Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:8]2[CH2:35][C:36]([CH2:43][CH3:44])([CH2:41][CH3:42])[C:37]([O:39]C)=[O:38])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28](=[O:34])[CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[C:8]2[CH2:35][C:36]([CH2:41][CH3:42])([CH2:43][CH3:44])[C:37]([OH:39])=[O:38])=[CH:45][CH:46]=1
Reactant: CCC(CC)(Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Temperature: 70 °C

Procedure:
The compound from Step E was hydrolysed using THF (2.5 mL), MeOH (0.6 mL) and NaOH (1N, 1.5 mL). The solution was heated at 70° C. for 2 weeks. The reaction was neutralized by addition of Na4OAc buffer (20 mL of 25% w/v) and extracted with EtOAc (3×30 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (eluant: EtOAc-hexane-HOAc (250:750:1)) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9]2[N:10]([CH2:13][C:14]([OH:16])=O)[CH:11]=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:22][CH:21]=1)[CH3:19].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:1]([C:4]1[C:9]2[N:10]([CH2:13][C:14]([NH:17][CH:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([C:27]#[N:28])([CH3:29])[CH3:30])=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH:11]=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2ncn(CC(=O)O)c12
Reactant: CC(N)c1ccc(C(C)(C)C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc2ncn(CC(=O)NC(C)c3ccc(C(C)(C)C#N)cc3)c12

Procedure:
2-(7-acetyl-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing 7-acetyl-1H-benzimidazol-1-ylacetic acid (90.0 mg, 0.413 mmol) prepared according to scheme 4, 2-[4-(1-aminoethyl)phenyl]-2-methylpropanenitrile (77.6 mg, 0.413 mmol) prepared according to scheme 6 and Et3N (125 mg, 1.24 mmol, 0.173 mL) and HATU (157 mg, 0.413 mmol) in dry MeCN (10.0 mL). The product is purified by reverse phase HPLC: Gilson prep pumps; Flow rate: 30 ml/min; Column: Synergi Polar (4μ) 21.2×50 mm; Mobile phase: A=water (0.05% TFA) B=MeCN (49.5 mg, 0.128 mmol, 31.0%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (d, J=7.03 Hz, 3H) 1.66 (s, 6H) 2.38 (s, 3H) 4.74-4.87 (m, J=7.23, 7.23 Hz, 1H) 5.14 (s, 2H) 7.26 (t, J=7.81 Hz, 1H) 7.35 (d, J=8.40 Hz, 2H) 7.45 (d, J=8.40 Hz, 2H) 7.71 (d, J=7.62 Hz, 1H) 7.85 (d, J=8.01 Hz, 1H) 8.21 (s, 1H) 8.65 (d, J=7.81 Hz, 1H); MS [M+H] calcd.: 389.19. found: 389.09.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][N:15]([CH:28]([CH3:30])[CH3:29])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17].O.NN.C(O)C>C(OCC)C>[NH2:3][CH2:12][CH2:13][CH2:14][N:15]([CH:28]([CH3:30])[CH3:29])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18]
Reactant: CC(C)N(CCCN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(C)N(CCCN)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 99.2 %

Procedure:
The compound (8.11 g, 18.80 mmol) obtained in step B and hydrazine monohydrate (5 ml) were added to ethanol (200 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was cooled, and diluted with diethyl ether. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was dissolved in dichloromethane, and the solution was extracted with hydrochloric acid. The aqueous layer was alkalified with aqueous sodium hydroxide solution, extracted with dichloromethane, and the organic layer was dried over potassium carbonate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (5.62 g, yield 99%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=O.CC(C)([O-])C.[K+].[C:29]([O:37]C)(=[O:36])[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].Cl>O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][C:29]([OH:37])=[O:36])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)c2ccc(C(C)(C)C)cc2)cc1OC
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(CC(=O)O)=C(c1ccc(C(C)(C)C)cc1)c1ccc(OC)c(OC)c1
Temperature: 90 °C

Procedure:
To a 2 L four-neck flask with overhead stirring was added the product from Step 1 (101 g), toluene (1.5 L) and potassium t-butoxide (50 g). Dimethyl succinate (60 mL) was added to the flask through addition funnel over 30 minutes. The reaction mixture was heated to 90° C. for 3 hours. The slurry was cooled and poured into ice water (1 L). The bottom water layer was acidified by hydrochloric acid (12N, 100 mL). The resulting slurry was extracted with ethyl acetate (1 L) and the top layer was washed with water and dried over sodium sulfate. The final solution was condensed to oily residue and the residue was dried in vacuum oven at 60° C. for 8 hours to afford 147 g of waxy solid, 4-(3,4-dimethoxyphenyl)-4-(4-t-butylphenyl)-3-methoxycarbonyl-3-butenoic acid. The product was used as is in next step without further purification.
Reaction SMILES: Br[CH:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C1CCN2C(=NCCC2)CC1>CC(C)=O>[F:16][C:12]1[N:11]=[C:10]([O:9][CH:2]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)C(=O)C(Br)Oc1cccc(F)n1
Reactant: c1c[nH]cn1
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)C(=O)C(Oc1cccc(F)n1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a stirred solution of 14.5 g (0.05 mole) of 1-bromo-1-(6-fluoro-2-pyridinyloxy)-3,3-dimethyl-2-butanone in 75 ml acetone cooled to -10° C. was added 3.4 g (0.05 mole) imidazole. Then, 7.61 g (0.05 mole) of 1,5-diaza(5.4.0)undec-5-ene was added dropwise. After the addition was complete, the mixture was stirred for 30 minutes at 0° C. and the solvent evaporated. Water was added to the residue and the mixture extracted with diethyl ether. The ether extract was dried using magnesium sulfate and the solvent evaporated. Chromatography on silica gel (8:2 hexane:acetone) gave 6.3 g (55% yield) of 1-(6-fluoro-2-pyridinyloxy)-3,3-dimethyl-1-(imidazol-1-yl)-2-butanone. Recrystallization from hexane gave product melting at 90°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:35])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccncc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccncc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-isonicotinoylpiperazin-1-yl)quinolin-7-yl]ethanone (0.030 g, 0.076 mmol) and ammonium acetate (0.0586 g, 0.760 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.19 mL, 0.19 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H23ClN5O (M+H)+: m/z=396.2; Found: 396.2.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:17]=[C:18]1OC(=O)[N:20]2[CH:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[S:25][CH2:26][CH:19]12>CS(C)=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:18]([CH:19]3[CH2:26][S:25][CH:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:20]3)=[O:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Reactant: O=C1OC(=O)N2C1CSC2c1cccnc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of 40 mg of 1-(3-phenylpropyl)piperazine in 0.5 ml of dimethyl sulfoxide was added to a solution of 50 mg of 1,3-dioxo-5-(3-pyridyl)thiazolidino[3,4-c]oxazolidine hydrochloride in 1 ml of dimethyl sulfoxide at room temperature. The reaction mixture was stirred for 2 hours at room temperature, then diluted with ethyl acetate, washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 70 mg of 1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine. The physicochemical properties of this product were in agreement with those of the compound of Example 108.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C@:19]1([CH3:25])[CH2:23][O:22]C(=O)[NH:20]1)[CH:13]=[CH:12]2.C(O)C.O.[OH-].[Li+].O>>[NH2:20][C@@:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][C@@H:2]3[CH2:3][C@@H:4]4[CH2:7][C@H:1]3[CH2:6][CH2:5]4)[CH:10]=2)[CH:15]=1)([CH3:25])[CH2:23][OH:22]
Reactant: C[C@@]1(c2ccc3cc(O[C@@H]4C[C@H]5CC[C@@H]4C5)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(O[C@@H]3C[C@H]4CC[C@@H]3C4)ccc2c1
Yield: 34.3 %

Procedure:
The compound was prepared in a manner similar as to that described (R)-4-(6-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.0003 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 32 mg of the desired product as a white solid (32%). ESI-MS: 339 (M−16)+. NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3H), 7.50 (d, J=8.5 Hz, 1H), 7.23-7.05 (m, 2H), 4.33-4.17 (m, 1H), 3.84-3.51 (m, 2H), 2.49-0.78 (m, 13H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:9][CH:8]=1)(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:61][OH:62].CN([CH:66]=[O:67])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:61]([O:67][CH3:66])=[O:62])=[CH:8][CH:9]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CO
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 78 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A mixture of 4-[2-(tert-butoxycarbonylamino)ethyl]-phenyl trifluoromethanesulfonate (6.11 g, 16.6 mmol), palladium(II) acetate (745 mg, 3.32 mmol), 1,3-bis-(diphenylphosphino)propane (1.37 g, 3.32 mmol), triethylamine (6.94 ml, 49.8 mmol), and MeOH (24ml) in DMF (60 ml) was purged for 30 min with carbon monoxide. The mixture was stirred under carbon monoxide atmosphere at 78° C. for 3 hours. After cooling the mixture to room temperature, the reaction mixture was diluted with EtOAc, washed with water, 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 4:1-3:1) to give methyl 4-[2-(tert-butoxycarbonylamino)ethyl]benzoate (3.52 g, 76%).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O-:19])(=O)[CH3:17].[NH4+:20]>>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:20][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:19][C:16]3[CH:17]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: [NH4+]
Product: c1ccc(Oc2ccc(CNCc3ccc(Oc4ccccc4)cc3)cc2)cc1

Procedure:
4-Phenoxybenzaldehyde was reacted with ammonium acetate to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C-:27]#[N:28].[K+].CC(O)=O>CO.O>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)([C:27]#[N:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [C-]#N
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N#CC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A solution containing 1-(pyridin-4-yl)piperazine (58.34 mmol, 1 equiv.), N-benzyl-piperidinone (1 equiv.), KCN (1.1 equiv.), AcOH (3.3 ml) and water (1.3 ml) in methanol was stirred at room temperature for 16 h. The reaction mixture was quenched with NH4OH solution (400 ml) and filtered. The solid precipitate was thoroughly washed with water, dried under vacuum and taken through to the next reaction without further purification. Yield: 47%.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[C:8]([C:27]([OH:29])=[O:28])[C:9]([O-:26])=[C:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]([C:22]([OH:24])=[O:23])[C:13]=3[O-:25])[C:4]2=[CH:3][CH:2]=1.[Na+].[Na+].C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(O)=O>>[CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][C:8]([C:27]([OH:29])=[O:28])=[C:9]([OH:26])[C:10]=2[CH2:11][C:12]2[C:13]([OH:25])=[C:14]([C:22]([OH:24])=[O:23])[CH:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:6]=1
Reactant: O=C(O)c1cc2ccccc2c(Cc2c([O-])c(C(=O)O)cc3ccccc23)c1[O-]
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2c(Cc2c(O)c(C(=O)O)cc3ccccc23)c1O

Procedure:
Alternative organic ions in addition to pamoate were investigated to explore the general utility of the present invention. Microparticle formulations were prepared by an oil-in-water emulsion/solvent extraction method. PLGA polymer (MW 24,000, 160 mg) was dissolved in EtOAc (1000 μL). Octreotide acetate (40 mg) was dissolved in BnOH (1000 μL) and added to the polymer solution yielding a homogenous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10-20 mM organic acid as its sodium salt to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (150 mL) and stirred for four hours to extract EtOAc. Hardened microparticles were collected by filtration, washed with water, air dried and stored at 4° C. This resulted in microparticle formulations with octreotide core loads between 6.8 and 15.3% as measured by RP-HPLC (Table 8). The effects of the tested organic ions on core load are revealing. Formulations AM-AP show no increase in the measured core load relative to control containing sodium pamoate (Formulations AT, AU, AY, Table 8). In contrast formulations AQ-AS, AV-AX and AZ-BB, which employed organic acids ranging from cholic acid to bicylic aromatics, provided peptide core loads comparable to pamoic acid (Table 8). These results imply that organic acids with appropriate physiochemical properties can be substituted for pamoic acid to produce comparable microparticle formulations.
Reaction SMILES: [CH:1]([C:3]1([N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=O.[CH2:15]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH3:16]>ClCCl>[C:9]([O:8][C:7]([N:6]([CH3:14])[C:3]1([CH:1]=[CH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:5][CH2:4]1)=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)C1(C=O)CC1
Solvent: ClCCl
Product: CCOC(=O)C=CC1(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
1.15 g of the product obtained in Step 1 and 2.01 g of (ethoxycarbonylmethylene)-triphenylphosphorane in 30 ml of dichloromethane are heated at reflux for 20 hours, concentrated under reduced pressure and then chromatographed over silica gel (dichloromethane/tetrahydrofuran: 97/3) allowing the expected product to be isolated.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20]([OH:34])([C:23]([NH:25][CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>ClCCl>[OH:34][C:20]1([C:23]([NH:25][CH:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27])=[O:24])[CH2:21][CH2:22][CH:17]([NH:16][S:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:18][CH2:19]1
Reactant: CC(NC(=O)C1(O)CCC(N)CC1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2cocn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)C1(O)CCC(NS(=O)(=O)c2ccc(-c3cocn3)cc2)CC1)c1ccccc1

Procedure:
4-Oxazol-4-yl-benzenesulfonyl chloride (Intermediate 26, 71.5 mg) was added to solution of 4-amino-1-hydroxy-N-(1-phenylethyl)cyclohexanecarboxamide (Intermediate 92, 70 mg) and diisopropylethylamine (0.103 ml) in dichloromethane (2.7 ml). After 16 hours the reaction was diluted with dichloromethane, rinse once using 1N hydrochloric acid followed by once using saturated aqueous sodium bicarbonate. The organics were dried over sodium sulfate, filtered and concentrate to 126 mg crude solid. The title compound was isolated by preparative basic reverse-phase chromatography to yield two isomeric samples of 1-hydroxy-4-(4-(oxazol-4-yl)phenylsulfonamido)-N-(1-phenylethyl)cyclohexanecarboxamide. Yield 4.5 mg.
Reaction SMILES: CNC(C/C=C/C1C=NC=C(Br)C=1)C.[Br:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[CH2:24][CH:25]([OH:27])[CH3:26])[CH:19]=[N:20][CH:21]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([O:27][CH:25]([CH2:24]/[CH:23]=[CH:22]/[C:18]2[CH:19]=[N:20][CH:21]=[C:16]([Br:15])[CH:17]=2)[CH3:26])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: CC(O)C/C=C/c1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CNC(C)C/C=C/c1cncc(Br)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3,5-dibromopyridine (23.60 g, 100.0 mmol), 4-penten-2-ol (10.8 g, 125.0 mmol), palladium(II) acetate (230 mg, 1.02 mmol), tri-o-tolylphosphine (1.20 g, 3.94 mmol), triethylamine (29.7 mL, 213.45 mmol), and acetonitrile (40 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation, followed by column chromatography over silica gel eluting with acetone-chloroform (1:9, v/v) furnished 8.10 g (34.0%) of a pale-yellow oil. (4E)-N-Methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine To a stirring solution of (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol (3.14 g, 13.0 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride (3.71 g, 19.5 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol p-toluenesulfonate. The resulting tosylate was treated with excess methylamine (40% solution in water), ethyl alcohol (10 mL), and stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation followed by column chromatography over silica gel eluting with chloroform-methanol (95:5, v/v) produced 1.50 g (45.0%) of a pale-yellow oil.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CO[C:17]1[C:21](OC)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>>[OH:31][CH:28]([CH2:29][OH:30])[CH2:27][NH:26][C:21]1[C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)=[N:18][S:19](=[O:24])(=[O:25])[N:20]=1
Reactant: NCC(O)CO
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2NCC(O)CO)cs1

Procedure:
When a methanolic solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide by the procedure of Example 31 and the resultant 3-methoxy-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadazole 1,1-dioxide is treated with 3-amino-1,2-propanediol, the title compound is thereby produced.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br.Br[CH:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C(N(CC)CC)C>C(#N)C>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:1]=[C:2]([NH2:4])[S:3][C:7]=2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2nc(N)sc2-c2cccnc2)cc1
Yield: 82 %

Procedure:
To a suspension of thiourea (0.52 g) in acetonitrile (40 mL) was added 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide (2.5 g) and triethylamine (0.95 mL) was slowly added dropwise with stirring. After completion of dropwise addition, the mixture was stirred at a refluxing temperature for 3 h, and after allowing to cool, the precipitated crystals were collected by filtration. The crystals were washed successively with saturated sodium hydrogencarbonate solution, water, ethanol and ethyl ether and dried. The obtained crude crystals were recrystallized from tetrahydrofuran to give the title compound (1.5 g, yield 90%).