C(=O)[O-])cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Temperature: 15 °C

Procedure:
Following the procedure of Example 3, the sodium salt produced in Example 5 is stirred with pyridine in benzene at 6° C. with rapid addition of oxalyl chloride. The mixture is stirred at 15° C. for one half hour, stripped and scrubbed twice with benzene to yield 1-(p-methoxybenzyl)-1H-tetrazole-5-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[F:21][C:22]([F:38])([F:37])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)=[CH:26][CH:25]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:38])([F:37])[F:21])=[CH:29][CH:28]=2)[CH2:31][C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Reactant: FC(F)(F)Oc1ccc(NCc2ncc[nH]2)cc1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(OC(F)(F)F)cc2)[C@@H]1O
Yield: 47.3 %

Procedure:
The title compound (181 mg, 47%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (200 mg, 0.71 mmol) and 4-trifluoromethoxyphenyl-1H-imidazol-2-ylmethylamine (183 mg, 0.71 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:31]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:31])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 60 °C
Yield: 55 %

Procedure:
To a solution of methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoate [Example 9 (4.34 g, 0.01 mol) in tetrahydrofuran (20 mL) was added N-chlorosuccinimide (1.35 g, 0.01 mol) in portions over a one hour period. The mixture was heated to 60° C. for one-hour. The tetrahydrofuran was evaporated, the residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate solution and water. The dried, concentrated product was flash chromatographed over silica gel with 1:1 hexane/ethyl acetate to provide 2.7 g (55%) of the title compound.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:18]1([C:24]2[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>CN(C)C=O>[N:1]1([CH2:10][C:11]([NH:30][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:29]=2)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cn1cnc2ccccc21
Reactant: Nc1cccc(-c2ccccc2)n1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Cn1cnc2ccccc21)Nc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1H-benzimidazol-1-yl)acetic acid (1 g, 5.68 mmol) (Example 1B) in N,N-dimethylformamide (25 mL) was added thionyl chloride (0.4 mL, 5.56 mmol) drop-wise and the reaction mixture stirred at room temperature for 1 h. 6-Phenyl-pyridin-2-ylamine (5.46 mmol) and pyridine (4 mL) were then added to the reaction mixture and stirred at room temperature for 17 h. The reaction mixture was then concentrated in vacuo and dichloromethane was added and transferred to a separating funnel where the organics were washed with 0.1M hydrochloric acid and 10% ammonium hydroxide solution. The organic layers were combined and washed with saturated aqueous sodium chloride, dried (Mg2SO4), filtered and concentrated in vacuo. The residue was then purified by column chromatography using silica and eluting with 0-10% methanol in dichloromethane, affording the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 5.29 (2H, s), 7.28-7.35 (2H, m), 7.39-7.48 (3H, m), 7.54 (1H, d, J=7.2 Hz), 7.62 (1H, d, J=7.7 Hz), 7.71 (1H, d, J=7.3 Hz), 7.81 (1H, t, J=7.9 Hz), 7.98 (1H, br d), 8.05 (2H, d, J=7.3 Hz), 8.23 (1H, s). MS (ES) m/z: 329.1 [M+H].
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]4[CH:35]=[CH:34][C:25]5[C@H:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:27][O:28][C:24]=5[CH:23]=4)[CH:15]=3)=[C:9]([CH3:36])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH3:36])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]4[CH:35]=[CH:34][C:25]5[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=5[CH:23]=4)[CH:15]=3)=[C:11]([CH3:13])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCCC5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OC2CCCC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
(S)-Methyl 2-(6-((4′-(cyclopentyloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 10d (40 mg, 0.08 mmol) was dissolved in 7 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=2:5), followed by addition of 1M aqueous lithium hydroxide solution (0.8 mL, 0.80 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 4˜5, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (S)-2-(6-((4′-(cyclopentyloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 10 (30 mg, yield 80.0%) as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]2=3)=[O:25])[CH2:20][CH2:19]1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2](=[O:3])[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]3=4)=[O:25])[CH2:20][CH2:19]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CN)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride (Compound number 149) (1.95 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethyl-amine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=533.3
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.[OH-].[Na+]>>[C:13]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)(=[O:15])[CH3:14]
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)Cc1ccc(O)c(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(C(C)=O)c1

Procedure:
In analogy to the procedure of Example XIV, the title compound is prepared from 2.9 g (0.014 mol) of the compound from Example VIII, 2.5 g (0.014 mol) of 2-chloromethylquinoline and 0.56 g (0.014 mol) of sodium hydroxide.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Product: c1cc(CN2CCCCC2)cc(OCCCNc2ccnc3ccccc23)c1
Temperature: 155 °C
Reaction time: 2 h

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (13.51 g) and 4-chloroquinoline (4.45 g) were heated with stirring at 155° C. for 21/2 hours. The cooled reaction mixture was dissolved in 2 Normal hydrochloric acid to pH 3-4 and the acidic solution was extracted with ethyl acetate. The aqueous solution was then basified to pH greater than 9 and was extracted with chloroform several times. The combined chloroform extracts were dried and evaporated to dryness to give the title compound as an oil. This was treated with maleic acid in ethanol to afford 4-[3-[3-(piperidionomethyl)phenoxy]propylamino]quinoline dimaleate (8.9 g), m.p. 127°-127.5° C. (recrystallised from isopropanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14].Cl.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][NH2:26]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[F:14])[N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])[N:26]=1)=[O:16]
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)cc1F
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
4-(4-Bromo-2-fluoro-phenyl)-2-oxo-3-butenoic acid methyl ester (2.0 g, 7.0 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (1.4 g, 7.7 mmol) were added to acetic acid (25.0 mL). The reaction mixture was stirred at 80° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3.0 g of the titled compound as a black liquid.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[N:23]=[N:24][NH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+].CN(C)CCN>CN(C=O)C.CCOC(C)=O.[Cu]I>[Si:1]([O:8][CH:9]([C:22]1[N:23]=[N:24][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Ic1ccccn1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nn[nH]n1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nnn(-c2ccccn2)n1
Temperature: 100 °C
Yield: 20.6 %

Procedure:
In a gas tight vessel, a solution of 5-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-2H-tetrazole (16 mg, 0.043 mmol), 2-iodopyridine (7 μL, 0.064 mmol), CuI (1 mg, 0.004 mmol), K2CO3 (12 mg, 0.085 mmol), and N,N-dimethylethylene diamine (1 μL, 0.006 mmol) in DMF (200 μL) was purged with Ar and sealed. The reaction mixture was warmed at 100° C. for 18 h before it was cooled to room temperature, diluted with EtOAc, and washed with H2O, 9:1 NH4OH: saturated aqueous NH4Cl, and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to afford the crude material that was purified by flash chromatography (SiO2, 1.5×15 cm, 5-10% acetone-hexanes) to afford 2-(5-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-2H-tetrazol-2-yl)-pyridine (4.0 mg, 21%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 8.69 (dd, 1H, J=0.9, 4.8 Hz), 8.16 (d, 1H, J=7.5 Hz), 7.98 (dt, 1H, J=1.8, 7.9 Hz), 7.48 (m, 1H), 7.26 (m, 2H), 7.16 (m, 3H), 5.16 (dd, 1H, J=5.9, 7.4 Hz), 2.58 (t, 2H, J=7.7 Hz), 1.99 (m, 2H), 1.60 (m, 2H), 1.34 (m, 6H), 0.88 (s, 9H), 0.10 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 169.7, 149.6, 149.0, 142.9, 139.5, 128.5, 128.4, 125.7, 125.0, 115.2, 67.4, 37.5, 36.1, 31.5, 29.3, 25.9 (3C), 25.4, 18.4, −4.1, −4.8; HRMS-ESI-TOF m/z 452.2823 ([M+H]+, C25H37N5OSi requires 452.2840).