Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:6]=1[O:13][CH3:14].[CH2:17](O)[CH2:18][OH:19]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH:11]2[O:19][CH2:18][CH2:17][O:12]2)[CH:8]=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: OCCO
Reactant: COc1ccc(C=O)cc1C(=O)N(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2OCCO2)cc1C(=O)N(C)OC
Yield: 84 %

Procedure:
N-Methoxy-N-methyl-5-formyl-2-methoxybenzamide (6.56 g, 29.4 mnmol), ethylene glycol (8.20 mL, 147 mmol), p-toluenesulfonic acid monohydrate (110 mg, 0.578 mmol) and toluene (100 mL) were mixed, and, while removing water generated using dean-stark apparatus, the mixture was refluxed for 4 hours. After allowed to stand for cooling, ethyl acetate was added, which was washed with saturated aqueous solution of sodium hydrogencarbonate and water in sequence. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:2 v/v) to obtain 6.60 g (84%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].N1C=CC=CC=1.[Cl:40][CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl.C(OCC)(=O)C>[Cl:40][CH2:41][CH2:42][CH2:43][S:44]([N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])(=[O:46])=[O:45]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCCCl)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 0.918 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 10 ml of dichloromethane was treated with 0.202 ml of pyridine and 0.354 g of 3-chloropropanesulphonyl chloride. The mixture was stirred for 2 hours at room temperature. A further 0.177 g of 3-chloropropanesulphonyl chloride and 0.160 ml of pyridine were added and the mixture was stirred for a further 2 hours at room temperature. Evaporation gave a residue which was dissolved in ethyl acetate and washed in sequence with water, 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate, evaporation, and trituration with ether/hexane gave a residue which was purified by column chromatography on silica gel using hexane/ethyl acetate (6:4) for the elution, to give 0.8 g of (E)-2′-(3-chloropropylsulphonyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale yellow solid.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[C:27]([N+:34]([O-:36])=[O:35])=[CH:26][CH:25]=1.[Cl:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[C:45]1[C:50]([C:51]2[NH:52][CH:53]=[CH:54][N:55]=2)=[CH:49][N:48]=[C:47]([NH:56][CH2:57][CH2:58][NH:59]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:46]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[C:45]1[C:50]([C:51]2[NH:55][CH:54]=[CH:53][N:52]=2)=[CH:49][N:48]=[C:47]([NH:56][CH2:57][CH2:58][NH:59][C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[C:27]([N+:34]([O-:36])=[O:35])=[CH:26][CH:25]=2)[N:46]=1
Reactant: CC(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(=O)Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
N-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)-amino]-3-nitro-2-pyridyl}acetamide was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and N-(6-chloro-3-nitro-2-pyridyl)acetamide in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]-ethyl}amine.
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6]1)(=O)C.O>O1CCCC1>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][CH:5]([OH:4])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Solvent: O
Solvent: C1CCOC1
Product: OC1CCc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.1 %

Procedure:
5.54 g of lithium hydroxide·hydrate was added to 24.2 g of 7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in 150 ml of tetrahydrofuran, and the mixture was stirred at room temperature for about 20 hours. After the reaction, water was added to the reaction mixture, and then the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then condensed. The obtained residue was applied to silica gel column chromatography to obtain 10.5 g of 4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].[H-].[Na+].[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.Cl>O1CCCC1.CO.O>[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[CH:8][C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[C:4]([O:3][CH3:2])=[O:5])=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccccc1C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.1 %

Procedure:
In 1.0 liter of tetrahydrofuran was suspended 60 g of (2-methoxycarbonylbenzyl)triphenylphosphonium bromide and, 3.2 g of sodium hydride was added to the suspension followed by stirring at room temperature for 3 hours. Then, 18 g of 4-bromobenzaldehyde was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 500 ml of water, 200 ml of methanol and 100 ml of 0.1 N hydrochloric acid aqueous solution were added thereto and the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. After washing in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure The resulting residue was recrystallized from methanol to give 17 g of methyl 2-(4-bromostyryl)benzoate as white needles.
Reaction SMILES: F[C:2](F)(F)[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([N:18]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=O)[NH:21][C:20]2[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[N:33][C:19]1=2)[CH3:17].C(Cl)Cl.C(N(C(C)C)CC)(C)C>[C-]#N.C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[CH2:16]([N:18]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]([O:6][S:3]([CH3:2])(=[O:5])=[O:4])[NH:21][C:20]2[C:30]([CH3:35])=[CH:31][C:32]([CH3:34])=[N:33][C:19]1=2)[CH3:17]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(C)nc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(OS(C)(=O)=O)Nc2c(C)cc(C)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
Trifluoromethanesulfonic anhydride (0.24 ml, 14 mmol) was added to a solution of 0.314 g (1.2 mmol) 5,11-dihydro-11-ethyl-2,4-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one in 15 ml of methylene chloride containing 0.25 ml (14 mmol) of diisopropylethylamine, and the resulting mixture was refluxed under argon for three hours. Ethyl acetate (~200 mL) was then added and the solution was washed three times with water and four times with brine. After drying (magnesium sulfate), the solution was concentrated in vacuo and the residue dried under high vacuum for 2 hr. The residue was dissolved in 20 ml of methylene chloride, and 0.23 g (14 mol) of tetraethylammonium cyanide was added. After stirring the resulting solution overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate, and the solution was washed with water and brine. The dried (magnesium sulfate) solution was concentrated in vacuo and the residue was chromatographed over silica with 5% ethyl acetate/hexane. The resulting solid was crystallized from heptane to provide 0.033 g of the title compound as red crystals. m.p. 154°-155° C.
Reaction SMILES: [K].[O-]CCCC.Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH2:24]([O:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[CH2:24]([O:26][CH2:27][CH2:28][O:29][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH3:25]
Reactant: CCOCCO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CCCC[O-]
Agent: [K]
Product: CCOCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 85 °C

Procedure:
To a stirred solution of potassium t.butoxide (9.3 g, 82.8 mmol) in 1-ethoxy-2-ethanol (70 ml) was added 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7 g, 27.6 mmol). The mixture was heated to 80-90° C. for 2 h. Then most of the solvent was removed by evaporation under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, concentrated to give a light brown solid, which was washed with petroleum ether, dried in vacuo (7.8 g, 92%).
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]1([CH:7]2[CH2:8][CH2:9][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C2CCN2)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Dissolve 4-phenyl-azetidin-2-one (1.0 g, 4.28 mmol) in anhydrous THF (20 mL) and treat with 1.0 M solution of lithium aluminum hydride (8.57 mL, 2.0 equiv.) at room temperature. Stir for 15 h, cool to 0° C. in an ice bath and quench with 8.5 mL 1.0 M NaOH then 8.5 mL H2O. Filter resulting solution through celite with additional EtOAc, dry with MgSO4, filter and evaporate to yield a milky white oil that solidifies upon standing. Use 2-Phenyl-azetidine without further purification.
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CCCCCC.[C:33](=[O:35])=[O:34].Cl>C1COCC1>[CH2:1]([O:11][C:12]1[C:13]([F:21])=[C:14]([F:20])[C:15]([C:33]([OH:35])=[O:34])=[C:16]([F:19])[C:17]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C=O
Reactant: CCCCCCCCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
36.8 g of the compound (10) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 100 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 26.5 g (76 mmol) of 4-decyloxy-2,3,5,6-tetrafluorobenzoic acid (11).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C[Al](C)C.C[O:18][C:19]([C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=3)=[CH:29][C:24]=2[O:23][CH:22]=1)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19]([C:21]2[C:25]3[CH:26]=[CH:27][C:28]([O:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=4)=[CH:29][C:24]=3[O:23][CH:22]=2)=[O:18])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COC(=O)c1coc2cc(Oc3ccnc(N)n3)ccc12
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)coc3c2)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 108 mg (0.60 mMol) 4-fluoro-3-trifluoromethyl-aniline are dissolved in 10 ml toluene and cooled to 10° C. Then 900 μl Me3Al (2 M in toluene; 1.8 mMol) are added via syringe. After 1 h at rt, a suspension of 171 mg (0.599 mMol) 6-(2-amino-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid methyl ester (Step 9.6) in 5 ml THF is added and the reaction mixture is stirred for 40 min in an oil bath of 110° C. The solution is cooled in ice and hydrolyzed with 20 ml of a sat. NH4Cl. After 10 min stirring, the mixture is filtered through Celite, the solid washed extensively with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc) and crystallization from EtOAc/hexane 1:1 gives the title compound: MS: [M+1]+=433; TLC(hexane/EtOAc 1:9): Rf=0.22.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
3-Nitro-phenylamine (5 g, 36.2 mmol) was dissolved in a biphasic mixture of ethyl acetate (100 ml) and aqueous sodium hydrogen carbonate (1N) (100 ml). 4-Fluoro-benzoyl-chloride (8.7 ml, 41.6 mmol) was added under vigorous stirring. The mixture was stirred for 2 hours at ambient temperature. The phases were separated, the organic phase was dried over sodium sulfate and concentrated. The residue was used without further purification (9.4 g, 100% yield). 1H-NMR (CDCl3, 400 MHz) as disclosed in Magnetic Resonance in Chemistry (1997), 35(8), 543-548.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:29][C:28]1[CH:30]=[CH:31][C:25]([S:22]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]([NH:5][C:6]2[C:7]([F:14])=[CH:8][C:9]([F:13])=[CH:10][C:11]=2[F:12])=[O:4])(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2c(F)cc(F)cc2F)cc1

Procedure:
Following the procedure of Example 52 only using the product of Example 50 and tosyl chloride, the title compound was obtained, mp 180°-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH2:14])=[CH:7][C:6]=1[F:15])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:14])=[CH:7][C:6]=1[F:15])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(N)c(N)cc1F

Procedure:
Prepared analogously to example 1b by hydrogenation of 4-amino-5-nitro-2-fluoro-benzoic acid ethyl ester using palladium/charcoal 10% in methanol.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:14])(=[O:4])=[O:3].CN.[CH2:17]([N:19](CC)CC)C>>[CH3:14][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[S:2](=[O:4])(=[O:3])[NH:19][CH3:17])[C:9]([OH:11])=[O:10]
Reactant: Cc1cc(C(=O)O)ccc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Agent: CN
Product: CNS(=O)(=O)c1ccc(C(=O)O)cc1C
Yield: 87.3 %

Procedure:
4-Chlorosulfonyl-3-methyl-benzoic acid (0.99 g, 4.2 mmol), methanamine (2.0 mL of 33% w/v, 21 mmol), and triethylamine (1.8 mL, 13 mmol) were stirred for 45 min at rt. The reaction mixture was evaporated and the resultant oil was partitioned between ethyl acetate and 1N HCl. The organics were separated and washed with another portion of 1N HCl and then brine. The organics were dried over sodium sulfate and evaporated to give 3-methyl-4-(methylsulfamoyl)benzoic acid (841 mg, 87%). ESI-MS m/z calc. 229.0, found 230.5 (M+1)+; Retention time: 0.64 minutes (3 min run).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C1(C#C[Li])C=CC=CC=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1.CCCCCC.[Cl-].[Cl-].[Zn+2].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.C(OCC)(=O)C>[Cl:23][CH2:24][C:25](=[O:26])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(Cl)CCl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C#Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(C#Cc1ccccc1)CCl
Temperature: 0 °C
Yield: 60.1 %

Procedure:
Anhydrous ZnCl2 (10 g, 73 mmol) was dissolved in THF (50 mL) and the solution cooled to 0° C. in an ice bath. In another flask phenylacetylene (8.0 mL, 73 mmol) was dissolved in THF (50 mL), cooled to 0° C. in an ice bath, and treated with n-butyllithium (32 mL of a 2.2M solution in hexane, 70 mmol). After 20 minutes the phenylethynyllithium solution was added via cannula to the ZnCl2 solution. After an additional 20 minutes Pd(PPh3)4 (1.23 g, 1.06 mmol) was added to the alkynylzinc solution. The resulting yellow solution was treated with chloroacetyl chloride (8.8 mL, 110 mmol) dropwise over 10 minutes. After 2 h at 0° C. the reaction mixture was quenched by the addition of cold aqueous 1M HCl (50 mL), and diethyl ether (500 mL). The acidic aqueous was extracted with diethyl ether (2×50 mL) and the combined organic extracts were washed with water (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The dark solution was dried and decolorized over Na2SO4 and charcoal and filtered through a pad of Celite™. The pad was washed thoroughly with ethyl acetate and the combined filtrates were concentrated in vacuo to afford a dark brown oil. The crude product was purified by column chromatography eluting with hexane, 99:1, 98:2, 96:4, then 94:6 hexane:ethyl acetate to afford 1-chloro-4-phenyl-3-butyn-2-one (7.83 g, 60% yield) as an orange oil which darkened and partially solidified upon standing in the freezer. 1H NMR (CDCl3, 300 MHz) δ 7.63–7.60 (m, 2H), 7.53–7.39 (m, 3H), 4.33 (s, 3H). MS (EI ionization) 178 (35Cl M+), 180 (37Cl M+).
Reaction SMILES: [Cl:1][CH:2]([Cl:31])[C:3]([NH:5][C@H:6]([CH2:29][F:30])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:17][CH:16]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:21][CH2:20][C:18]1[S:19][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C@@H:7]([OH:8])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[Cl:31])[CH2:29][F:30])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product of Step 1, Example 4 (0.248 g, 0.50 mmol) in CHCl3 (10 mL) is added trifluoroacetic acid (1.1 mL) and stirred the reaction mixture at room temperature for 2 hours. Reaction mixture is concentrated in vacuo and washed the residue with diethyl ether. Residue is dissolved in 10% methanol in CH2Cl2 and evaporated to dryness then dried under vacuum to give the title compound 1H-NMR (400 MHz, DMSO-d6) δ: 4.20-4.22 (m, 1H), 4.28-32 (m, 0.5H), 4.40-4.49 (m, 2.5H), 4.56-4.60 (m, 0.5H), 467-4.71 (m, 0.5H), 4.89 (t, J=3.8 Hz, 1H), 6.02 (d, J=4.28 Hz, 1H), 6.50 (s, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H), 8.28 (s, 1H), 8.48 (bs, 2H), 8.63 (d, J=9 Hz, 1H). m/z (Cl) 392 [M−H].
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH:11]=[CH2:12])[CH:4](O)[CH2:5][C:6](O)=O)[CH3:2].C([O-])(=O)C.[K+].[H-].[Na+].COP([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(OC)=O>C(OC(=O)C)(=O)C.O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH2:10][C@@H:11]2[C@H:5]([CH:4]=1)[C:6](=[CH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:12]2)[CH3:2]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: C=CCC(CC)C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
4-Ethyl-3-hydroxyhept-6-enoic acid (3.13 g, 18.2 mmol) was dissolved in acetic anhydride (15 mL). To the solution, potassium acetate (4.27 g, 43.6 mmol) was added, and the mixture was stirred at room temperature for 100 minutes. The reaction solution was heated to reflux and stirred for 3.5 hours. To the reaction solution, ice water and toluene were then added, and this mixture was stirred overnight at room temperature. The mixture was separated into aqueous and organic layers by the addition of saturated saline (50 mL) and toluene (20 mL). Then, the organic layer was washed with a 1 N aqueous sodium hydroxide solution and saturated saline in this order, then dried over anhydrous magnesium sulfate, and then filtered. This filtrate was added to a reaction solution prepared by adding sodium hydride (>65% oil, 761.9 mg, 20 mmol) to a tetrahydrofuran solution (50 mL) of tert-butyl dimethoxyphosphorylacetate (4.48 g, 20 mmol) under ice cooling, and the mixture was further stirred for 1 hour. The reaction solution was separated into aqueous and organic layers by the addition of a saturated aqueous solution of ammonium chloride and saturated saline. The aqueous layer was subjected to extraction with ethyl acetate. These organic layers were combined, then washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (1.32 g, 31%, E/Z mixture).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14](Cl)=[O:15].COC1C=C2C(C(=O)C=[CH:25][NH:26]2)=CC=1C(O)=O.CN.O>O1CCCC1>[CH3:25][NH:26][C:14]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][CH:8]=[C:7]2[Cl:13])=[O:15]
Reactant: COc1cc2[nH]ccc(=O)c2cc1C(=O)O
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc2c(Cl)ccnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
After dissolving 7-methoxy-4-chloro-quinoline-6-carbonyl chloride synthesized by the method of Production Example 152-2 from 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (947 mg) in tetrahydrofuran (70 ml), the solution was cooled to 0° C. A 40% aqueous methylamine solution (0.4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added, extraction was performed 3 times with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate and then dried under reduced pressure to obtain the title compound (710 mg).