Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.[O-:41][C:42]#[N:43].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)[C:42]([NH2:43])=[O:41]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(N)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(NC(N)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 40 °C
Reaction time: 2.3 h
Yield: 56 %

Procedure:
4-(4-Aminophenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (39.2 mg, 0.0730 mmol) was dissolved in acetic acid (1.57 mL) and water (1.57 mL), and the solution was added with aqueous sodium cyanate solution (0.139 mol/L, 1.57 mL, 0.219 mmol), followed by stirring at 40° C. for 2.3 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=10/0.5/0.5) to obtain 4-(4-ureidophenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (23.7 mg, yield 56%).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O>C1COCC1>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccs1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC=Cc1cccs1
Yield: 58.5 %

Procedure:
This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-thiophenecarboxaldehyde (2.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization afforded the product (2.79 g, 59%) as white crystals (mp 45-46° C.). IR: 3400-2500, 1720, 710 cm-1 ; 1H-NMR: 1.45 (m, 8 H), 2.35 (m, 4 H), 5.55 (m, 1 H), 6.50 (d, 1 H), 7.00 (m, 3 H), 11.00 (bs, 1 H). Anal. Calcd. for C13Hl8SO2 : C, 65.51, H, 7.61%; Found: C, 65.58, H, 7.63%. Z:E=75:25.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:18])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH3:10])[N:6]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>COCCOC>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]([CH3:10])[C:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:25](=[O:28])[CH2:26][CH3:27])[S:3][CH:4]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CN(C(=O)Cc1csc(N)n1)c1ccc(Cl)cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: COCCOC
Product: CCC(=O)Nc1nc(CC(=O)N(C)c2ccc(Cl)cc2)cs1
Yield: 52.2 %

Procedure:
A 300 ml reaction flask was charged with 6.0 g (0.021 mole) of 2-amino-4-[N-4-chlorophenyl-N-methyl(carbamoylmethyl)] thiazole, 100 ml of 1,2-dimethoxyethane and 2.6 g (0.03 mole) of pyridine. The propionyl chloride (2.8 g, 0.03 mole) which was dissolved in 15 ml of 1,2-dimethoxyethane was added portionwise and the reaction solution was heated at 65° for two hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic phase was extracted with water and dried over sodium sulfate. After evaporating most of the ethyl acetate, hexane was added. There was obtained 3.7 g (51%) of product, M.P. 153°-5°. N.M.R. (CDCl3) ∂1.2-1.4 (CH3), 2.3-2.5 (CH2), 3.3 (NCH3), 3.5 (0=CCH2), 6.5 (hetero-aromatic) 7.2-7.4 (aromatic).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[CH3:25][O:26][C:27](=[O:33])[CH:28]([CH2:31][NH2:32])[CH2:29][CH3:30]>CO>[CH3:25][O:26][C:27](=[O:33])[CH:28]([CH2:31][NH:32][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[CH2:29][CH3:30]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CCC(CN)C(=O)OC
Solvent: CO
Product: CCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (60 mg, 0.19 mmol) and 2-aminomethyl-butyric acid methyl ester (crude, 1.57 mmol) in MeOH (3 mL) were heated at 150° C. in a microwave for 3 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 55 mg. MS: (−) m/z 418.14 (M−1).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[NH:4].S(O)(O)(=O)=O.CNC(N)=N.C[O-].[Na+].[NH2:19][C:20]1[C:21]([C:33](OC)=[O:34])=[N:22][C:23]([Cl:32])=[C:24]([NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[N:25]=1>CO>[CH3:1][NH:2][C:3]([NH:5][C:33]([C:21]1[C:20]([NH2:19])=[N:25][C:24]([NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:23]([Cl:32])[N:22]=1)=[O:34])=[NH:4]
Reactant: COC(=O)c1nc(Cl)c(NC2CCCC2)nc1N
Reactant: CNC(=N)N
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CNC(=N)NC(=O)c1nc(Cl)c(NC2CCCC2)nc1N
Temperature: 0 °C

Procedure:
To a solution of methylguanidine in methanol (150 ml.) prepared from methylguanidine sulfate (108.5 g.) and sodium methoxide (40.4 g.) is added methyl 3-amino-5-cyclopentylamino-6-chloropyrazinoate (32.85 g.). The reaction is refluxed for 1/2 hour then poured into ice water (300 ml.) affording 28.0 g. of N-methylamidino-3-amino-5-cyclopentylamino-6-chloro-2-pyrazinecarboxamide which melts at 184°-187° C. after recrystallization from 2-propanol.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[CH:14]=[CH2:15])[CH3:5].C(O)(=O)C>C(OCC)C>[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[CH:14]1[CH2:15][CH2:3][N:1]=[N:2]1)[CH3:5]
Reactant: C=Cc1ncccc1C(=O)OCC
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cccnc1C1CCN=N1
Reaction time: 8 h

Procedure:
An excess of diazomethane in diethylether is added to 3.35 g of 2-vinylnicotinic acid ethyl ester and stirred at -10° overnight. Acetic acid is added until gas evolution ceases and the solvent is removed by evaporation under vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[O:10][CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[O:10][CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CN2CCC1CC2
Yield: 86.8 %

Procedure:
Using general procedure E, quinuclidin-3-yl 2-bromophenylcarbamate (130 mg, 0.400 mmol), phenylboronic acid (96 mg, 0.8 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (112 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 8.07 (br s, 1H), 7.55-7.33 (m, 6H), 7.25-7.21 (dd, J=7.6 & 1.6 Hz, 1H), 7.43 (td, J=8.0, 1.2 Hz, 1H), 6.65 (br s, 1H), 4.78 (m, 1H), 3.24 (m, 1H), 2.90-2.68 (m, 5H), 2.04 (m, 1H), 1.80-1.62 (m, 2H), 1.61-1.50 (m, 1H), 1.41-1.30 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 151.2, 135.9, 132.5, 129.5, 128.0, 127.0, 126.9, 126.2, 125.7, 121.4, 117.9, 69.9, 53.1, 45.1, 44.3, 23.1, 22.3, 17.2 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.47 min: (M+1) 323.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2)[CH2:2][CH2:3][CH3:4].CN([CH:23]=[O:24])C>>[CH2:1]([O:5][C:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:23]=[O:24])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c2ccccc2cc2ccccc12
Reactant: CN(C)C=O
Product: CCCCOc1c2ccccc2c(C=O)c2ccccc12

Procedure:
10-Butoxyanthracene was formylated using DMF as both solvent and electrophile by the procedure of E. Campaigne and W. L. Archer, J. Amer. Chem. Soc. 75 989 (1953), affording 10-butoxy-9-anthracenecarbaldehyde mp 65°-67°, (pentane), (C, H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[N:12]([OH:24])[C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([Br:23])[CH:14]=2.N.CO>C(#N)C>[NH2:5][C:3]([NH:10][C:11]1[N:12]([OH:24])[C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([Br:23])[CH:14]=2)=[O:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1c(N)n(O)c2cc(Br)ccc12
Agent: N
Solvent: CC#N
Solvent: CO
Product: NC(=O)Nc1c(C(N)=O)c2ccc(Br)cc2n1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.5 %

Procedure:
Trichloroacetyl isocyanate (0.10 mL, 0.85 mmol) was added to a solution of 2-amino-6-bromo-1-hydroxyindole-3-carboxamide (Reference compound 2-1, 180 mg, 0.71 mmol) in acetonitrile (5 mL), and the mixture was stirred at room temperature for 5 hours. 2.0 M Ammonia in methanol solution (4.5 mL, 9.0 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, 1 N hydrochloric acid (6 mL) and water (25 mL) was added to the residue and the whole was extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (10 mL), and dried under reduced pressure to give the title compound (90 mg) as a slightly brown solid (yield 42%).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11]Br)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[OH:19][CH:20]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>C(#N)C>[OH:18][C:5]1[C:6]([CH2:15][CH2:16][CH3:17])=[C:7]([O:8][CH2:9][CH2:10][CH2:11][O:36][C:33]2[CH:32]=[CH:31][C:30]([CH:20]([OH:19])[CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:35][CH:34]=2)[CH:13]=[CH:14][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: Oc1ccc(C(O)CCCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(O)CCCc3ccccc3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
To a solution of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide (J. Med. Chem. 29, 1573-1576, 1986) (315 mg) and the phenol of Step 1 (242 mg) in acetonitrile (5 mL) was added cesium carbonate (650 mg) and the mixture was heated to reflux for 5 hrs. The suspension was cooled to 25° C. and poured into 25% aqueous NH4OAc and EtOAc. The organic layer was washed with brine, dried with MgSO4 and the solvents are removed in vacuo. The residue was purified by chromatography on silica gel using EtOAc and hexanes (1:2) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[CH:23]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([NH:15][CH2:23][C:19]1[S:20][CH:21]=[CH:22][C:18]=1[Br:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1sccc1Br
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)NCc1sccc1Br
Yield: 80 %

Procedure:
To a stirred solution of 2-Amino-3-phenyl-propionic acid tert-butyl ester (50.6 mg, 0.229 mmol) in ethanol (1 mL), were added 3-Bromo-thiophene-2-carbaldehyde (50 mg, 0.208 mmol.) and acetic acid (21 μL). The reaction mixture was stirred at room temperature under nitrogen for 2 hrs as the progress of imine formation was monitored by TLC. Then, sodium cyanoborohydride (20 mg, 0.312 mmol) was added. The mixture was acidified with sodium bicarbonate and then extracted with dichloromethane. After removal of the solvent, the crude product was purified by silica plate (hexane/ethylacetate 90%:10%) to give 2-[(3-Bromo-thiophen-2-ylmethyl)-amino]-3-phenyl-propionic acid tert-butyl ester in 80% yield: 1H NMR (Varian 400 MHz, CDCl3) δ7.23 (m, 6H, ArH), 6.90 (d, 1H, J=5.3 Hz, thiophenH), 4.00 (d, 1H, J=14.6 Hz, NCH2), 3.85 (d, 1H, J=14.6 Hz, NCH2), 3.48 (m, 1H, CHCH2), 3.00 (m, 2H, CHCH2), 1.37 (s, 9H, tBu).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14].Cl>C(#N)C>[F:8][C:9]([F:19])([F:20])[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:14]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 1.5 °C

Procedure:
Glycine 0.763 g (10.16 mmol) was suspended into acetonitrile 20 ml and 2M NaOH aqueous solution 12.7 ml (25.40 mmol, 2.5 eq.) was also added. After chilling at 0-3° C., 2.12 g (10.16 mmol, 1.0 eq.) of 3-(trifluoromethyl)-benzoyl chloride was diluted with 4 ml acetonitrile and was added dropwise slowly to reaction mixture. After one hour agitation at same temperature, pH was controlled to 2 to 3 with 3N hydrochloric acid aqueous solution. After keeping upright at room temperature, upper organic solution was separated, and lower aqueous solution was extracted with ethylacetate three times. Those organic solution obtained as above was brought all together, dried with anhydrous magnesium sulfate and concentrated removing its solvent under decompression. Residues was solidified with tolene, filtered, washed with normal hexane and 2.28 g (91%) target compound as white solid was yielded.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[O:12][C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:14][N:15]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:3]=[C:4]([C:8]([NH:10][C:11]4[O:12][C:13]([C:16]5[O:17][CH:18]=[CH:19][CH:20]=5)=[N:14][N:15]=4)=[O:9])[CH:5]=[N:6][CH:7]=3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH3:22]
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cncc(Br)c1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3cncc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 5-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-3-pyridinecarboxamide prepared in Reference Example 8 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])[CH3:33])[C:11]([N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=C(NC(OC(C)(C)C)=O)C=1)C.C(OC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=C([NH:85][C:86]([NH2:88])=[O:87])C=1)C>>[C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])[CH3:33])[C:11]([N:13]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([NH:85][C:86]([NH2:88])=[O:87])[CH:31]=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1ccccc1
Reactant: CCOC(=O)CN(Cc1cccc(NC(N)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Agent: CCOC(=O)CN(Cc1cccc(NC(=O)OC(C)(C)C)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1cccc(NC(N)=O)c1

Procedure:
Compound 741 was prepared by a method similar to the method used to prepare compound 706, except compound 703 was replaced with compound 740. ##STR120##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23][C:24]#[N:25])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:10]=1.Cl.[CH3:32][O:33][NH2:34].C(N(CC)CC)C>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23]/[C:24](/[NH2:25])=[N:34]\[O:33][CH3:32])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[N:10]=1
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCNC#N)c1ccccc1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO/N=C(/N)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)C(C)C
Temperature: 70 °C
Yield: 36.6 %

Procedure:
Crude (3-(5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)cyanamide (35 mg, 0.08168 mmol) was transferred to a sealed tube in 3 mL of EtOH. Methoxyamine hydrochloride (170.5 mg, 2.042 mmol) and triethylamine (0.2846 ml, 2.042 mmol) were then added and the reaction heated to 70° C. for 18 hours. An additional 50 eq. of methoxyamine hydrochloride was added along with 50 equivalents of TEA. The reaction was then heated for 24 hours. The reaction was concentrated in vacuo, and the salts washed with ethyl acetate. The filtrate was then concentrated in vacuo, and the residue was purified by flash column chromatography (5-10% MeOH/CH2Cl2), to afford the desired product (14.2 mg, 36% yield) as a clear oil. MS ESI (+) m/z 476 (M+E) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 1H), 7.38 (m, 4H), 7.13 (ms 3H), 3.73 (s, 3H), 3.54 (m, 1H), 3.38 (m, 4H), 2.50 (m, 1H), 2.13 (m, 1H), 1.64 (m, 1H), 1.19 (d, J=7.2 Hz, 6H).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19]C)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([NH:2][NH2:3])=[O:19])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccsc1C(=O)NN

Procedure:
0.4 g of hydrazine hydrate is added to a solution of 1.3 g of methyl 3-(tert-butoxycarbonylamino)thiophene-2-carboxylate in 10 ml of ethanol and the mixture is heated to reflux for 5 hours. After the volatile fractions had been removed under reduced pressure at 40° C., the remaining oil was purified by column chromatography (silica gel, eluent: methylene chloride:methanol=95:5).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[C:12]1([C:10]2[N:2]=[C:3]3[CH2:7][CH2:6][CH2:5][N:4]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: N=C1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2cn3c(n2)CCC3)cc1
Temperature: 80 °C
Yield: 89 %

Procedure:
Prepare 2-iminopyrrolidine hydrochloride (6.98 g, 57.8 mmol) according to Callahan, et al., J. Med. Chem. 2002, 45, 999-1001) and combine 2-bromoacetophenone (3.8 g, 19.3 mmol) with Na2CO3 (8.2 g, 77.2 mmol) in dry DMF (25 mL) and heat at 80° C. for 18 hours. Then, cool the mixture to room temperature, add water (60 mL), and extract with EtOAc (3×100 mL). Concentrate the combined organic layers in vacuo, dilute the residue with ether (100 mL), and wash with cooled water (3×80 mL). Concentrate the organic layer in vacuo to give a white solid, 3.2 g, 89% yield. MS(ES+): m/z=185.1 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][C:9]2[C:18]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(Cl)([Cl:33])=O>>[Cl-:33].[Cl-:33].[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][C:18]2[C:9]([O:8][C:7]3[CH:29]=[CH:30][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=3)=[CH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=2)=[CH:21][CH:22]=1)([OH:28])=[O:27]
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1ccc(Oc2cc3ccccc3cc2Oc2ccc(C(=O)O)cc2)cc1
Product: [Cl-]

Procedure:
The compound 2,3-bis-(4-carboxyphenoxy)naphthalene dichloride was prepared by reacting 2,3-bis-(4-carboxyphenoxy)naphthalene with thionyl chloride according to the procedure of Example 20. After initial crystallization, the product was again recrystallized from cyclohexane/toluene (1;1) to give a 96.5% yield of the title compound with the formula: ##STR25##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[O:6][C@@H:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[O:6][C@@H:7]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:22]=[CH:21][C:19]([NH:20][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(O[C@H](CCN2CCC(c3ccc(N)cc3)CC2)c2ccccc2)cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(O[C@H](CCN2CCC(c3ccc(NC(=O)C(C)C)cc3)CC2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
A mixture of 4-{1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}aniline (5.31 mg, 0.0119 mmol), isobutyryl chloride (2.08 mg, 0.019 mmol), N,N-diisopropylethylamine (8.40 mg, 0.0650 mmol) in methylene chloride (1.0 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated and chromatographed using a preparative TLC plate [2.5% of NH3 (2.0 M in methanol) in CHCl3] to give the product (3.5 mg, 56.5%) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H, J=8.6 Hz), 7.30–7.20 (m, 4H), 7.20 (m, 1H), 7.11 (d, 2H, J=8.6 Hz), 7.04 (s, 1H), 6.57 (d, 1H, J=8.3 Hz), 6.44 (d, 1H, J=2.6 Hz), 6.22 (dd, 1H, J=2.6, 8.3 Hz), 5.09 (apparent dd, 1H, J=4.4, 8.1 Hz), 3.72 (s, 3H), 3.70 (s, 3H), 3.08 (m, 2H), 2.57 (m, 2H), 2.43 (apparent sept, partially hidden, 2H, J=6.8 Hz), 2.30–2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 517.3 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:6]=1)[CH3:4]>C(O)(=O)C>[Br:1][C:9]1[C:5]([CH2:3][CH3:4])=[N:6][N:7]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:8]=1[CH2:10][CH3:11]
Reactant: BrBr
Reactant: CCc1cc(CC)n(-c2c(C)cc(C)cc2C)n1
Solvent: CC(=O)O
Product: CCc1nn(-c2c(C)cc(C)cc2C)c(CC)c1Br
Reaction time: 1 h

Procedure:
A solution of 6.4 g (0.04 mol) of bromine in 20 mL of glacial acetic acid was added dropwise to a stirred solution of 9.00 g (37 mmol) of 3,5-diethyl-1-(2,4,6-trimethylphenyl)pyrazole in 100 mL of glacial acetic acid. After 1 hour at room temperature, the acetic acid was evaporated under reduced pressure and the residues were dissolved in ethyl acetate. This solution was washed with saturated sodium bicarbonate to remove residual acetic acid, dried with brine and magnesium sulfate, and was concentrated on the rotovap. The product was a tan solid (10.26 g, purification. 1H-NMR(CDCl3):0.92 (3H, t, J=7), 1.15 (3H, t, J=7), 1.86 (6H, s), 2.24 (3H, s), 2.32 (2H, q, J=7), 2.60 (2H, q, J=7), 6.82 (2H, s).