Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20]C)=[O:19].[OH-].[Na+]>O.C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1c(CC(=O)O)cccc1C(=O)c1ccccc1

Procedure:
A mixture of 500 mg. (1.85 mmole) of methyl 2-dimethylamino-3-benzoylphenylacetate and 15 ml. of 3 N sodium hydroxide was refluxed for 1.5 hr. under nitrogen. The cooled filtered reaction mixture was diluted with an equal volume of water and neutralized with glacial acetic acid. The precipitate which formed could not be recrystallized and was therefore dissolved in benzene and placed on a magnesium silicate column. The column was eluted with benzene-acetone to give 300 mg. of product which melted at 144°-146° C. after recrystallization from benzene-isooctane.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:1]([O:5][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH3:6])(=[O:4])[C:2]#[CH:3]
Reactant: COCCOCCO
Reactant: C#CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C#CC(=O)OCCOCCOC

Procedure:
12.3 ml (0.2 mol) of propiolic acid are heated at reflux for 20 hours together with 23.6 ml (0.2 mol) of diethylene glycol monomethyl ether, 1.5 g (8 mmol) of p-toluenesulphonic acid monohydrate and 80 ml of toluene, and the resulting reaction water was distilled off azeotropically and collected in a water separator. After completion of the water separation the reaction mixture was washed in succession with saturated sodium bicarbonate solution and with water. The toluene phase was dried over sodium sulphate and concentrated. The crude product was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 2-(2-methoxyethoxy)ethyl propiolate as a colorless oil.
Reaction SMILES: [Si](O[C:9]1[N:10]([CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[C:13](C)[C:12]=2[N:18]=1)(C(C)(C)C)(C)C.[O:20]1CCC[CH2:21]1.C(O)(=O)C>O>[OH:20][CH2:21][C:9]1[N:10]([CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:18]=1
Reactant: Cc1nccc2c1nc(O[Si](C)(C)C(C)(C)C)n2C
Reactant: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(CO)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.00 g of 2-t-butyldimethylsilyloxy-methyl-1-methylimidazo[4,5-c]pyridine (prepared as described in Preparation 72) in 60 ml of a 1:1:1 by volume mixture of tetrahydrofuran, acetic acid and water was stirred at room temperature for 1 hour and then at 60° C. for 5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.97 g of the title compound, melting at 285-290° C.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5](=[O:12])[NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CS(C)=O>[CH2:20]([O:13][C:3]1[C:2]([NH2:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5](=[O:12])[N:4]=1)[CH3:21]
Reactant: CCI
Reactant: CCOC(=O)C1C(N)C(=O)NS1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1=C(N)C(OCC)=NS1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.55 g (7.6 mmole) of 4-amino-5-ethoxycarbonylisothiazolin-3-one-1-oxide, 1.38 g (10.0 mmole) of potassium carbonate, and 0.64 ml (8.0 mmole) of ethyl iodide in 6 ml dimethylsulfoxide was stirred at room temperature for 18 hours. The suspension was then poured onto crushed ice and extracted with ethyl acetate (3×30 ml). The combined organic phases were washed one time each with ice water and brine, then dried over sodium sulfate. The title compound, which was obtained upon removal of the solvent, was identical to the product of Example 7.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[N:5][C:4]=1[NH2:19].[CH2:22](OC(OCC)CBr)[CH3:23]>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:4]2[N:5]([CH:22]=[CH:23][N:19]=2)[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1nnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3n2)cc1
Yield: 94.6 %

Procedure:
Prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine (example C.26 step 9) (4.44 g, 14.4 mmol) and bromoacetaldehyde diethyl acetal (90%, 4.98 mL, 29 mmol) as described in example C.20 step 1. Obtained the title compound as a yellow solid (4.51 g, 94%).MS (ISP) 332.0 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:11][C:4]1([CH3:12])[C:5]2[C:10](=[CH:9][C:8]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:7][CH:6]=2)[C:2]([CH3:14])([CH3:1])[CH:3]1[CH3:13]
Reactant: O=C1CCC(=O)O1
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC1C(C)(C)c2ccc(C(=O)CCC(=O)O)cc2C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
To a solution of 11 g of 1,1,2,3,3-pentamethyl indane (0.058 mole) and 7 g of succinic anhydride (0.07 mole) in 100 cm3 of anhydrous 1,2-dichloroethane, stirred at 0° C., there are added, by small portions, 9.4 g of aluminum chloride in a manner such that the temperature remains lower than 30° C. The reaction mixture is stirred for 3 hours at ambient temperature and then poured into 250 cm3 of ice water. The organic phase is decanted and the aqueous phase is extracted twice with 1,2-dichloroethane. The organic phases are combined, washed with water and dried on magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting product is crystallized in isopropyl ether. 7 g of 4-(1,1,2,3,3-pentamethyl-5-indanyl)-4-oxo butyric acid in the form of white crystals whose melting point is 161° C. are obtained.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16](=[O:50])[CH:17]([CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:18]([C:27](N1C(CC2C=CC=CC=2)COC1=O)=[O:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1COCC1>[CH3:14][O:15][C:16](=[O:50])[CH:17]([CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:18]([C:27]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28])[CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21]
Reactant: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of benzyl alcohol (0.5 mL, 4.41 mmol) in anhydrous THF (16 mL) at −70° C., was added n-butyl lithium (2.5M, 1.4 mL, 3.53 mmol). After 10 minutes of stirring, the solution was transferred by means of a cannula to a solution of the compound of example 51 in anhydrous THF (15 mL) at −70° C. The reaction was allowed to warm to −10° C. over a period of 2 h, after which time, it was placed in an ice bath and stirred for another 50 minutes. Finally, the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times using ethyl acetate. The recombined organic layer was extracted with brine, dried over sodium sulfate, filtered and evaporated. The resultant crude was flashed using 10% ethyl acetate in hexanes to give the product as a colorless oil. 1H-NMR(CDCl3, 300 MH: 1.39, 1.40(2 s, 9H); 1.70(m, 1H); 2.01(m, 1H); 2.31–2.74(m, 4H); 2.83(m, 1H); 3.21(m, 1H); 3.61, 3.64(2s, 3H); 5.11(m, 2H); 7.08–7.35(m, 10H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH:42]1([S:45](Cl)(=[O:47])=[O:46])[CH2:44][CH2:43]1>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:16]2[C:15](=[O:34])[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)=[C:23]([OH:24])[C@H:22]3[C@@H:17]2[C@H:18]2[CH2:25][C@@H:21]3[CH2:20][CH2:19]2)=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(C2=NS(=O)(=O)c3c(CNS(=O)(=O)C4CC4)csc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of (1R,2S,7R,8S)-5-(7-aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.10 g, 0.20 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (56 μL, 0.40 mmol) and cyclopropanesulfonyl chloride (23 μL, 0.22 mmol). The reaction was stirred at 0° C. for 30 min, then at 25° C. for 2 h. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-1% methanol in dichloromethane) to afford the desired product, cyclopropanesulfonic acid {3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-amide (0.10 g, 0.17 mmol, 84%), as a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: COc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Reactant: Cc1noc(N)c1Br
Product: COc1ccccc1-c1ccc(S(=O)(=O)Nc2onc(C)c2Br)s1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 1. Reaction of 2-chlorosulfonyl-5-(2-methoxyphenyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyoxyphenyl)thiophene-2-sulfonamide in 32% yield, m.p. 114-117° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[O:30]1[C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=[N:31]1>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:35]([C:34]3[O:30][N:31]=[CH:32][CH:33]=3)=[O:36])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccno1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccno4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (2.7 g, 8.4 mmol) in CH3CN (25 ml), were added triethyl amine (2.9 mL, 8.4 mmol) and isoxazole-5-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL). The solid was dissolved in CH2Cl2 (5 mL) and purified by ISCO silica gel flash chromatography (eluent: 2% MeOH in CH2Cl2) to afford isoxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a light yellow solid (0.87 g, 27%): mp, 257-259° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.62 (99%); 1H NMR (DMSO-d6): δ 2.04-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.93 (d, J=5.6 Hz, 2H), 5.17 (dd, J=6, 12 Hz, 1H), 7.14-8.78 (m, 5H), 9.60 (t, J=5.6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 37.96, 48.87, 106.26, 122.11, 127.25, 131.56, 133.14, 134.89, 138.00, 151.75, 155.95, 162.35, 166.90, 167.44, 169.80, 172.73. Anal Calcd for C18H14N4O6: C, 56.55; H, 3.69; N, 14.65. Found: C, 56.20; H, 3.36; N, 14.47.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[C:34]([CH3:35])=[N:33][CH:32]=[N:31]3)=[C:26]([F:36])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:36][C:26]1[CH:25]=[C:24]([NH:23][C:20]2[N:19]=[C:18]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=2)[CH:29]=[CH:28][C:27]=1[N:30]1[C:34]([CH3:35])=[N:33][CH:32]=[N:31]1
Reactant: Cc1ncnn1-c1ccc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)cc3)n2)cc1F
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ncnn1-c1ccc(Nc2nc3n(n2)CCCCC3c2ccc(OC(F)(F)F)cc2)cc1F
Yield: 18.8 %

Procedure:
A solution of 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (2.00 g, 3.81 mmol), sodium iodide (2.90 g, 19.1 mmol), and diisoproplylethylamine (3.33 mL, 19.1 mmol) in acetone (25 mL) was heated in a sealed vessel at 100° C. for 6 h. The reaction was concentrated in vacuo. Water (250 mL) was added and the mixture was extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (70% EtOAc/chloroform) to afford 350 mg (19% yield) of the titled compound as a white solid. LC-MS (M+H)+ 488.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.96 (s, 1 H), 7.68 (dd, J=12.7, 2.3 Hz, 1 H), 7.26-7.29 (m, 1 H), 7.19-7.25 (m, 4 H), 7.04 (dd, J=8.9, 2.1 Hz, 1H), 6.87 (s, 1 H), 4.31 (dd, J=8.9, 2.4 Hz, 1 H), 4.27 (t, J=5.0 Hz, 2 H), 2.39 (s, 3 H), 2.17-2.29 (m, 1 H), 2.06-2.16 (m, 1 H), 1.84-2.04 (m, 4 H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C([Li])CCC.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>O1CCCC1.CCCCCC>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCCC2=O)cc1
Temperature: -20 °C
Reaction time: 0.42 h
Yield: 50.5 %

Procedure:
1.65 g of 2-pyrrolidinone in solution in 75 cm3 of tetrahydrofuran is cooled to -5° C., and 12.1 cm3 of a 1.6M solution of n-butyllithium in hexane is added, maintaining the temperature between -5° C. and 0° C. Agitation is carried out for 25 minutes at -5° C.; the mixture is cooled to -20° C. and 4.5 g of 4-tert-butyl-phenylsulphonyl chloride is added [Recueil Trav. Chim. Pays-Bas, 53, 1101 (1934)]. After allowing to return to ambient temperature, the tetrahydrofuran is evaporated off under reduced pressure, the residue is taken up with water, filtered and crystallized from ethanol. 2.75 g of expected product is obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([OH:12])([CH2:10][CH3:11])[CH2:8][CH3:9])=[N:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[O:23][C:22](=[O:32])[CH:21]=2)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:8]([C:7]([C:5]1[O:6][C:2]([NH:1][CH2:30][C:26]2[CH:25]=[C:24]3[C:29]([C:20]([C:17]4[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=4)=[CH:21][C:22](=[O:32])[O:23]3)=[CH:28][CH:27]=2)=[N:3][N:4]=1)([OH:12])[CH2:10][CH3:11])[CH3:9]
Reactant: O=Cc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Reactant: CCC(O)(CC)c1nnc(N)o1
Solvent: Cc1ccccc1
Product: CCC(O)(CC)c1nnc(NCc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)o1
Temperature: 25 °C

Procedure:
A mixture of 3-(5-amino-1,3,4-oxadiazol-2-yl)pentan-3-ol (0.446 g, 2.6 mmol) and 4-(4-fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde (0.350 g, 1.3 mmol) in 5 mL of toluene was refluxed with a Dean-Stark trap overnight. After cooling to rt the solvent was removed and the crude imine diluted in ethanol (8 ml) at 0° C. Solid NaBH4 (49 mg) was added to the solution and after 30 min of stirring aqueous NH4Cl was added to destroy the excess hydride. After dilution with EtOAc-brine, the organic phase was dried with MgSO4. Purification on silica gel with toluene-EtOAc (2:8) gave the title compound. 1H NMR (400 MHz, acetone-d6): δ 7.67 (m, 2H), 7.48 (m, 2H), 7.37 (m, 3H), 7.19 (bt, 1H), 6.33 (s, 1H), 4.66 (m, 2H), 4.31 (s, 1H), 1.85 (m, 4H), 0.85 (t, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][NH:10][NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17](=O)[CH:18]=[C:19]([NH2:23])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:23][C:19]1[NH:11][N:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=2)[C:17](=[O:16])[CH:18]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: CC(C)(C)c1ccc(CNN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(Cn2[nH]c(N)cc2=O)cc1

Procedure:
24.6 g of p-tert.butylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 22 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 100 ml of ethanol, in the course of which the temperature rose from 24° to 30°C. After stirring overn the solvent was distilled off in vacuo and the oily residue solidified after addition of 50 ml of petroleum ether. The compound identified above was filtered off and recrystallised from ethanol. Melting poing: 126°, 8 g (24%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[F:22][C:23]([F:40])([F:39])[C:24]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([OH:29])[C:25]([F:28])([F:27])[F:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:34](=[O:35])[C:33]4[CH:32]=[CH:31][C:30]([C:24]([OH:29])([C:23]([F:22])([F:39])[F:40])[C:25]([F:26])([F:27])[F:28])=[CH:38][CH:37]=4)[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(OC2CCN(C(=O)c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
1-(cyclopropylmethyl)-3-(4-(piperidin-4-yloxy)phenyl)urea (1.037 mmol, 300 mg), 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoic acid (1.037 mmol, 299 mg) and triethylamine (3.11 mmol, 0.432 mL, 315 mg) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (1.555 mmol, 0.926 mL, 990 mg; 50% solution in ethyl acetate) was added and the reaction stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and the organic layer was separated, dried and concentrated under vacuum. The residue was dissolved in dichloromethane and purified by silica column chromatography (eluent 2-8% methanol in dichloromethane) to afford the title compound (24 mg). MS (ESI) m/z 560.2 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[C:6]([CH2:21][CH2:22][CH3:23])[C:5]=1[OH:24])(=[O:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI.Cl>C(C(C)=O)C>[CH3:25][N:18]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:19]=[CH:20][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:24])[C:6]=2[CH2:21][CH2:22][CH3:23])=[N:15][N:16]=[N:17]1
Reactant: CCCc1c(OCCCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: CCCc1c(OCCCCCc2nnnn2C)ccc(C(C)=O)c1O

Procedure:
A solution of 5 g. of 5-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]-tetrazole, 3 g. of potassium carbonate, and 2.4 g. of methyl iodide in 250 ml. of methyl ethyl ketone was allowed to reflux overnight. The reaction mixture was treated with dilute hydrochloric acid and the layers were separated. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography over silica gel (2% ethanol in methylene chloride). The appropriate fractions were pooled and evaporated to an oil. Crystallization from ethyl acetate/hexane afforded 1.5 g. of the title product, m.p. about 72°-75° C.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]3[CH3:29])=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][C:19]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH:8]3[CH2:9][CH2:10][CH:6]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:7]3)=[CH:13][CH:14]=2)[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: C1CCNC1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(OS(C)(=O)=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(N3CCCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
3-[4-({3-[(methylsulfonyl)oxy]cyclopentyl}oxy)phenyl]-2-methyl -4(3H)-quinazolinone (550 mg, 1.33 mmol), pyrrolidine (474 mg, 6.7 mmol) and potassium carbonate (277 mg, 2.0 mmol) were mixed in dimethylformamide (10 mL) and stirred at 80° C. overnight. Distilled water was added, and the mixture extracted with ethyl acetate. The organic phase was dried by anhydrous magnesium sulfate, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain the title compound (143 mg) as a colorless solid. 2-methyl-3-[4-{[3-(1-pyrrolidinyl)cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone (trans isomer)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]CC)=[O:15])=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][C@@H:5]1[CH3:20])(=[O:3])[CH3:2].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])[CH2:23][CH2:22]1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[CH:28]=2)[CH2:6][C@@H:5]1[CH3:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)C[C@H](C)N2C(C)=O
Reactant: Nc1cccc(N2CCOCC2)c1
Product: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2cccc(N3CCOCC3)c2)C[C@@H]1C
Yield: 32 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 2, using ethyl (2S)-1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate and 3-morpholinoaniline, and subsequently, hydrolysis of the ester was carried out by a known method. Thus, 70 mg (32%) of the title compound was obtained as a light orange-colored powder.