Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:18]2[C@@H:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH:13](SC2C=CC=CC=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:18]2[C@@H:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@@H]2[C@@H](COC(=O)c3ccccc3)OC(Sc3ccccc3)[C@@H]2O1
Agent: [Ni]
Solvent: CCO
Product: O=C1C[C@H]2[C@H](CO[C@@H]2COC(=O)c2ccccc2)O1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A 3-neck, 1000 mL round-bottom flask, equipped for overhead mechanical stirring, was charged with 29.6 g of 8 (80 mmol), 500 mL of ethanol and approximately 30 g of Raney-Ni (Aldrich, which had been washed to neutrality with distilled water). The resulting slurry was heated at reflux for 5 h while stirring vigorously. The reaction mixture was then cooled to room temperature, and the solids were carefully filtered off through a pad of celite. The residue was washed thoroughly with ethanol, and the combined filtrates were concentrated to afford a yellow solid which was purified by chromatography on silica gel to afford 7.63 g (36% yield) of 9 as a white solid. A small sample was recrystallized from acetone/hexane to afford colorless needles: mp 89.5-90.0° C.; [α]D22+3.18 (c=0.8 in CHCl3); Rf0.36 (60% EtOAc/hexane); 1H-NMR (CDCl3) δ 8.01 (m, 2H), 7.40-7.65 (m, 3H), 5.15 (m, 1H), 4.41 (m, 2H), 4.05-4.32 (m, 3H), 2.80-3.05 (m, 2H), 2.56 (d, 1H, J=15.7 Hz); MS m/z at 263 for (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[NH:6]2.CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[N:6]2[CH3:21]
Reactant: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCOC(=O)c1nc2ccc(OC)cc2n(C)c1=O

Procedure:
3,4-Dihydro-6-methoxy-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (1.9 g), methyl iodide (2 ml) and anhydrous potassium carbonate (6 g) in 2-butanone (100 ml) were stirred and heated under reflux for 1.5 hours. The solid was filtered off and the filtrate was evaporated. The residue was crystallised from aqueous methanol, m.p. 166° (80%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]1([CH3:43])[CH2:22][CH2:21][CH2:20][C:19](=O)[CH:18]1/[CH:24]=[CH:25]/[C:26]#[C:27][C:28]1[CH:42]=[CH:41][C:31]([C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])=[CH:30][CH:29]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:16][C:17]1([CH3:43])[C:18](/[CH:24]=[CH:25]/[C:26]#[C:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])=[O:33])=[CH:41][CH:42]=2)=[C:19]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:20][CH2:21][CH2:22]1
Reactant: CC1(C)CCCC(=O)C1/C=C/C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CCCC(OS(=O)(=O)C(F)(F)F)=C1/C=C/C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoromethanesulfonic anhydride (0.109 mL, 0.65 mmol) was added to a solution of (trimethylsilyl)ethyl (±)-(E)-4-(4-(2,2-dimethyl-6-oxocyclohexyl)but-3-en-1-ynyl)benzoate (Compound G, 150 mg, 0.38 mmol) and 2,6-di-tert-butyl-4-methylpyridine (DBMP, 218 mg, 1.06 mmol) in dichloromethane (4 mL). The flask was sealed with a plastic cap and stirred for 2 days at room temperature. The solution was diluted with ethyl acetate and washed with 10% aqueous H3PO4. The layers were separated and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were washed with 5% aqueous NaHCO3, and brine, and dried (Na2SO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (10:1, hexane:ethyl acetate) to give the title compounds as a 1:1 mixture of isomers. The compounds were separated by HPLC using a Whatman Partisil-10 1×50 cm column (95:5, hexane:ethyl acetate) to provide the title compound as a colorless oil:
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:14][O:15][C:16](=O)[O:17]C>>[CH3:14][O:15][C:16](=[O:17])[CH2:12][C:11](=[O:13])[C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
The procedure is as described in Example 1, except that 54 g of sodium methylate in 600 ml dimethylcarbonate are used and 154.5 g of p-chloro-acetophenone are added dropwise over a period of 2.5 hours at 60°C. Working up in accordance with Example 1 gives at 60°C 187 g (87% of the theoretical amount) of p-chloro-benzoylacetic acid methyl ester with a boiling point of 113°C/0.3 torr.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].IC.[C:22]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:22][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([C:16]#[N:17])=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2cccnc2)c(C#N)c2ccccc21
Reaction time: 0.5 h

Procedure:
To 2-pyridin-3-yl-1H-indole-3-carbonitrile (1.0 g, 4.56 mmol) in DMF (17 mL) is added 60% sodium hydride in mineral oil (547 mg, 13.68 mmol) and the suspension is stirred for 30 min. Iodomethane (971 mg, 6.84 mmol) is then added to the reaction mixture and stirred at ambient temperature for 1 h. Aqueous NaHCO3 (3 mL) is added and the mixture is concentrated in vacuo. The residue is purified by purified by silica gel flash chromatography (dichloromethane-methanol gradient) to give 1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 3.83 (s, 3H), 7.35 (t, J=7.5 Hz, 1H), 7.40-7.46 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.67-7.74 (m, 2H), 8.16 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.76 (dd, J=5.1, 1.5 Hz, 1H), 8.86 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 234.1029 [(M+H)+ Calcd for C15H12N3: 234.1031].
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:20][NH2:21]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:21][CH2:20][C:19]1[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=1)#[N:2]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3,5-bis(trifluoromethyl)benzylamine (0.71 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.34 g, 0.91 mmol, yield: 35%) as colorless crystals.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C@@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:19][N:20]([CH:22]([N:26](C)C)[N:23](C)C)C.CO.C(=O)(O)O.NC(N)=N>C1(C)C=CC=CC=1>[NH2:26][C:22]1[N:20]=[CH:19][C:11]2[CH2:10][CH2:9][C@@H:8]3[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][C@H:3]3[C:2]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2C(=O)CCC[C@H]21
Reactant: CN(C)C(N(C)C)N(C)C
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]2c3nc(N)ncc3CC[C@@H]21

Procedure:
To a refluxing solution, under nitrogen, of 8.89 g (35 mmol) of cis and trans octahydro-5-oxo-1(2H)-quinolinecarboxylic acid, 1,1-dimethylethyl ester, (Example 8), in 400 ml of toluene is added dropwise a solution of 6.37 g (43.8 mmol) of tris-(dimethylamino)methane in 200 ml of toluene. The solution is refluxed for 2 hours. The reaction mixture is concentrated and the residue is dissolved in 500 ml of methanol. To the methanol solution is added 12.64 g (70.1 mmol) of guanidine carbonate, and the reaction mixture is refluxed, under nitrogen, for 12 hours. The mixture is concentrated and partitioned between brine and chloroform. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated to a yellow solid. Medium pressure chromatography (silica gel, ethyl acetate) afforded 4.55 g (51%) of recovered starting ketone, 0.94 g (8.8%) of (±) cis-2-amino-6,6a,8,9,10,10a-hexahydropyrido[2,3-h]quinazoline-7(5H)-carboxylic acid, 1,1-dimethylethyl ester (Rf =0.33 (ethyl acetate)) as a foamy off-white solid, mp 178°-182° C., and 2.47 g (23%) of (±) trans-2-amino-6,6a,8,9,10,10a-hexahydropyrido[2,3-h]quinazoline-7(5H)-carboxylic acid, 1,1-dimethylethyl ester (Rf =0.27 (ethyl acetate)) as a white solid, mp 200°-206° C. (dec.).
Reaction SMILES: C(OC([N:8]1[N:15]2[C:11]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)([C:12](=[O:25])[N:13]([C:17]3[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=3)[C:14]2=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:11]23[CH2:10][CH2:9][NH:8][N:15]2[C:14](=[O:16])[N:13]([C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=2)[C:12]3=[O:25])=[CH:32][CH:31]=1)#[N:34]
Reactant: CC(C)(C)OC(=O)N1CCC2(Cc3ccc(C#N)cc3)C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CC23CCNN2C(=O)N(c2cc(Cl)nc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of the compound from Example 56 (102 mg) in CH2Cl2 (5 mL) at −10° C. was added TFA (1 mL). After warming to room temperature, the reaction mixture was stirred for a total of 1 hour while monitoring the progress by TLC. Upon consumption of the starting material, the reaction mixture was cooled to 0° C. and DIEA (4.5 mL) was added carefully. After 2 hours, water (20 mL) and EtOAc (30 mL) were added and the mixture shaken. The aqueous phase was then separated and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by liquid chromatography (SiO2, EtOAc) and re-crystallization from EtOAc/hexanes to give the titled compound (62 mg). MS (m/z) 402 (M); mp 187° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16]>O.[OH-].[Na+]>[CH2:15]([S:17]([OH:19])(=[O:1])=[O:18])[CH3:16].[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)Cl
Agent: Cc1c(C)c2ccc(O)cc2oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCS(=O)(=O)O

Procedure:
5.0 g of 7-hydroxy-3,4-dimethylcoumarin were dissolved in 20 ml of H2O/1.1 g of NaOH at room temperature, while stirring, and 3.4 g of ethanesulfonyl chloride were added. The mixture was stirred overnight, and the precipitate was filtered off under suction and recrystallized from ethanol.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH:26]([CH3:29])[CH:27]=[O:28])=[CH:20][CH:19]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH2:25][CH:26]([CH3:29])[CH:27]([OH:28])[CH2:2][C:3](=[O:4])[CH3:5])=[CH:22][CH:23]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C=O)CSc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)C(C)CSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
9.86 Grams of methyl acetoacetate were dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution was added dropwise while cooling the mixture to not higher than 25° C. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.49 g of sodium acetate and 2.42 g of tetrabutylammonium bromide were added thereto and then an additional conc. hydrochloric acid was added thereto to control the mixture to pH 6.8-6.9. Further, 27.1 g of a toluene solution containing 36.5% of 3-(4-fluorophenylthio)-2-methylpropanal were added thereto and the resulting mixture was stirred at 45°-50° C. for 8 hours. The organic layer was separated, washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain a crude 6-(4-fluorophenylthio)-4-hydroxy-5-methyl-2-hexanone. A purified product was obtained by column chromatography in a yield of 40.2%. The purified product had an nD21 of 1.5396.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].NC(N)=S.C[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.Cl>>[OH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: COc1ccc2ccccc2c1
Agent: Cl
Agent: NC(N)=S
Agent: [Al+3]
Product: Oc1ccc2ccccc2c1
Temperature: 90 °C
Yield: 89.5 %

Procedure:
To a mixture of 5.32 g (40 mmol) of aluminium chloride and 1.52 g (20 mmol) of thiourea 3.16 g (20 mmol) of 2-methoxynaphtalene of the formula (VII) is added. The reaction mixture is heated to 90° C. and maintained at this temperature for 1 hour. The mixture is then cooled to room temperature and 20 ml of 5 wt % hydrochloric acid is added. The precipitated product is filtered, washed and dried to give 2.58 g (89.5 %) of 2-hydroxynaphthalene.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:38])=[C:24]([N:26]3[C:30]4=[N:31][C:32]([CH2:35][OH:36])=[CH:33][CH:34]=[C:29]4[NH:28][C:27]3=[O:37])[CH:25]=2)=[C:16]([F:39])[C:15]([F:40])=[CH:14][CH:13]=1)=O)(C)(C)C.Cl>C(OCC)C>[ClH:38].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:38])=[C:24]([N:26]3[C:30]4=[N:31][C:32]([CH2:35][OH:36])=[CH:33][CH:34]=[C:29]4[NH:28][C:27]3=[O:37])[CH:25]=2)=[C:16]([F:39])[C:15]([F:40])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(F)c(F)c1COc1ccc(Cl)c(-n2c(=O)[nH]c3ccc(CO)nc32)c1
Agent: Cl
Solvent: CCOCC
Product: NCCOc1ccc(F)c(F)c1COc1ccc(Cl)c(-n2c(=O)[nH]c3ccc(CO)nc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To 3-(5-{6-[2-(tert-butoxycarbonylamino)ethoxy]-2,3-difluorobenzyloxy}-2-chloro-phenyl)-5-hydroxymethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) was added hydrochloric acid (4 mol/L ethyl acetate solution, 2 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added diethyl ether, and the precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give 3-{5-[6-(2-aminoethoxy)-2,3-difluorobenzyloxy]-2-chlorophenyl}-5-hydroxymethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (12 mg). To this material were added methylene chloride (2 mL), tetrahydrofuran (1 mL), pyridine (0.1 mL) and acetic anhydride (0.003 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=10/1) to give the title compound (10 mg).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(Cn2c(Oc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)c1
Yield: 55 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-methoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (217 mg, yield: 55.0%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][N:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:19]2[CH:18]=[N:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-fluoro-2-hydroxybenzoate (23.5 g) and 2-nitro-5-chloropyridine (21.9 g) in N,N-dimethylformamide (120 mL) was added cesium carbonate (45 g). The mixture was stirred at 50° C. overnight. The mixture was diluted with ethyl acetate (800 mL) and washed three times with water and brine. After drying over Na2SO4 and filtration, the solvent was evaporated under vacuum and the residue was purified by silica gel chromatography (2% ethyl acetate in dichloromethane) to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([OH:14])=O)[S:5][N:4]=1)[CH3:2].S(Cl)([Cl:17])=O.CN(C)C=O.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:17])=[O:14])[S:5][N:4]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1nsc(C(=O)O)c1C(=O)OC
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1nsc(C(=O)Cl)c1C(=O)OC

Procedure:
73 g of the carboxylic acid from Example c and 80 g of thionyl chloride in 200 ml of toluene are refluxed in the presence of a little dimethylformamide until the evolution of gas is complete. The crude carbonyl chloride which remains in quantitative yield after evaporation is directly reacted further.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[C:24]([O:26]C)=[O:25])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C(O)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[C:24]([OH:26])=[O:25])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C(=O)OC)cccc2c1Nc1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)c1cnc2c(C(=O)O)cccc2c1Nc1ccccc1C
Yield: 64.6 %

Procedure:
Methyl 3-butyryl-4-(2-methylphenylamino)quinoline-8-carboxylate (0.3 g, 0.8 mmol) and potassium hydroxide (0.06 g, 1 mmol) were dissolved in ethanol (5 ml) and refluxed for 30 minutes, then the ethanol was evaporated, the product dissolved in water, the solution neutralised with dilute hydrochloric acid, and the solid filtered off and washed with water. Recrystallisation from ethanol gave 3-butyryl-4-(2-methyl-phenylamino)quinoline-8-carboxylic acid (0.18 g, 62%), m.p. 179-180°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21].N1CCCCC1.C(OCC)(=O)C>CO.O>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3/[CH:18]=[CH:21]/[C:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:22])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CC(=O)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: O=C(/C=C/c1c[nH]c2ccc(OCc3ccccc3)cc12)c1ccncc1

Procedure:
In a dried, 25 mL round bottom flask under argon, 5-benzyloxyindole-3-carboxaldehyde (100 mg, 0.40 mmol) was dissolved in anhydrous methanol (3 mL). 4-Acetyl-pyridine (75 μL, 0.68 mmol) and piperidine (20 μL, 0.2 mmol) were added. The reaction was stirred under reflux, during which a crude yellow solid precipitated. The solid was filtered, rinsed with cold methanol and dried under vacuum. This crude product (107 mg) was purified from residual aldehyde by column chromatography in ethyl acetate:hexanes (1:1-3:1 gradient), yielding pure, yellow solid (70 mg, 49%). 1H NMR (600 MHz, d6-DMSO): δ 8.837-8.827 (dd, J1=4.5, J2=1.5, 2H, pyr-2,6H), 8.148-8.143 (d, J=3.0, 1H, indole-2H), 8.095-8.069 (d, J=15.6, 1H, C═CH), 7.932-7.922 (dd, J1=4.5, J2=1.5, 2H, pyr-3,5H), 7.556-7.553 (d, J=1.8, 1H, indole-4H), 7.523-7.511 (d, J=7.2, 2H, phenyl-2,6H), 7.460-7.434 (d, J=15.6, 1H, C═CH), 7.411-7.370 (m, 3H, phenyl-3,5H, indole-7H), 7.330-7.306 (t, J=7.2, 1H, phenyl-4H), 6.979-6.961 (dd, J1=8.4, J2=2.4, 1H, indole-6H), 5.252 (s, 2H, methylene). 13C NMR (150 MHz, d6-DMSO): 188.4, 154.1, 150.7, 144.9, 140.9, 137.7, 134.6, 132.5, 128.4, 127.7, 127.6, 125.8, 121.5, 114.2, 113.3, 113.1, 112.7, 104.1, 69.8. Melting point: 218-221° C. TLC (in 4:1 ethyl acetate:hexanes) Rf=0.26. Elemental analysis calculated (for C23H19N2O2.0.2 C6H14.0.05 H2O): C, 78.02; H, 5.93; N, 7.52. found: C, 77.69; H, 5.62; N, 7.24.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CC1C=CC(C)=CC=1CC(N1CCC(C2SC=C([C:75]([N:77](C)[C@@H:78]([C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=3)[CH2:79][CH3:80])=O)N=2)CC1)=O>C(#N)C>[CH3:75][N:77]([C@@H:78]([C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)[CH2:79][CH3:80])[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1-(1,1-Dimethylethyl) 4-(4-carboxy-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (3.1 g, 9.9 mmol) was suspended in 10 mL of dry acetonitrile and treated with triethylamine (3.0 mL, 21 mmol) to give a homogeneous solution. To this was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.98 g, 10.5 mmol) followed by (α,R)-α-ethyl-N-methylbenzenemethanamine (i.e. the product of Example 1, Step C) (10 mmol, 1.50 g). The mixture was stirred at ambient temperature for 4 days, concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4 and concentrated under reduced pressure to give 5.1 g of a dark oil. Purification by silica gel chromatography using 25% ethyl acetate in hexanes gave 3.6 g of the title compound as a yellow oil.