Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:32])[C:10]([CH2:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:30][N:28]([CH3:29])[C:27]([CH2:26][C:10]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH:11]([CH3:13])[CH3:12])[C:9]([OH:32])=[O:8])=[O:31]
Reactant: COc1ccc(S(=O)(=O)NC(CC(=O)N(C)C)(C(=O)OCc2ccccc2)C(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)NC(CC(=O)N(C)C)(C(=O)O)C(C)C)cc1

Procedure:
To a solution of dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyric acid benzyl ester (1.77 grams, 3.83 mmol) in ethanol (100 mL) was added 10% palladium on activated carbon (644 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyric acid as a white foam, 1.42 grams (100%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[N:8][N:9]([CH3:11])[CH:10]=2)[N:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)=[C:13]([NH:12][C:2]2[C:3]3[C:4](=[N:8][N:9]([CH3:11])[CH:10]=3)[N:5]=[CH:6][CH:7]=2)[CH:18]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Cn1cc2c(Cl)ccnc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nn(C)cc23)cc1
Temperature: 25 °C
Yield: 17.1 %

Procedure:
A mixture of the product of Example 8c (47.3 mg, 0.282 mmol), the product of Example 7b (84.6 mg, 0.310 mmol), Pd2(dba)3 (12.9 mg, 0.0141 mmol), sodium t-butoxide (67.8 mg, 0.706 mmol), and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicycl[3,3,3]undecane (19.3 mg, 0.0564 mmol) in toluene (4 mL) was degassed, left under a positive pressure of nitrogen, and heated under reflux for 2 h. Additional amounts of Pd2(dba)3 (4.0 mg, 0.0044 mmol) and PN3 (4.5 mg, 0.013 mmol) were added the reaction mixture was heated under reflux for an addition 2 h. The mixture was then cooled to room temperature and partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate and the combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 5% MeOH/CH2Cl2, to provide the title compound (0.0195 g, 17% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.03 (s, 3H), 2.29 (s, 3H), 4.11 (s, 3H), 5.97 (d, J=5.15 Hz, 1H), 6.94-7.00 (m, 1H), 7.05 (dd, J=8.09, 1.47 Hz, 1H), 7.19 (s, 1H), 7.26 (d, J=8.82 Hz, 2H), 7.56 (d, J=8.82 Hz, 2H), 8.09 (d, J=5.15 Hz, 1H), 8.20 (s, 1H), 8.80 (s, 1H), 10.04 (s, 1H); MS (ESI+) m/z 404.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:5].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1.Cl>C(#N)C>[Cl:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:5][C:4]3[CH:6]=[C:7]([CH2:16][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[C:8]([N:9]4[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:24][CH:25]=[N:26]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1cc(N)cc(CN2CCCC2)c1N1CCN(C)CC1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(Nc2ccnc3cc(Cl)ccc23)cc(CN2CCCC2)c1N1CCN(C)CC1
Yield: 85.2 %

Procedure:
3-Methyl-4-(4-methylpiperazin-1-yl)-5-(pyrrolidin-1-ylmethyl)aniline (70 mg, 0.24 mmol) and 4,7-dichloroquinoline (50 mg, 1 eq) were refluxed overnight in 5 mL of acetonitrile with 1.25 mL of HCl 1M. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a white solid (92 mg, 84% yield). m/z (ESI) 450.1 [M+H]+;
Reaction SMILES: CS(O[CH:6]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([C:25]#[N:26])[CH:9]=1)[CH3:7])(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O>[N:27]([CH:6]([C:8]1[CH:9]=[C:10]([C:25]#[N:26])[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:16]=2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH3:7])=[N+:28]=[N-:29]
Reactant: CC(OS(C)(=O)=O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[5-cyano-8-(3-fluorophenyl)quinolin-7-yl]ethyl methanesulfonate (28 mg, 0.076 mmol) and sodium azide (24 mg, 0.38 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature overnight. The mixture was then quenched with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, and then dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step (20 mg, 83%). LCMS calculated for C18H13FN5 (M+H)+: m/z =318.1; Found: 318.1.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[C@H:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34](O)=[O:35])=[CH:28]2.Cl.C(N=C=N)C.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:22]([O:21][C:19]([C@H:18]1[C@H:9]([NH:8][C:34]([C:29]2[NH:30][C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:24])=[CH:33][CH:32]=3)=[O:35])[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2C[C@H]1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1Cc2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a stirred solution of trans 2-amino-3-carboethoxy-1,2,3,4-tetrahydronaphthalene trifluoroacetic acid salt (130 mg, 0.39 mmol) and 5-chloroindole-2-carboxylic acid (92 mg, 0.47 mmol) in tetrahydrofuran (8 mL) at room temperature under nitrogen was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 0.78 mmol), 1-hydroxy-7-azabenzotriazole (106, 0.78 mmol), and diisopropylethylamine (0.14 mL, 0.78 mmol). After 2 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1.0 M aqueous hydrochloric acid solution, 1.0 M aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The resulting residue was suspended in methanol. The suspension was filtered and the solid was washed with methanol to obtain the title compound (120 mg, 77%). 13C NMR (400 MHz, d8-tetrahydrofuran) δ 173.5, 161.3, 136.1, 135.2, 135.0, 134.6, 129.8, 129.5, 129.1, 126.9, 126.8, 126.0, 124.4, 121.5, 114.0, 101.8, 61.1, 48.5, 46.5, 36.0, 32.5, 14.5. 1H NMR (400 MHz, d8-tetrahydrofuran) δ 11.18 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.04-7.17 (m, 4H), 6.89 (s, 1H), 4.62 (m, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.15-3.26 (m, 2H), 2.87-3.09 (m, 3H), 1.11 (t, J=7.0 Hz, 3H). MS [M+H]+, 397; [M−H]−, 395.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][C:32]=2[CH3:38])=[O:27])[CH:20]=1)[CH2:13]C(OCC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([C@@H](NC(=O)OCC2C=CC=CC=2)C)C=CC=1.BrC1C=CC(CCO)=C(C)C=1>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][C:32]=2[CH3:38])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Agent: C[C@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Agent: Cc1cc(Br)ccc1CCO
Product: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc([C@H](C)NC(=O)OCc2ccccc2)c1
Yield: 9 %

Procedure:
Using a procedure analogous to that used to prepare 34D, 59B (1.5 g 5.5 mmol) was reacted with 30B to give 59C (2.46 g, 9%) as an oil. MS (ESI) m/z 512.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[CH3:14][C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:17][N:16]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[N:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C)nn1-c1ccc2ccccc2c1
Reaction time: 48 h
Yield: 70 %

Procedure:
To the solution of 2-naphthylboronic acid (5.00 g, 29.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (4.48 g, 29.1 mmol) in 100 mL dry dichloromethane (DCM) were added pyridine (4.7 mL, 58.2 mmol) and anhydrous powder of copper(II) acetate (7.94 g, 43.7 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 2 days under argon. The mixture was diluted with DCM. It was filtered through a celite bed. The blue filtrate was washed with water (X2), dried over MgSO4, concentrated, purified by silica column to yield ethyl 3-methyl-1-(2-naphthyl)-1H-pyrazole-5-carboxylate and its regioisomer in a 1:1 ratio in 70% yield. Rf 0.59 (1:2 EtOAc: hexane), M+H 281; regioisomer, ethyl 5-methyl-1-(2-naphthyl)-1H-pyrazole-3-carboxylate, Rf 0.44 (1:2 EtOAc:hexane). ES-MS: (M+H)+281.
Reaction SMILES: [CH:1]([C:4]1[C:13]([C:14](OCC)=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)Cl.CCCCCC>C1COCC1>[CH:1]([C:4]1[C:13]([CH2:14][OH:15])=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CCCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1CO)CCCC2(C)C
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To the intermediate obtained in Step B (1.32 g, 3.6 mmol) in THF (35 mL) was added lithium aluminum hydride (1 M/THF, 2 eq., 7.2 mL) dropwise. The reaction was refluxed for 1.5 hours and cooled to room temperature. Then the reaction was quenched with water and the THF was evaporated. The residue was partitioned between diethyl ether (150 mL) and water (100 mL). The organic layer was washed with brine (1×100 mL), dried with MgSO4, filtered, and concentrated to afford a solid. Flash chromatography (40% CH2Cl2/hexane) afforded the title compound as a white solid (808 mg, 2.5 mmol, 70%). 1H NMR (300 MHz, CDCl3): δ 7.13 (d, J=7.0 Hz, 4H), 4.36 (d, J=5.5 Hz, 2H), 3.42 (septet, J=6.6 Hz, 1H), 2.24 (t, J=5.5 Hz, 2H), 1.67 (m, 4H), 1.32 (m, 13H). FAB-MS: calculated for (C21H26FNO) 327, found 328 (M+H). mp 146-149° C. Rf=0.2 (50% CH2Cl2/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19](CC5C=NC=CC=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[CH:19]=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3
Reactant: COc1cc2c3c(c1)c(=O)c(Cc1cccnc1)cn3-c1cc(Br)ccc1S2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2c3c(c1)c(=O)ccn3-c1cc(Br)ccc1S2
Yield: 88.3 %

Procedure:
The compound (2 g) obtained in Example 36 <step 2> was suspended in dioxane (110 mL) and to the suspension was added DDQ (1.88 g). The mixture was heated under reflux for 3 hours. After allowing to cool, to the mixture were added 1N-sodium hydroxide (20 mL) and ethyl acetate(50 mL) . The precipitate crystals were collected by filtration and washed with water and ethanol in turns to obtain the title compound (1.41 g; 71%).
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20]([CH2:22]Cl)[C:19]([C:24]([O:26]CC)=[O:25])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20]([CH2:22][OH:1])[C:19]([C:24]([OH:26])=[O:25])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1CCl
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1CO
Yield: 44.2 %

Procedure:
Ethanol (80 ml) and 2.64 g (40.0 mmoles) of 85% potassium hydroxide were added to 5.0 g (13.3 mmoles) of ethyl 2-(4-benzylpiperazino)-4-chloromethylpyrimidine-5-carboxylate (produced in accordance with Referential Example 41 of Japanese Laid-Open Patent Publication No. 140568/1986), and the mixture was refluxed for 30 minutes. Ethanol was evaporated under reduced pressure. The residue was dissolved in water, and adjusted to pH about 4 with concentrated hydrochloric acid. The crystals that formed were collected by filtration, and washed with acetone to give 1.93 g (yield 44%) of 2-(4-benzylpiperazino)-4-hydroxymethylpyrimidine-5-carboxylic acid as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH3:16][C:17]([CH3:20])([NH2:19])[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:17]([CH3:20])([CH3:18])[CH3:16])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CC(C)(C)N
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)NC(C)(C)C)ccc1Br

Procedure:
From 4-bromo-3-methylbenzoic acid (400 mg), thionyl chloride (0.4 ml) and 1,1-dimethylethanamine (0.8 ml).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=O)[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CN(C=O)C.[CH3:41][O:42][CH2:43][CH2:44][NH:45][CH2:46][CH2:47][O:48][CH3:49]>C1(C)C=CC=CC=1.O1CCOCC1.C(N(CC)CC)C>[CH3:41][O:42][CH2:43][CH2:44][N:45]([CH2:46][CH2:47][O:48][CH3:49])[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:27]
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: COCCNCCOC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 and DMF in toluene. Subsequent treatment with triethylamine and bis(2-methoxyethyl)-amine in dioxan.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH:14]([CH3:16])[CH3:15])[C:6]1=[O:17].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[CH3:15][C:14]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:26][CH2:27]2)[C:6]1=[O:17])=[CH2:16]
Reactant: CC(C)n1c(=O)n(CCCCl)c2ccccc21
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCN(Cc3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 60.5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethyl)-2H-benzimidazol-2-one, 31.68 parts of 1-(phenylmethyl)piperazine, 21.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 400 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 1,3-dihydro-1-(1-methylethenyl)-3-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-2H-benzimidazol-2-one as a residue.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53]([OH:55])=O)[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:27]=[C:28]([F:30])[CH:29]=1.[CH3:56][N:57]1CC[O:60][CH2:59][CH2:58]1.CNCCO>CN1C(=O)CCC1>[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53]([N:57]([CH2:58][CH2:59][OH:60])[CH3:56])=[O:55])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNCCO
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Product: CN(CCO)C(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
TBTU (102 mg, 0.32 mmol) was added to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (105 mg, 0.21 mmol), 4-methylmorpholine (0.070 mL, 0.63 mmol) and 2-(methylamino)ethanol (0.022 mL, 0.28 mmol) dissolved in NMP (1.5 mL). The resulting solution was stirred at room temperature for 16 h then purified by preparative HPLC. The fractions were evaporated to dryness and triturated in diethyl ether to afford a solid. This material was collected by filtration, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (77 mg, 71%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH2:28][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.O>CN(C=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([CH2:29][CH2:28][C:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=2)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(CCBr)cc1
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(C#N)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.70 g (0.17 mol) of sodium hydride are added in portions to a solution of 55.71 g (0.17 mol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate in 34 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 1 hour. The reaction solution is then cooled to 0° C. again, 42.98 g (0.20 mol) of 4-(2-bromoethyl)benzonitrile in 21 ml of DMF are added, and the mixture is stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture, which is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 3:1; 3 kg of silica gel). 36 g (78 mmol, 46% of theory) of a colorless solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH3:25])[C:12]=2[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:32]N1C(=O)CCC1=O>>[Br:32][CH2:25][C:13]1[C:12]([C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=1
Reactant: CCCCC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Product: CCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Reference Example 5, 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methyl-3-valerylquinoline was brominated with N-bromosuccinimide (NBS) to give 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 150°-151° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:14][C:13]1=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH2:25]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:33])=[O:2])[C:13](=[O:32])[CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OCc2ccccc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OCc2ccccc2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
To a stirred solution of (S)-2-[4-(2-benzyloxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (310 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (87 mg, 0.004 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-2-[4-(2-benzyloxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (245 mg, 82%).