Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].I[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH2:42][CH2:43][O:44][CH3:45])[CH:37]=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:35]2=[O:51].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:8]=[CH:9][C:10]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH2:42][CH2:43][O:44][CH3:45])[CH:37]=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:35]3=[O:51])=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[N:17]=2)[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(CCOC)c2ccc(I)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
1-Ethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-2-yl)urea (0.171 g, 0.39 mmol, Intermediate 17), ethyl 6-iodo-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.155 g, 0.39 mmol, Intermediate 20), cesium carbonate (0.214 g, 0.66 mmol, Aldrich) and tris(dibenzylideneacetaone)palladium (0) (0.035 g, 0.04 mmol, Aldrich) or tetrakis(triphenylphosphine)palladium (0) (5 mol %, Strem) were combined in dioxane (2 mL)/water (0 mL) and heated to 100° C. The reaction mixture was stirred for 1 h. The reaction mixture was cooled to room temperature and then placed in an ice-bath. The resulting precipitate was collected by filtration and dried under vacuum to provide the desired product (0.090 g).
Reaction SMILES: [Na].[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5](=[O:13])[C:4]=1[C:14]([O:16][CH3:17])=[O:15].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([N:6]1[C:7]2[C:12](=[N:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]1=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the sodium salt of methyl 4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (2.0 g, 7.57 mmol) in water (50 mL) was added a solution of benzyl bromide (3.89 g, 22.72 mmol) in methylene chloride (50 mL). To the biphasic solution was then added tetrabutylammonium bromide (1.2 g, 3.79 mmol) and the reaction was sealed and heated to 50° C. After stirring overnight the reactions was cooled and the two layers were separated. The aqueous layer was extracted one time with methylene chloride and the combined organics were dried over sodium sulfate, filtered and concentrated. The crude mixture was separated by normal phase chromatography using an Isco 120 gram silica gel cartridge with a 50 minute gradient running at 40 mL/min. of 10% to 60% EtOAc/hexanes. The tubes containing the desired product were concentrated and taken on to the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1Cl.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1[NH:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CCn1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1ncc(NCCc2ccc(OC)cc2)c(Cl)c1=O
Reaction time: 8 h

Procedure:
A mixture comprising 0.5 g of 4,5-dichloro-2-ethyl-3(2H)pyridazinone, 1.18 g of 4-methoxyphenylethylamine, 0.36 g of potassium carbonate, 18 ml of water and 6 ml of 1,4-dioxane, was refluxed under stirring for 8 hours. Then, 1,4-dioxane was distilled off under reduced pressure, and the residue thereby obtained was extracted with ethyl acetate. The extract was washed sequentially with dilute hydrochloric acid and water, and dried over sodium sulfate. Then, solvent was distilled off. The residue was purified by silica gel column chromatography by using benzene-ethyl acetate (1:1, v/v) as the developer, whereby 400 mg of the above identified compound was obtained as colorless crystals having a melting point of from 135° to 135.5° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:45]([C:47]1[CH:52]=[C:51]([C:53](=[NH:56])[NH:54]O)[CH:50]=[C:49]([CH3:57])[C:48]=1[CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH3:46]>C(Cl)Cl>[CH2:45]([C:47]1[CH:52]=[C:51]([C:53]2[N:54]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:6]=3)[O:13][N:56]=2)[CH:50]=[C:49]([CH3:57])[C:48]=1[CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH3:46]
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)cc(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
To a solution of 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (126 mg, 637 μmol) in DCM (5 mL), DIPEA (249 mg, 1.93 mmol) is added followed TBTU (202 mg, 628 μmol). The mixture is stirred at rt for 30 min before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid (159 mg, 637 μmol) is added. The mixture is stirred at rt for 16 h before it is diluted with DCM, washed with 1 N aq. HCl solution, dried over Na2SO4, filtered and concentrated. The residue is dissolved in toluene (20 mL) and the reaction mixture is stirred at 110° C. for 18 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with DCM containing 5% of methanol to give 3-{2-ethyl-4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (41 mg) as a beige solid; LC-MS: tR=1.17 min, [M+1]+=413.30; 1H NMR (CDCl3): δ 0.94 (d, J=6.4 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H), 1.84-1.96 (m, 1H), 2.43 (s, 3H), 2.45 (s, 3H), 2.46-2.60 (m, 4H), 2.75 (q, J=7.3 Hz, 2H), 3.02-3.12 (m, 2H), 7.66 (s, 1H), 7.79 (s, 1H), 7.81 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethylacetophenone (0.714 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol) m.p. 154°-155° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (d, 6H), 2.35 (s, 6H), 3.40 (m, 1H), 6.90 (d, 1H), 7.05 (t, 1H), 7.11 (dt, 2H), 7.20 (s, 1H), 7.27 (d, 1H), 7.45 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[H-].[Na+].I[C:13]1[C:14](=[O:20])[NH:15][C:16]([CH3:19])=[CH:17][CH:18]=1>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:13]2[C:14](=[O:20])[NH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(I)c(=O)[nH]1
Reactant: COc1ccc(S)cc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2ccc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
4-Methoxythiophenol (1.7 mL, 13.85 mmol) was added to a suspension of NaH 60% in oil (831 mg, 20.80 mmol) in DMF (30 mL) at 0° C., and the mixture was allowed to warm to 25° C. 3-Iodo-6-methyl-1H-pyridin-2-one (3 g, 12.78 mmol) was added to the solution at 0° C., followed by CuI (533 mg, 2.8 mmol). The reaction was stirred at 25° C. for 1 h and heated at 120° C. for 5 h. It was then allowed to cool and partitioned between CH2Cl2 (30 mL) and 9:1 NH4Cl/NH4OH (30 mL) and stirred for 15 min. The mixture was extracted with CH2Cl2 (3×70 mL each) and the combined CH2Cl2 extracts were washed with water (3×30 mL), brine, dried and stripped in vacuo to give the crude product (3.6 g), which was further purified by washing with ether to give 2.93 g of 3-(4-methoxyphenylsulfanyl)-6-methyl-1H-pyridin-2-one which was used in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:3])[NH2:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:17][CH2:16][CH2:15][NH2:18])(=[O:3])[NH2:2]
Reactant: NCCN
Reactant: NC(=O)c1ccccc1OCC1CO1
Product: NCCNCC(O)COc1ccccc1C(N)=O
Reaction time: 1 h

Procedure:
1-(o-Carbamoylphenoxy)-2,3-epoxypropane (20 g.) is added to ethylenediamine (125 ml.) and the mixture is stirred at laboratory temperature for 1 hour and then evaporated to dryness under reduced pressure. The residue is stirred with water (150 ml.), the mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallised from acetonitrile and there is thus obtained as residue 1-(o-carbamoylphenoxy)-3-(β-aminoethyl)aminopropan-2-ol, m.p. 91°-93° C.
Reaction SMILES: [C:1]([CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([OH:29])[C:20]2[N:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:23][CH:24]=2)[CH3:16])=[CH:10][CH:9]=1)[CH3:7])([O:3][CH3:4])=[O:2].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=O>>[C:1]([CH:5]=[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([N:17]2[CH2:18][CH:19]([C:20]3[N:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[S:23][CH:24]=3)[O:29][CH:31]2[C:30]([O:34][CH3:35])=[O:33])[CH3:16])=[CH:12][CH:13]=1)[CH3:7])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=O
Reactant: COC(=O)CC(C)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC2C(=O)OC)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-(2-carbomethoxy-1-methylethyl)phenyl)-1-methyl-ethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with methyl glyoxylate followed by purification of the base on a silica gel column using chloroform/petroleum ether/ethyl acetate =5:4.5:0.5 as eluant.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:35][C:23]([F:22])([F:34])[C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring dichloromethane (50 mL) solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.90 g, 19.4 mmol), 4-(dimethylamino)pyridine (0.23 g, 1.9 mmol), and triethylamine (8.0 mL, 57 mmol) was added 4-(trifluoromethyl)benzenesulfonyl chloride (4.75 g, 19.4 mmol). The reaction mixture was stirred for two hours at room temperature. The reaction was quenched with 1.0 M hydrochloric acid (100 mL) and extracted with diethyl ether (2×250 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. It was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=8.2 Hz, 2H), 7.83 (d, J=8.2 Hz, 2H), 4.79 (tt, J=7.6, 3.6 Hz, 1H), 3.62 (ddd, J=13.6, 7.4, 4.0 Hz, 2H), 3.27 (ddd, J=13.8, 7.8, 3.9 Hz, 2H), 1.86-1.79 (m, 2H), 1.75-1.68 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[C:15]1([C@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[Al](C)C.CCCCCC>ClCCl>[C:15]1([C@H:21]([NH:23][C:4]([C:6]2[S:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[N:14]=2)=[O:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)c1nc2ccncc2s1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1nc2ccncc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (16 mg, 0.08 mmol) and 1(R)-phenyl ethyl amine (0.03 mL, 0.23 mmol) in dichloromethane(0.3 mL)was added a solution of trimethylaluminum in hexane(0.115 mL, 2.0 M., 0.23 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 1:1)and triturated in hexane to give 14 mg of the thiazolo derivative.
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:18](O)[CH2:19]CCCC=C>>[CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:18]=[CH2:19]
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Reactant: C=CCCCCCO
Product: C=CCCCCCOC(=O)N[C@@H](CCCC)C(=O)O

Procedure:
N-[(Hept-6-en-1-yloxy)carbonyl]-L-norleucine was prepared according to the procedure for N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucine by using 6-heptenol instead of 4-pentenol. LRMS (ESI) m/z 272 [(M+H)+; calcd for C14H26NO4: 272].
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:31]([CH2:33]Br)=O)[CH:28]=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:31]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: COc1cccc(C(=O)CBr)c1
Product: COc1cccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)c1
Yield: 54 %

Procedure:
4-[4-(3-Methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (148 mg, 54%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3′-methoxyphenacyl bromide (available from Aldrich Chemical Company, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.27 (dd, J=6.0, 2.0 Hz, 1H), 8.15 (dd, J=8.1, 1.1 Hz, 1H), 7.76-7.82 (m, 1H), 7.61-7.69 (m, 3H), 7.38-7.48 (m, 3H), 6.97 (dd, J=8.2, 2.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[C:18]([CH2:19]Br)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]>>[F:12][C:13]1[C:18]([CH2:19][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Product: O=C(O)c1cc(NCc2c(F)c(F)c(F)c(F)c2F)ccc1O
Yield: 59.8 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and pentafluorobenzyl bromide (1.02 g, 3.92 mmole), 650 mg (60% yield) of 5-(pentafluorobenzyl)aminosalicylic acid was obtained as a white solid.:mp>190° C. (decompose).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][O:4][C:5]([N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][C:22]=3[CH:35]=2)=[CH:14][CH:13]=1)=[O:6].FC(F)(F)C(O)=O>ClCCl>[O:27]1[C:21]2[CH:20]=[CH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4[N:7]([C:5]([O:4][CH2:3][CH:2]([CH3:36])[CH3:1])=[O:6])[CH:11]=[CH:10][N:9]=4)=[CH:17][CH:16]=3)=[CH:35][C:22]=2[CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 1,1-dimethylethyl 7-[4-(1-{[(2-methylpropyl)oxy]carbonyl}-1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.30 g, 0.61 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (20 mL) and the reaction mixture was heated to reflux. After cooling to room temperature the solvent was evaporated. The residue was dissolved in ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2×100 mL), brine, dried over anhydrous sodium sulfate then filtered and concentrated to give 2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (0.22 g, 92%). MS (EI) for C23H25N3O3: 392 (MH+).
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH2:20]([S:32]([CH2:35][C:36]#[N:37])(=[O:34])=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>C(O)C>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][C:7](=[C:35]([S:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])[C:36]#[N:37])[CH2:12]1
Reactant: CCCCCCCCCCCCS(=O)(=O)CC#N
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCCCS(=O)(=O)C(C#N)=C1C=C(N2CCCC2)CC(C)(C)C1

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (3.2 g.), dodecylsulfonylacetonitrile (2.7 g.) and triethylamine (3.1 ml.) are dissolved in ethanol (15 ml.) and heated at reflux for 5 minutes. After chilling, the solid is collected on a filter, washed with methanol and dried. Obtaining pure dye by recrystallization from methanol proved difficult. The product is eluted from basic alumina, using a 10% methanol-90% chloroform solvent mixture, and then recrystallized from methanol. The yield of purified dye is 0.5 g. (11%), m.p. 114°-115°C. This dye compound shows good ultraviolet absorption characteristics as indicated in the data in Table 1 below.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](N)=[O:7])=[CH:4][N:3]=1.P(=O)(O)(O)[OH:12]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=P(O)(O)O
Reactant: NC(=O)c1ccc(N)nc1
Product: Nc1ccc(C(=O)O)cn1
Temperature: 100 °C

Procedure:
6-Aminonicotinamide, 200 g, was dissolved in warm 85% phosphoric acid, 700 ml. The clear solution was heated to 100° C. for 8 hours. The solution was then diluted with 1.5 Kg of ice water. The white crystals thus obtained were separated by filtration, and washed with ice water followed with an acetone wash. The yield of 6-aminonicotinic acid phosphoric salt was 310 g. This product in its phosphoric salt form may be directly incorporated into the therapeutic compositions of the present invention.
Reaction SMILES: [OH-].[Na+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[N:20]3[C:16]([S:17][C:18]([C:24]([O:26]CC)=[O:25])=[C:19]3[CH:21]([CH3:23])[CH3:22])=[N:15][C@:14]2([C:30]2[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH3:29])=[CH:9][C:8]=1[F:37]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[N:20]3[C:16]([S:17][C:18]([C:24]([OH:26])=[O:25])=[C:19]3[CH:21]([CH3:22])[CH3:23])=[N:15][C@:14]2([C:30]2[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH3:29])=[CH:9][C:8]=1[F:37]
Reactant: CCOC(=O)C1=C(C(C)C)N2C(=N[C@@](C)(c3ccc(Cl)nc3)[C@H]2c2ccc(Cl)c(F)c2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C1=C(C(=O)O)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Temperature: 60 °C
Yield: 77.6 %

Procedure:
1 N aqueous sodium hydroxide solution (6 ml) was added to an ethanol (30 ml) solution of the compound (2.06 g, 4.17 mmol) obtained in Step 12 above and the resulting mixture was stirred under heating at 60° C. for 16 hours. After cooling, the solvent was concentrated under reduced pressure and the residue obtained was diluted with water and then washed with diethyl ether. The aqueous layer was made into an acidic solution by the gradual addition of 1 N aqueous hydrochloric acid solution under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, a diethyl ether/n-hexane mixed solvent was added to the residue and the resulting precipitate was collected by filtration and dried to give the title compound (1.51 g, 87%) as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][NH:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.CN(C(ON1N=NC2[CH:35]=[CH:36][CH:37]=[N:38]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>C1COCC1>[CH:37]1([NH:38][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([N:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([NH:4][CH2:3][CH:2]([CH3:23])[CH3:1])[C:13]=4[N:12]=[CH:11]3)=[CH:22][CH:21]=2)[CH2:35][CH2:36]1
Reactant: CC(C)CNc1cccc2c1ncn2-c1ccc(C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNc1cccc2c1ncn2-c1ccc(C(=O)NC2CC2)cc1
Reaction time: 4 h
Yield: 34.4 %

Procedure:
To a stirred solution of 4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzoic acid (63 mg, 0.2 mmol) which was prepared according to intermediate example 4-1 in THF (5 mL), at rt was added HATU (85 mg, 0.22 mmol), DIPEA (29 mg, 0.22 mmol) and cyclopropylamine (12.8 mg, 0.22 mg) in one portion. After stirring for 4 h, the solution was evaporated and the remaining solid was purified by flash chromatography to yield N-cyclopropyl-4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzamide as an off-white solid (24 mg, 33.8%).