Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1>ClCCl>[C:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C1=COCCC1
Reactant: C=CC(=O)O
Solvent: ClCCl
Product: C=CC(=O)OC1CCCCO1
Yield: 26 %

Procedure:
A solution of 10.5 g (146 mmol, 10 ml) acrylic acid and 14.0 g (166 mmol, 15.2 ml) dihydropyran in 40 ml dichloromethane was stirred at room temperature for one day. The mixture was washed with saturated aqueous sodium bicarbonate and the organic layer was concentrated in vacuo. The residue was distilled to give 5.93 g (38.0 mmol, 26% yield) tetrahydropyran-2-yl acrylate, bp 40° C. at 0.2 torr.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O.CCO>CCOC(C)=O>[Cl:12][C:5]1[C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]2[N:1]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=3)[C:3]=2[CH:4]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCO)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCc1ccc(-n2c(-c3ccccn3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (1.83 g, 5.54 mmol), 2-pyridinecarboxaldehyde (0.53 ml, 5.54 mmol), and EtOH (40 ml) was refluxed for 1 hour. After cooling to room temperature, the solvent was removed. The residue was dissolved with benzene (50 ml) and treated with Pb(OAc)4 (3.38 g, 6.10 mmol) at room temperature for 1 hour. The mixture was diluted with EtOAc and the solution was washed with sat. NaHCO3 aq. and brine. The organic fraction was dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with hexane/EtOAc=5/2 to afford 1.20 g (52%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[NH:15][S:12](=[O:14])(=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Cl)cccc1S(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1NS(=O)(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
504 g (2.02 mol) of methyl 6-chloro-2-aminosulfonylbenzoate was added in portions to a solution of 80 g (2.0 mol) of sodium hydroxide in 2.5 liters of water; the temperature rose from 25° C. to 50° C. After 30 minutes at this temperature, the mixture was cooled to 25° C. and extracted with methyl tert-butyl ether, and the aqueous phase was stirred into 2N hydrochloric acid. The precipitate was isolated, washed with water and dried. There was obtained 330 g (75.8% of theory) of the title compound, m.p.: 210°-212° C.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[N:7][C:8](O)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[N:7]=[CH:6][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)cnc1Cl
Temperature: 130 °C

Procedure:
5-(Chlorosulfonyl)-2-hydroxynicotinic acid (500 mg, 2.10 mmol) vas suspended in 5 ml of POCl3 in a sealed tube and heated to 130° C. until all solid had dissolved. The reaction was cooled to 0° C. and poured onto ice and stirred until a solid formed. The filtered white solid was dried to afford 2-chloro-5-(chlorosulfonyl)nicotinic acid. 1H NMR (400 MHz, Acetone-d6) δ ppm 8.9 (d, J=2.6 Hz, 10H), 9.3 (d, J=2.6 Hz, 10H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC>>[CH3:11][NH:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCC[C@H]1CN
Reactant: C1CCNCC1
Product: CNCCN1CCCCC1

Procedure:
By using piperidine (983.5 mg) as a starting material, the title compound (120 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(Cl)CCCCl
Product: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 73 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 4-chlorobutyryl chloride as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained at a yield of 73%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][S:10]([CH2:12][CH2:13][NH2:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:15][S:16][C:17](S(C)=O)=[CH:18][N+:19]([O-:21])=[O:20]>>[CH3:15][S:16][C:17]([NH:14][CH2:13][CH2:12][S:10]([CH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:11])=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: COc1cccnc1CS(=O)CCN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Product: COc1cccnc1CS(=O)CCNC(=C[N+](=O)[O-])SC

Procedure:
Reaction of 3-methoxy-2-(2-aminoethylsulphinylmethyl)pyridine with 1-methylthio-1methylsulphinyl-2-nitroethylene yields 1-methylthio-2-nitro-1-[2-((3-methoxy-2-pyridyl)methylsulphinyl)ethylamino]ethylene which, when reacted with 4-(4-aminobutyl)imidazole yields 1-nitro-2-[2-((3-methoxy-2-pyridyl)methylsulphinyl)ethylamino]-2-[4-(4-imidazolyl)butylamino]ethylene.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=[CH:15][CH:16]=1.C(O)(=O)C>C(O)C.[Fe]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17]
Reactant: Cc1cccc(NCc2cccc([N+](=O)[O-])c2)c1C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc(NCc2cccc(N)c2)c1C

Procedure:
To a solution of 15 (0.40 g) in ethanol (8 mL) was added elemental iron (Fe) (0.31 g) and acetic acid (0.66 g). The mixture was refluxed for 18 h. The mixture was filtered, concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an oil. NMR (300 MHz, CDCl3) δ 7.13 (1H, t, J=3 Hz), 6.99 (1H, t, J=3 Hz), 6.77 (1H, d, J=3 Hz), 6.72 (1H, s), 6.60 (2H, d, J=3 Hz), 6.50 (1H, d, J=3 Hz), 4.25 (2H, s), 3.85 (1H, s), 3.65 (1H, s), 2.29 (3H, s), 2.05 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]([C:19](O)=[O:20])[CH2:11][CH:10]2[CH3:22])=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[CH2:40]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:41]>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH2:43]([N:42]([CH2:40][CH3:41])[C:19]([C@@H:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=2)[C@@H:10]([CH3:22])[CH2:11]1)=[O:20])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCNCc1ccccc1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(C(=O)O)CC2C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(Cc1ccccc1)C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(OC)cc2)c2ccccc21
Reaction time: 2 h
Yield: 22.9 %

Procedure:
1-(4-Methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (2.00 g, 6.15 mmol) was suspended in methylene chloride (50 mL). One drop of dimethylformamide was added, followed by oxalyl chloride (1.56 g, 1.07 mL, 12.3 mmol). The suspension became homogeneous on stirring. After 2 hours, the yellow solution was concentrated under reduced pressure and azeotroped with toluene. To a solution of the resulting acid chloride (120 mg, 349 mmol) in methylene chloride (1 mL) was added diisopropylethylamine (451 uL, 0.349 mmol), followed by ethyl-benzyl-amine (71 mg, 77 uL, 0.523 mmol). The mixture was shaken overnight at room temperature. Upon completion, the reaction was diluted with ethyl acetate, washed with saturated sodium bicarbonate (aqueous) and brine, dried over sodium sulfate, filtered and concentrated to afford the crude amide. Purification by silica gel chromatography (elution with a hexane/ethyl acetate gradient) afforded pure (±)-trans-1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid benzyl-ethyl-amide (53 mg, 34%). 1H-NMR (CDCl3) δ: 0.98 (d, 3H), 1.13 (t, 3H), 1.74 (ddd, 1H), 2.52 (ddd, 1H), 3.62-3.92 (m, 8H), 5.03-5.13 (m, 1H), 6.44 (d, 1H), 6.72-6.84 (m, 4H), 6.86-6.92 (m, 1H), 7.19-7.23 (m, 2H), 7.43-7.54 (m, 4H). MS m/z: 443 (M+1).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH:17]=1)=[O:10])(=[O:4])=[O:3].[H-].[Na+].[CH3:37]I.O>CN(C=O)C>[CH3:37][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH:17]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(NS(C)(=O)=O)c3)ccc2C)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)S(C)(=O)=O)c3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-[5-(3-methanesulphonylaminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.3 g) in DMF (5 ml) was added portionwise to a stirred mixture of sodium hydride (0.025 g) in DMF (5 ml). The resultant mixture was stirred at ambient temperature for 40 minutes. Methyl iodide (0.088 g) was added and the mixture was stirred at ambient temperature for 3 hours. The mixture was poured into water (150 ml). The resultant precipitate was isolated, washed in turn with water and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.18 g); m.p. 168-169° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.99 (s, 3H), 3.82 (s, 6H), 7.07 (d, 1H), 7.21 (d, 1H). 7.59 (m, 5H), 7.79 (s, 1H), 7.87 (d, 1H), 7.93 (s, 1H), 9.75 (br s, 1H), 10.25 (br s, 1H); Mass Spectrum: M+H+ 498.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1>C(O)(C)C>[CH3:2][O:3][C:4]([C@H:5]1[NH:6][C@@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccc3c(c2)OCO3)N1
Temperature: 70 °C
Yield: 101.6 %

Procedure:
D-Tryptophan methyl ester hydrochloride (50.0 kg, 196 mol) was suspended in isopropyl alcohol (500 L) and treated with piperonal (32.4 kg, 216 mol) at ambient temperature under an N2 atmosphere. The mixture was stirred between 70° C. and reflux (82° C.) for 16 to 18 hours. At this time, the reaction mixture contained less than 3% Compound IIa. The reaction mixture then was cooled to 0° C., filtered, and washed with cold isopropyl alcohol (150 L). The product was dried under vacuum at less than 60° C. to yield 69.8 kg (92%) of cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (Compound II)). 1H NMR (400 MHz DMSO) δ: 10.81 (1H, s), 10.67 (1H, exch.), 10.21 (1H, exch.), 7.52 (1H, d, J=8.0 Hz), 7.27 (1H, d, J=8.0 Hz), 7.11 (1H, m), 7.05-6.95 (4H, m), 6.08 (2H, s); 5.85 (1H, m), 4.71 (1H, m), 3.82 (3H, s), 3.39-3.23 (2H, m). HPLC Details: Column: SB-Phenyl 4.6×250 mm; ACN/(H2O+0.1% TFA) gradient; Temperature: 40° C.; Flow Rate=1 mL/min; UV Det.=285 μm; Injection Volume=20 μL; Diluent=1:1 ACN/H2O; Sample concentration: about 0.1 mg/mL; and Retention time=6.0 min.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](C(OCC)C)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.Cl.[OH-].[Na+]>COC(C)(C)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Method A. To a 1 L round bottom flask equipped with a stir bar and nitrogen inlet was charged {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7yl]methyl pivalate (18, theoretical amount 41.6 g, 0.112 mol) made as described above and tetrahydrofuran (THF, 610 mL, 7.5 mol) at room temperature, and the resulting mixture was treated with an 2.0 N aqueous solution of hydrochloric acid (140 mL, 0.28 mol, 2.5 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for overnight. When the reaction was deemed complete, the reaction mixture was cooled to 0-5° C. before pH was adjusted to 9-10 with a 3 M aqueous sodium hydroxide (NaOH) solution (95 mL). The mixture was then extracted with ethyl acetate (2×300 mL) and the combined organic extracts were washed with 20% aqueous brine solution (250 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to afford the crude product as off-white to light yellow solids. The crude product was treated with methyl t-butylether (MTBE, 200 mL) and the slurry was warm to reflux for 30 minutes before being cooled to room temperature. The solids were collected by filtration and washed with MTBE (2×40 mL), dried under reduced pressure to afford [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 30.5 g, 33.52 g theoretical, 91% for two steps) as white to off-white solids. For 19: 1H NMR (DMSO-d6, 300 MHz) δ ppm 13.40 (br s, 1H), 8.75 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H); C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60.3 %

Procedure:
The ethyl 3-(4-nitrophenyl)acrylate (512.8 mg) obtained in the above step (a) was dissolved in dioxane (5.1 ml), and the solution was added with 5 N sodium hydroxide (2.78 ml) and stirred at room temperature for 3.5 hours. Separation and extraction with diethyl ether was made to remove impurities, and then 5 N hydrochloric acid was added to the aqueous layer to reduce the pH to 2. The precipitated crystals were collected by filtration to obtain 3-(4-nitrophenyl)acrylic acid (270.1 mg, 60.3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:39](=[O:40])[C:38]2[CH:42]=[CH:43][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:36][CH:37]=2)=[CH:22][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl{2-[(4-aminophenyl)ethynyl]-4-chlorophenoxy}acetate (Intermediate 222; 72 mg; 0.20 mmol) and triethylamine (83 μl; 0.60 mmol) in DCM (2 ml) was treated with 4-(trifluoromethyl)-benzoyl chloride (30 μl; 0.20 mmol). After stirring at RT for 1 hour, the reaction was quenched with a saturated aqueous ammonia solution (1 mL). EtOAc and a saturated NH4Cl solution in water were added, the phases separated and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].I[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1.O>C(O)C.O1CCCC1>[C:1]([NH:4][C:5]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: O=C(CCCCc1ccccc1)c1ccc(CCI)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCc1ccc(C(=O)CCCCc2ccccc2)cc1)(NC(C)=O)C(=O)OCC
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
A solution of diethyl 2-acetamidomalonate (30.6 g), sodium ethoxide (7.6 g) and molecular sieves 3A (5.5 g) in ethanol (80 ml) was stirred at room temperature for 20 hours. A solution of 1-[4-(2-iodoethyl)phenyl]-5-phenylpentan-1-one (18.4 g) in tetrahydrofuran (60 ml) was added thereto over 10 minutes and the mixture was refluxed under heating for 15 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (40 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to give diethyl 2-acetamido-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}malonate (13.8 g) as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[C:26]([F:33])[CH:25]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1F
Temperature: 100 °C
Yield: 79.4 %

Procedure:
To a suspension of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.059 mg; 0.05 mmol), and 4-chloro-2-fluorophenylboronic acid (0.131 g; 0.75 mmol) in a mixture of DME-water (2 mL) was added N,N-diisopropylethylamine (0.345 mL; 2 mmol) and the mixture was heated in a sealed tube to 100° C. for 3 h. The mixture was diluted with brine and extracted with ethyl acetate. The combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.164 g (75%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH3:9])[C:4](=[O:10])[C:3]=1[N+:11]([O-:13])=[O:12].[NH3:14]>C1COCC1>[NH2:14][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH3:9])[C:4](=[O:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCn1ccc(Cl)c([N+](=O)[O-])c1=O
Reactant: N
Solvent: C1CCOC1
Product: CCn1ccc(N)c([N+](=O)[O-])c1=O
Yield: 75.1 %

Procedure:
A solution of 4-chloro-1-ethyl-3-nitro-1H-pyridin-2-one (1.40 g, 6.91 mmol) and 28% aqueous ammonia (6.92 g, 55.3 mmol) in THF (30 mL) was stirred at room temperature for 17 h. The solvent was evaporated under reduced pressure and water was added to the residue. The resulting precipitate was filtered and washed with water to give 4-amino-1-ethyl-3-nitro-1H-pyridin-2-one (0.95 g, 75% yield). 1H-NMR (DMSO): δ, 8.03 (m, 2H), 7.57 (d, 1H, J=7.2 Hz), 5.90 (d, 1H, J=7.2 Hz), 3.78 (q, 2H, J=7.2 Hz), 1.15 (t, 3H, J=7.2 Hz). MS: calculated for C7H7N3O3+H 184.1; found: 184.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[S:13])[NH:8]3.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]2[C:24]1=[O:25])=[N:8]3
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: Cc1nc2cccc3[nH]c(=S)c1n23
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3nc(SCCCCCN4C(=O)c5ccccc5C4=O)c1n23
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a suspension of 2.03 g (10.7 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-thione in 50 ml of N,N-dimethylformamide were added 3.18 g (10.7 mmol) of N-(5-bromopentyl)phthalimide and 2.24 ml (16.1 mmol) of triethylamine. The mixture was stirred for two hours at 100° C. After cooling, the resulting precipitates were collected by filtration, washed with N,N-dimethylformamide, ethanol, and diethylether, successively, dried to afford 3.44 g of the desired compound (79.3%, a pale brown solid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22](F)[C:23]=3[Cl:25])[C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+].CN(C)C=O>C(OCC)(=O)C>[N:36]([C:22]1[C:23]([Cl:25])=[C:24]2[C:19]([C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][N:15]2[C:13]2[CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([F:35])=[CH:11][C:12]=2[F:34])=[CH:20][C:21]=1[F:27])=[N+:37]=[N-:38]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N=[N+]=[N-])c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1,545 mg) and sodium azide (230 mg) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 60° C. After the reaction mixture was cooled back to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (1,280 mg) as an amorphous substance.