Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]([C:27](O)=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:45]([O:52][C:53](=[O:71])[C@H:54]([CH2:67][CH:68]([CH3:70])[CH3:69])[NH:55][C:56](=[O:66])[C@H:57]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH2:58])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[CH2:45]([O:52][C:53](=[O:71])[C@H:54]([CH2:67][CH:68]([CH3:69])[CH3:70])[NH:55][C:56](=[O:66])[C@H:57]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH:58][C:27](=[O:28])[C@H:25]([CH3:26])[NH:24][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
14.0 Parts N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine and 3.5 parts N-methylmorpholine are dissolved in 200 parts dimethylformamide and cooled to -15° C. Then, 5.2 parts isobutyl chloroformate is added dropwise over a 30 minute period while maintaining the temperature at -15° C. Then, a solution of 9.8 parts L-phenylalanyl-L-leucine benzyl ester in 50 parts dimethylformamide is slowly added at -15° C., and the mixture stirred at this temperature for 30 minutes. The cooling apparatus is removed and the mixture stirred at ambient temperatures for an additional two hours. The product is isolated by diluting the reaction mixture with 10 volumes water and extracting with ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure. Purification of the residue by low pressure column chromatography affords N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanyl-L-phenylalanyl-L-leucine benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([NH:9][C:10](=[O:13])[O:11]C)[C:5](O)=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:11][C:10](=[O:13])[NH:9][C:4]=2[C:3]=1[F:14]
Reactant: COC(=O)Nc1c(O)ccc(Cl)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(F)c(Cl)ccc2o1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a mixture of methyl (3-chloro-2-fluoro-6-hydroxyphenyl)carbamate (173 mg) and DMF (1.5 mL) was added K2CO3 (218 mg), followed by heating and stirring at 120° C. for 20 minutes. The reaction mixture was cooled to room temperature, and then added to ice water. To the reaction mixture was added concentrated hydrochloric acid (263 μL) under ice-cooling, followed by stirring at the same temperature for 30 minutes. The resulting solid was collected by filtration and then washed with water to obtain 5-chloro-4-fluoro-1,3-benzoxazol-2(3H)-one (117 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5]([Br:11])=[C:4]([Br:12])[C:3]=1[Br:13].[H-].[Na+].C[O:17][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[Br:11][C:5]1[C:6]2[N:7]=[CH:8][N:9]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:27])=[O:17])[C:10]=2[C:2]([Br:1])=[C:3]([Br:13])[C:4]=1[Br:12]
Reactant: COC(=O)CCCCCCCBr
Reactant: Brc1c(Br)c(Br)c2[nH]cnc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCn1cnc2c(Br)c(Br)c(Br)c(Br)c21
Reaction time: 48 h
Yield: 63.4 %

Procedure:
4,5,6,7-tetrabromo-1H-benzimidazole (115 mg, 0.26 mmol) and NaH suspension (12 mg, ˜0.28 mmol) were stirred in DMF for 30 min and then 8-bromooctanoic acid methyl ester (182 mg, 0.77 mmol) was added. The solution was stirred for 2 days and then evaporated to dryness. The residue was purified by flash chromatography (CHCl3: methanol; 20:1 by volume). The methyl ester was hydrolyzed in the mixture of methanol and aqueous KOH for 1 hour and the solvents were removed in vacuum. The obtained residue was partitioned between ethyl acetate and KHSO4, the organic layer was dried and evaporated to yield 8-(4,5,6,7-tetrabromo-1H-benzimidazole-1-yl)octanoic acid (95 mg, 62% over two steps). 1H NMR (200 MHz; DMSO6d; Me4Si) 1.28 (m, 6H), 1.48 (m, 2H), 1.76 (m, 2H), 2.19 (t, J=7.3 Hz, 2H), 4.48 (t, J=7.6 Hz, 2H), 8.51 (s, 1H), 11.91 (br, 1H). 13C NMR (50 MHz; DMSO6d; Me4Si) 24.3, 25.5, 28.1, 28.3, 31.5, 33.6, 46.4, 106.5, 116.6, 120.4, 122.3, 131.3, 143.7, 148.9, 174.4. B. Synthesis of TBBI-OcA-(D-Asp)-(L-Asp)5-(L-Lys)-OH
Reaction SMILES: C([O:4][CH:5]([C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=2[N:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[OH-].[K+]>C(O)C>[OH:4][CH:5]([C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=2[N:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(C(OC(C)=O)c3ccccc3)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(C(O)c3ccccc3)nc12

Procedure:
(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)(phenyl)methyl acetate (1.311 g, 0.004 mol) was added to a solution of potassium hydroxide (232 mg, 0.0041 mol) in ethanol (60 ml). The resulting mixture was refluxed for 1 hour to give a colourless solution. On cooling, this was concentrated under reduced pressure, and the resulting residue partitioned between water and dichloromethane. The aqueous phase was acidified to pH3 with 1M aqueous hydrochloric acid solution and was extracted with dichloromethane/methanol (100 ml). The organic extracts were combined, dried (MgSO4), filtered and concentrated under reduced pressure.
Reaction SMILES: [Si]([O:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:18]2[N:17]=[CH:16][C:15]([CH2:14][O:13][C:12]3[CH:30]=[CH:31][C:9]([OH:8])=[CH:10][CH:11]=3)=[CH:20][N:19]=2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2cnc(Nc3ccc(Cl)c(Cl)c3)nc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(OCc2cnc(Nc3ccc(Cl)c(Cl)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
5-((4-((tert-butyldimethylsilyl)oxy)phenoxy)methyl)-N-(3,4-dichlorophenyl)pyrimidin-2-amine (0.022 g, 0.046 mmol) was dissolved in THF (4.6 mL) and TBAF (0.231 ml, 0.231 mmol) was added. The mixture was stirred at room temperature for 16 h, quenched with ammonium chloride solution and extracted with ethyl acetate. The organic extract was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel using 20-50% ethyl acetate in hexanes. The desired fractions were concentrated to give 4-((2-(3,4-dichlorophenylamino)pyrimidin-5-yl)methoxy)phenol as a white solid (0.006 g, 34%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52 (2H, s), 7.99 (1H, dd, J=1.88, 0.88 Hz), 7.33-7.45 (2H, m), 7.23 (1H, s), 6.82-6.90 (2H, m), 6.71-6.84 (2H, m), 4.91 (2H, s), 4.65 (1H, br. s.). LCMS: R.T.=1.04 min; [M+H]+=362.04
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (0.2 g, 0.83 mmol), 2-methylpropan-2-amine (66 mg, 0.91 mmol), EDCI (476 mg, 2.49 mmol) and HOBt (112 mg, 0.83 mmol) in dry dichloromethane (20 mL) was stirred at room temperature for 16 hours. Reaction mixture was concentrated to about half the volume and the formed precipitate was separated by filtration, the filter cake was washed with dichloromethane and dried to afford 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (103 mg, 42%) as a yellow solid. LCMS: (M+H)+=297.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[S:21][C:22]([CH2:25][NH:26][CH2:27][CH3:28])=[CH:23][N:24]=1.O>CN(C)C=O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([N:26]([CH2:25][C:22]2[S:21][C:20]([Cl:19])=[N:24][CH:23]=2)[CH2:27][CH3:28])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCNCc1cnc(Cl)s1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(Cc1cnc(Cl)s1)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 57.8 %

Procedure:
1.26 g 2-chloro-6-methoxy-3-nitropyridine and 10 mL N,N-dimethylformamide (DMF), and 2.00 g of potassium carbonate were added into a 100 mL single neck flask, under stirring at room temperature, 1.20 g of 2-chloro-5-ethylaminomethylthiazole, prepared according to the example 1, in 5.0 mL DMF were added dropwise. After that, the reaction solution was heated to 40-80° C. and then reacted for 3-6 hr. After cooling down, the resulting mixture was added to water (50 mL), then treated by the method according to the example 1 to obtain 1.27 g of 6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, as a golden yellow solid, having the content of 98.6%, a yield of 58.3%, and the structure was confirmed by GC-Mass and 1H NMR.
Reaction SMILES: [CH2:1]([C@H:8]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([Br:29])[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:36]1([C:42](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[CH2:1]([C@H:8]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([Br:29])[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:9][O:10][C:42]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of (S)-4-(1-benzyl-2-hydroxy-ethylamino)-3-(6-bromo-4-methyl-1H-benzimidazol-2-yl)-1H-pyridin-2-one (0.9 g, 1.98 mmol) in THF (30 mL), was added Cs2CO3 (1.29 g, 3.96 mmol) followed by triphenylmethyl chloride (1.10 g, 3.96 mmol). The reaction mixture was heated to reflux for 14 h under nitrogen and then cooled to room temperature. After removal of the solvent, the residue was diluted with ethyl acetate and washed with water. The aqueous fraction was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over Na2SO4. After concentration in vacuo, the residue was purified by flash column chromatography (30% EtOAc/hexane) to yield the title compound (1 g, 73%) as a white solid. 1N NMR (300 MHz, DMSO-d6) δ 11.77 (1H, broad s), 11.73 (1H, d, J=5.2 Hz), 11.46 (1H, broad s), 7.13–7.54 (23H, m), 5.87 (1H, d, J=4.5 Hz), 4.09–4.14 (1H, m), 3.07–3.42 (4H, m), 2.54 (3H, s). LCMS (M+H)+ m/z 695 (t=2.79 min.).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.CC(C)([O-])C.[K+].Cl[CH2:19][C:20]1[NH:21][C:22](=[O:36])[C:23]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:27]([CH3:35])[S:26][C:24]=2[N:25]=1>C1COCC1>[CH3:35][C:27]1[S:26][C:24]2[N:25]=[C:20]([CH2:19][N:5]3[CH:6]=[C:7]([CH:8]=[O:9])[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4]3)[NH:21][C:22](=[O:36])[C:23]=2[C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Reactant: Cc1sc2nc(CCl)[nH]c(=O)c2c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1sc2nc(Cn3cc(C=O)c(C(F)(F)F)n3)[nH]c(=O)c2c1-c1ccccc1
Yield: 38.1 %

Procedure:
To a stirred suspension of 3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (100 mg, 0.609 mmol) and potassium tert-butoxide (137 mg, 1.22 mmol) in THF (3 mL) was added 2-(chloromethyl)-6-methyl-5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (177 mg, 0.609 mmol) and the resultant solution was stirred at RT for 2 days. The reaction mixture was quenched with water and concentrated in vacuo to give the crude product as a beige solid (97 mg, 0.232 mmol, 38%). The material was used without further purification.
Reaction SMILES: [C:1](=[S:3])=S.[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][NH2:9])[CH3:5]>O1CCCC1>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=[C:1]=[S:3])[CH3:5]
Reactant: CCOC(CN)OCC
Reactant: S=C=S
Solvent: C1CCOC1
Product: CCOC(CN=C=S)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 120 ml of carbon disulfide and 60.6 g of dicyclohexycarbodiimide in 300 ml of tetrahydrofuran is cooled to -8° with an ice/salt mixture. Thereupon, 39.9 g of aminoacetaldehyde diethyl acetal are added dropwise while stirring so that the temperature of the reaction mixture does not exceed -5° (approximately 1 hour). The mixture is then warmed slowly to room temperature while stirring (approximately 2 hours) and left to stand overnight. The resulting precipitate (dicyclohexylthiourea) is then removed by filtration and washed thoroughly with n-hexane. The filtrate is concentrated in a vacuum and the separated dicyclohexylthiourea is again removed by filtration and washed with n-hexane. This procedure is repeated until dicyclohexylthiourea no longer separates upon concentration. Finally, the filtrate is freed completely from solvents. The residue is distilled at 11 Torr (bath temperature 130°-134°), whereby there is obtained 2,2-diethoxyethyl isothiocyanate in the form of a colorless oil; b.p. 100°/11 Torr.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([Cl:22])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23]N(C)CCCN=C=NCC.C(N(CC)CC)C.CO>C(Cl)Cl>[C:1]12([CH2:11][O:12][C:13]3[C:21]([Cl:22])=[CH:20][C:16]([C:17]([O:19][CH3:23])=[O:18])=[CH:15][N:14]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Reactant: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Yield: 43.2 %

Procedure:
A solution of 6-(adamantan-1-ylmethoxy)-5-chloronicotinic acid (4.20 g, 13.10 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (5.00 g, 26.10 mmol), triethylamine (3.6 mL, 26.10 mmol) and methanol (1.05 mL, 26.10 mmol) in methylene chloride (100 mL) was stirred under nitrogen for 18 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL). The mixture was washed with a 1:1(v/v) mixture of 1 M aqueous hydrochloric acid/brine (2×100 mL), brine (2×100 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to afford the title compound as a white solid (1.90 g, 43%); 1H NMR (300 MHz, CDCl3) δ 8.66-8.62 (m, 1H), 8.19-8.16 (m, 1H), 3.99 (s, 2H), 3.89 (s, 3H), 2.04-1.96 (m, 3H), 1.78-1.62 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1C1(N)CCCCC1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:20]([C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=1)=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][C:12]2[N:1]([CH:2]3[CH2:3][CH2:4][CH2:10][CH2:11][CH2:12]3)[C:20]([C:22]3[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)c1ccc(C2(N)CCCCC2)c(N)c1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCC(=O)O)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Following the procedure of example 1, ethyl 3-amino-4-(aminocyclohexyl)benzoate (1.077 g, 4.1 mmol) and 4-formylphenoxyacetic acid (0.748 g, 4.15 mmol) were dissolved in a mixture of DMF (8 mL) and water (0.5 mL). Oxone® (0.7 equivalent, 2.87 mmol, 1.764 g) was added and the mixture stirred for 30 min at room temperature (HPLC complete). Water was added to precipitate the product, which was collected by filtration, washed with water and dried (1.130 g, 65% yield, brown solid).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N+:10](C)C3C=CC=CC=3)[S:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].N[N:27]1[C:31](=[O:32])[CH2:30][S:29][C:28]1=[S:33].CN(C)C=O>O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N:10][N:27]3[C:31](=[O:32])[CH2:30][S:29][C:28]3=[S:33])[S:9][C:5]=2[CH:4]=1
Reactant: NN1C(=O)CSC1=S
Reactant: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSC(=S)N1N=c1sc2ccc(Cl)cc2s1
Temperature: 50 °C
Yield: 79 %

Procedure:
A mixture of the methiodide of 5-chloro-N-methyl-N-phenyl-1,3-benzodithiol-2-iminium iodide (1.9 g), sodium carbonate (121 mg), N-aminorhodanine (338 mg) and dimethylformamide (20 ml) is heated at 50° C for 3 hours. The mixture is poured into water and the precipitate which forms is filtered and washed with water. The product is recrystallized from dimethylformamide to yield 600 mg of the title compound, melting point 312°-314° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(O)CCC>CCOC(C)=O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COc1ccc(CNc2cccc(Br)n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2,6-dibromopyridine 16-1 (15 g, 70 mmol), 4-methoxybenzylamine (25 mL, 191 mmol) and butanol (25 mL) was heated at 100° C. for 6 days. After cooling, EtOAc was added, the solids removed by filtration and the solution concentrated in vacuo. Purification of the residue by silica gel chromatography (Hexane:EtOAc 4:1) afforded the title compound 16-2 as a white solid.
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:36].CCOC(C)=O>CCOC(C)=O>[ClH:36].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:30]=[CH:31][C:32]([Br:35])=[CH:33][CH:34]=1)[CH3:28])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1)c1ccc(Br)cc1

Procedure:
Prepared according to the method described in Example 1(d) above from crude (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-[1-(4-bromophenyl)ethyl]ornithine amide (2.46 g; 4.5 mmol; from step (a) above), EtOAc (75 mL) and HCl/EtOAc (50 mL), 2 hours reaction time. The solution was concentrated to give the crude product as a yellow crushable foam (2.4 g) which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([C:14](N)=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:17].[K+]>>[NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([C:14]([OH:15])=[O:17])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: NC(=O)C1CN(c2cccc(N)c2)CCN1
Agent: [K+]
Product: Nc1cccc(N2CCNC(C(=O)O)C2)c1

Procedure:
In a manner similar to Preparation 17, react 4-(3-aminophenyl)-2-piperazinecarboxamide with potassium hydroxide to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>>[O:1]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: Oc1cccc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: c1ccc(-c2cccc(Oc3cccc(-c4ccccc4)n3)n2)cc1
Temperature: 200 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A mixture of 2-hydroxy-6-phenylpyridine (1.0 g, 5.8 mmol), 2-bromo-6-phenylpyridine (1.4 g, 5.8 mmol) and potassium carbonate (807 mg, 5.8 mmol) was stirred at 200° C. for 8 hours. After the reaction mixture was cooled, to which was then added an aqueous 1 mol/L sodium hydroxide solution, the mixture was extracted with dichloromethane, the solvent was distilled off, and the residue was purified by silica gel column chromatography, thereby obtaining 1.3 g of 2,2′-oxybis(6-phenylpyridine) as colorless crystal.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH3:35])[C:22]=3[NH:23][C:24]([O:26][C@@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:28])=[O:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:35][N:21]1[C:22]([NH:23][C:24]([O:26][C@@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])=[O:25])=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH:9]3[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:36])=[O:3])[CH2:7][CH2:8]3)=[CH:17][CH:16]=2)[N:19]=[N:20]1
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3nnn(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(C3CCC(CC(=O)O)CC3)cc2)nnn1C)c1ccccc1
Reaction time: 15 h
Yield: 69.7 %

Procedure:
To a solution of (4-{4-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-phenyl}-cyclohexyl)-acetic acid ethyl ester (15 mg, 0.031 mmol) in THF (2 mL) and ethanol (2 mL) was added a 1.0 M solution of sodium hydroxide (310 μL, 0.31 mmol) at room temperature. The resulting colorless solution was stirred for 15 h at which time TLC analysis indicated the absence of the starting material. Then, the solvent was removed under vacuum and the basic aqueous layer was neutralized with 1 N HCl. The resulting solids were collected by filtration and washed with water and hexanes. After air drying, (4-{4-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-phenyl}-cyclohexyl)-acetic acid (10 mg, 71% yield) was isolated as a white solid. 1H NMR (DMSO-d6) δ ppm 12.04 (br. s., 1H), 9.85 (br. s., 1H), 7.62 (d, J=7.3 Hz, 2H), 6.84-7.54 (m, 7H), 5.78 (br. s., 1H), 3.83 (s, 3H), 2.16 (d, J=6.8 Hz, 2H), 1.65-1.93 (m, 5H), 1.39-1.64 (m, 5H), 1.01-1.35 (m, 3H). LC/MS calcd. for C26H30N4O4 (m/e) 462, obsd. 463.3 [M+H, ES+].