Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:19](Br)[CH3:20].Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:20][CH2:19]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(Br)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
20 g of ethyl 4-nitrophenylacetate are dissolved in 30 ml of DMF and added dropwise to a suspension of 4 g of sodium hydride in 20 ml of DMF with ice-cooling. 8.5 ml of dibromoethane are subsequently added, and the mixture is stirred at 55° C. for 1 h. A further 5 g of sodium hydride and 8.5 ml of dibromoethane are added with ice-cooling, and the mixture is then stirred at 50° C. for 2 h. After cooling, the reaction mixture is stirred into a mixture of 100 ml of 1 N hydrochloric acid and 200 g of ice. The mixture is washed four times with 100 ml of diethyl ether each time, the combined organic phases once with 100 ml of sodium chloride solution, dried over sodium sulfate and, after filtration, evaporated to dryness in vacuo. The residue is purified by column chromatography (reversed phase). Yield: 8.5 g (38%) of ethyl 1-(4-nitrophenyl)cyclopropanecarboxylate; LC-MS retention time: 2.01 min (“nonpolar” gradient);
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][CH:19]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[O:17])=[CH:13][CH:14]=3)[C:9]([CH3:31])=[C:8]2[CH3:32])=[CH:4][CH:3]=1.[ClH:35].C(OCC)(=O)C.CO>C(OCC)(=O)C>[ClH:35].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][CH:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)=[O:17])=[CH:13][CH:14]=3)[C:9]([CH3:31])=[C:8]2[CH3:32])=[CH:33][CH:34]=1
Reactant: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NC3CCN(C(=O)OC(C)(C)C)C3)cc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NC3CCNC3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 775 mg portion of tert-butyl 3-({[1-(4-fluorobenzyl)-2,3-dimethyl-1H-indol-5-yl]carbonyl}amino)pyrrolidine-1-carboxylate was dissolved in 3.2 ml of ethyl acetate, and 2.1 ml of 4 M hydrogen chloride/ethyl acetate was added, followed by stirring at room temperature for 15 minutes. Then, 2 ml of methanol was added, followed by overnight stirring at room temperature. The resulting solid was collected by filtration and washed with ethyl acetate/methanol (3/1) to obtain 479 mg of 1-(4-fluorobenzyl)-2,3-dimethyl-N-pyrrolidin-3-yl-1H-indole-5-carboxamide hydrochloride as a pale pink solid.
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][CH2:5][OH:6].[CH2:7]([O:14][C:15](=[O:21])[CH2:16][C:17]([CH2:19]Br)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1>[CH2:7]([O:14][C:15](=[O:21])[CH2:16][C:17]([CH2:19][O:6][CH2:5][CH2:4][Cl:3])=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCl
Reactant: O=C(CBr)CC(=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCCl)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.00 g (21.0 mmol) of acetoacetic acid benzyl ester was dissolved in 40 ml of ether. 1.1 ml (21.0 mmol) of bromine was dropped at 0° C. After stirring at 0° C. for 30 minutes and then at room temperature for 5 hours, about 4 g of ice and sodium carbonate were added so that pH showed 7 or more. The organic layer extracted with ether was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated and dried in vacuo to obtain 4-bromoacetoacetic acid benzyl ester. 1.68 g (24.0 mmol) of sodium hydride (60% oily substance) was susptended in 20 ml of THF and 11.7 g (21.0 mmol) of 2-chloroethanol was added at −40° C. 4-bromoacetoacetic acid benzyl ester was dropped at −40° C., gradually heated and stirred at room temperature for 16 hours. After adding 1 N hydrochloric acid and extracting with ethyl acetate, the obtained mixture was washed with water and saturated aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=7/3) to obtain the title compound.
Reaction SMILES: [C:1]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[CH2:2].[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:29])=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:27]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH3:17])[CH:19]=[CH:20]3)=[O:29])=[CH:8][CH:9]=1)([C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:27]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH3:17])[CH:19]=[CH:20]3)=[O:29])=[CH:12][CH:11]=1)=[CH2:2]
Reactant: C=C(c1ccc(N)cc1)c1ccc(N)cc1
Reactant: Cn1ccc2cc(C(=O)O)ccc21
Product: C=C(c1ccc(NC(=O)c2ccc3c(ccn3C)c2)cc1)c1ccc(NC(=O)c2ccc3c(ccn3C)c2)cc1

Procedure:
Compound 702 was prepared according to the procedure described in Scheme IV from 4,4′-(ethene-1,1-diyl)dianiline and 1-methylindole-5-carboxylic acid. 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 2H), 7.93 (s, 2H), 7.79 (dd, J=1.7, 8.5 Hz, 2H), 7.66 (dd, J=1.7, 6.8 Hz, 4H), 7.42 (d, J=2.3 Hz, 2H), 7.39 (d, J=8.5 Hz, 4H), 7.15 (d, J=2.3 Hz, 2H), 6.61 (d, J=2.9 Hz, 2H), 5.44 (s, 2H), 3.86 (s, 6H).
Reaction SMILES: [NH:1]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[C@H:2]([C:12]([NH:14][C@H:15]([C:33]([NH:35][C@H:36]([C:41]([N:43]1[CH2:68][CH2:67][CH2:66][C@H:44]1[C:45]([NH:47][CH2:48][C:49]([N:51]1[CH2:65][CH2:64][CH2:63][C@H:52]1[C:53]([O:55]CC1C=CC=CC=1)=[O:54])=[O:50])=[O:46])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:32])[NH:21][S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl.CCOCC>CO>[NH:1]([C:69]([O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:70])[C@H:2]([C:12]([NH:14][C@H:15]([C:33]([NH:35][C@H:36]([C:41]([N:43]1[CH2:68][CH2:67][CH2:66][C@H:44]1[C:45]([NH:47][CH2:48][C:49]([N:51]1[CH2:65][CH2:64][CH2:63][C@H:52]1[C:53]([OH:55])=[O:54])=[O:50])=[O:46])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:32])[NH:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=1)(=[O:24])=[O:23])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)NCC(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)NCC(=O)N2CCC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
The substance [14] (105.44 g, 97.43 mM) was dissolved in methanol (350 ml). 1 N NaOH (125.36 ml, 1.3 molar excess) was added dropwise with ice cooling and the mixture was stirred at room temperature for 2 hours. 1 N NaOH (20 ml) was added to the reaction mixture, which was then stirred at room temperature for 1.5 hours. 1 N HCl (49 ml) was added to the reaction mixture to adjust the same to pH 6 and the methanol was distilled off in vacuo. Water was added to the aqueous layer, which was then washed with ether (100 ml). 1 N HCl (50 ml) was added dropwise with ice cooling to the aqueous layer. As the stirring became impossible due to the formation of a precipitate of viscous material, ethyl acetate (300 ml) was added and 1 N HCl (60 ml) was added dropwise to adjust the pH of the aqueous layer to pH 2. The aqueous layer was extracted with ethyl acetate (1 l. and 500 ml), and washed twice with saturated sodium chloride solution and water. After drying with anhydrous sodium sulfate, the ethyl acetate layer was concentrated in vacuo to obtain an oily material which was solidified by adding ether. Recrystallization was effected from ethyl acetate-ether to obtain the substance [15] (95.12 g, yield: 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][CH2:16][CH2:15][Br:14])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CCCBr)c2ccccc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
In a flask was dissolved indole-3-carboxylic acid methyl ester (2.0 g, 11.4 mmole) and 1,3-dibromopropane (11.5 g, 57 mmol) in 15 mL of DMF. To this solution was added cesium carbonate (5.5 g, 17 mmol). The flask was sealed and the content was stirred at 40° C. overnight. The solution was then partitioned between ether and water. The ethereal phase was washed twice with water and once with brine and was finally evaporated. The residue was purified on silica (heptane-ethyl acetate 4:1), to give 2.2 g (75%) of the sub-title compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.C[OH:10]>>[NH2:2][C@@H:1]1[CH:6]=[CH:5][C@H:4]([C:3]([OH:8])=[O:10])[CH2:7]1
Reactant: CO
Reactant: O=C1NC2C=CC1C2
Product: N[C@@H]1C=C[C@H](C(=O)O)C1

Procedure:
Methanol (300 ml) and 60 g (0.465 mol) (+)-cis-3-amino-4-cyclopentenecarboxylic acid (obtained from the bioresolution of 2-azabicyclo[2.2.1]hept-5-en-3-one) were stirred together, then 194 ml (1.39 mol) triethylamine slowly added. The reaction was cooled to 8° C. with ice, then 99 g (0.45 mol) di-t-butyl dicarbonate dissolved in 400 ml methanol was slowly added. After stirring for 48 hrs at ambient temperature the reaction was concentrated under reduced pressure to 100 ml and acidified to pH 3 with 1M KHSO4. The solution was extracted twice with an equal volume of methyl t-butyl ether, the organic layer dried with MgSO4, then evaporated under reduced pressure to give an off-white solid. This was recrystallised from a mixture of methyl t-butyl ether and heptane to give 90 g of N-Boc (+)-amino acid whose structure was verified by proton NMR.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[N:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1
Reactant: FC(F)(F)c1cnn2c(-c3ccnc(Cl)c3)cnc2n1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccn1
Yield: 4 %

Procedure:
7-(2-Chloropyridin-4-yl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium carbonate, at 80° C. in aqueous 1,2-dimethoxyethane, to give the title compound in 4% yield: 1H NMR (360 MHz, CDCl3) δ 7.60 (1H, td, J 1.1, 7.7), 7.78 (1H, td, J 1.1, 7.7), 7.89 (1H, dd, J 1.1, 7.7), 7.97 (1H, dd, J 7.0, 0.7), 8.13 (1H, dd, J 1.8, 5.3), 8.65 (1H, d, J 0.7), 8.84 (1H, s), 8.94 (1H, s), 8.99 (1H, dd, J 0.7, 5.3).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:14]=[CH2:15])=[CH:6][C:7]3[CH2:11][O:10][C:9](=[O:12])[C:8]=3[CH:13]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH:1]1([C:4]2[C:5]([CH:14]3[CH2:15][O:24]3)=[CH:6][C:7]3[CH2:11][O:10][C:9](=[O:12])[C:8]=3[CH:13]=2)[CH2:3][CH2:2]1
Reactant: C=Cc1cc2c(cc1C1CC1)C(=O)OC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OCc2cc(C3CO3)c(C3CC3)cc21
Reaction time: 12 h

Procedure:
6-Cyclopropyl-5-vinyl-2-benzofuran-1(3H)-one (0.45 g, 2.25 mmol) was dissolved in dichloromethane (10 mL) and treated with meta-chloro perbenzoic acid (1 g, 6.3 mmol) at 0° C. and stirred for 12 h. TLC indicated completion of the reaction; the mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane (2×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The epoxide was purified by silica gel column chromatography (hexanes/EtOAc=1/1) to give 6-Cyclopropyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one. The oxirane was further resolved over a chiral column giving two isomers:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[O:9]([CH2:16][C:17]1[CH:26]=[C:20]2[C:21](=[O:25])[NH:22][CH2:23][CH2:24][N:19]2[N:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Cl:1][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:16][C:17]2[CH:26]=[C:20]3[C:21](=[O:25])[NH:22][CH2:23][CH2:24][N:19]3[N:18]=2)=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1NCCn2nc(COc3ccccc3)cc21
Solvent: ClC(Cl)Cl
Product: O=C1NCCn2nc(COc3ccc(Cl)cc3)cc21
Temperature: 80 °C
Reaction time: 20 h
Yield: 87.8 %

Procedure:
N-chlorosuccinimide (61 mg, 0.45 mmol) was added to a solution of 2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.1 g, 0.41 mmol) in CHCl3 (3 mL) and the mixture was stirred at 80° C. for 20 hours. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(4-chloro-phenoxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.1 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([NH:23][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=1.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][CH2:7][N:5]3[CH:6]=[C:2]([NH:1][C:52](=[O:53])[CH2:51][O:50][CH3:49])[N:3]=[CH:4]3)=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc(N)c3)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cn(CCOc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
To a suspension of 1-(4-(2-(4-amino-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate I) (50 mg, 0.095 mmol) in DCM (2.0 mL) was added DIPEA (33 μl, 0.191 mmol) and 2-methoxyacetyl chloride (10 μl, 0.105 mmol). The mixture was stirred at RT overnight and then partitioned between saturated aq NaHCO3 solution (5.0 mL) and DCM (2.0 mL). The layers were separated through a phase separator cartridge and the organics were collected and evaporated under reduced pressure. The resulting residue was subjected to SCX capture and release and column chromatography (12 g), eluting with 0 to 10% MeOH in EtOAc. Trituration with EtOAc (5.0 mL) gave N-(1-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido) naphthalen-1-yloxy)ethyl)-1H-imidazol-4-yl)-2-methoxyacetamide (Example 24) as a white solid (8 mg, 14%): m/z 596 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.38 (3H, s), 3.29 (3H, s), 3.93 (2H, s), 4.37 (2H, t), 4.47 (2H, t), 6.34 (1H, s), 6.93 (1H, d), 7.34 (2H, m), 7.41-7.45 (3H, m), 7.48-7.62 (4H, m), 7.88 (1H, d), 8.13-8.15 (1H, dd), 8.54 (1H, s), 8.75 (1H, s), 9.84 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][NH2:10])=[S:8].[N+:12]([C:15]1[O:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].C(O)(C)C>C(O)C>[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[N+:12]([C:15]1[O:19][C:18]([CH:20]=[N:10][NH:9][C:7](=[S:8])[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:11])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CN(C)CCCNC(=S)NN
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: CN(C)CCCNC(=S)NN=Cc1ccc([N+](=O)[O-])o1

Procedure:
N-(3-dimethylaminopropyl)hydrazinecarbothioamide (0.12 g) was reacted with 5-nitro-2-furaldehyde (0.15 g) in 5 ml ethanol at reflux for 15 minutes. The mixture was cooled and treated with methanesulfonic acid (0.055 ml) and isopropanol and stored at 4° C. to give 0.15 g of the title compound as orange needles, mp 184°-187° C.
Reaction SMILES: O.[NH2:2]N.[N:4]1([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:18])[CH2:13][CH2:12]2)=[S:10])C=CN=C1>C(O)C>[F:26][C:25]([F:28])([F:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([NH:4][NH2:2])=[S:10])[CH2:12][CH2:13]1)=[O:18]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(C(=S)n2ccnc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=S)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
The mixture of hydrazine hydrate (0.584 mL, 12.03 mmol) and [4-(imidazole-1-carbothioyl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (4.03 g, 10.94 mmol) in anhydrous ethanol was refluxed for 3 hours. The reaction mixture was cooled to room temperature and kept in the fridge overnight. The precipitate formed was collected by filtration and washed with ethanol, dried in vacuo to yield 4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioic acid hydrazide in 60% yield (2.20 g). 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J=7.8 Hz, 1H), 7.62 (dd, J=7.5, 7.5 Hz, 1H), 7.55 (dd, J=7.5, 7.5 Hz 1H), 7.33 (d, J=7.5 Hz, 1H), 3.70-4.00 (m, 8H). MS (ES+) m/z 333 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][C:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[NH2:21])([CH3:17])[CH3:16]>>[CH3:17][C:15]([C:18]1[CH:19]=[C:20]([NH:21][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[OH:13])[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)([CH3:14])[CH3:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(NC(=O)c2cc([N+](=O)[O-])ccc2O)cc(C(C)(C)C)c1
Yield: 46.7 %

Procedure:
Using 5-nitrosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:49]>C(O)C>[Na+:49].[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: Cc1ccnc(-c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc(-c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)[O-])cn2)c1

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (85 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methylpyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (68 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (101 μl), and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (69 mg). MS (m/z): 671 [M−Na]−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14](OCC)=[O:15].O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:10])[NH:11][C:14](=[O:15])[O:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)N(O)c1cccc(Cl)c1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2cccc(Cl)c2)o1
Reaction time: 1 h

Procedure:
1-(3-Chlorophenyl)-1-hydroxyurea (0.2 mole) dissolved in aqueous sodium hydroxide (200 ml; 2 N) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10°C and ethyl chloroformate (0.21 mole) is slowly added with stirring. After the addition is completed stirring is continued for a period of about one hour. The reaction mixture is then poured into 2 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The dried product is then dissolved in a methylene chloride-tetrahydrofuran mixture and the resulting solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3-chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH:3]([OH:6])[C:4]#[CH:5].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:22]=[CH:23][C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([CH3:27])[CH:26]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][CH:11]=1>>[CH2:29]([O:28][C:24]1[CH:23]=[CH:22][C:21]([C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:5]#[C:4][CH:3]([OH:6])[C:2]([CH3:8])([CH3:7])[CH3:1])=[CH:15][CH:14]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:26][C:25]=1[CH3:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCC(CC)(c1ccc(Br)cc1)c1ccc(OCc2ccccc2)c(C)c1
Reactant: C#CC(O)C(C)(C)C
Product: CCC(CC)(c1ccc(C#CC(O)C(C)(C)C)cc1)c1ccc(OCc2ccccc2)c(C)c1

Procedure:
In a manner similar to that described for Example 1D, but replacing 2-methyl-3-butyn-2-ol with 4,4-dimethylpent-1-yn-3-ol, the title compound was prepared from 5-[1-(4-bromophenyl)-1-ethylpropyl]-2-benzyloxytoluene: 1H-NMR (CDCl3) δ 7.44-7.48 (2H, m), 7.37-7.42 (2H, m), 7.31-7.36 (3H, m), 7.14 (2H, d, J=8.6), 6.94 (1H, dd, J=2.3, 8.3), 6.90 (1H, d, J=2.3), 6.79 (1H, d, J=8.3), 5.05 (2H, s), 2.22 (3H, s), 2.07 (4H, q, J=7.3), 1.07 (9H, s), 0.62 (6H, t, J=7.3).