Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.O>[CH2:13]([O:20][C:21]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccccc12)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of tryptamine 1.0 g (6.2 mmol) in a mixture of CHCl3 and H2O, was added 1.1 g (6.2 mmol) benzylchloroformate, followed by dropwise addition of sat. NaHCO3 solution to maintain alkaline conditions. The reaction was stirred for 2 hrs. The reaction was extracted with CHCl3 and the organic layer was concentrated to dryness giving a dark yellow oil. The oil was crystallized from ethanol/water to give an off-white crystalline product.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=O)O)cc1OC1CCCC1

Procedure:
A suspension of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.8 g; that is prepared as described in Reference Example 54) in methanol (10 mL) and water (5 mL) is treated with potassium carbonate (0.48 g) and the mixture is heated at reflux for 7 hours. The mixture is concentrated, and the resulting residue is partitioned between diethyl ether (20 mL) and water (20 mL). The aqueous layer is separated, acidified to pH 1 by treatment with dilute hydrochloric acid (2N), and extracted with dichloromethane (2×25 mL). The combined organic extracts are dried and concentrated, to give 3-cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) in the form of a white solid m.p. 150-152° C.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([O-:3])[NH2:2].[NH4+:6].[S:7](=[O:11])(=[O:10])([OH:9])[NH2:8].O.[OH-].[K+:14]>>[S:1]([NH:2][S:7]([O-:11])(=[O:10])=[O:9])([O-:3])(=[O:5])=[O:4].[NH4+:8].[NH4+:6].[S:1]([NH:2][S:7]([O-:11])(=[O:10])=[O:9])([O-:3])(=[O:5])=[O:4].[K+:14].[K+:14]
Reactant: NS(=O)(=O)[O-]
Reactant: NS(=O)(=O)O
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])NS(=O)(=O)[O-]

Procedure:
Diammonium imidodisulfate was prepared by adding 114 grams (1.0 mole) of ammonium sulfamate to 97 grams (1.0 mole) of sulfamic acid in a 1-liter beaker. The mixture was heated on a hot plate with constant stirring. At about 130° C. a stirrable slurry was obtained and at about 155° C. an exothermic reaction began, forming a solid. When the solid cooled, it was dissolved in about 375 grams of 45 percent potassium hydroxide. Water was added to bring the total volume to 800 milliliters. The solution was filtered and then heated under vacuum to expel ammonia. Upon cooling, concentrated hydrochloric acid was carefully added to the solution to adjust the mixture to pH 7.5. A precipitate was obtained and upon filtering, about 150 grams of potassium imidodisulfate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 48.9 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (51 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzo-imidazole-5-carboxylic acid (90 mg), 2-methoxyethylamine (21 mg), HBTU (114 mg), and DIEA (66 uL). LC/MS: m/z 416.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.36 (bs, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.46 (d, 1H), 7.38 (dd, 1H), 3.62 (bs, 3H), 3.50-3.39 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:8][CH2:18][C:17]1[C:10]([F:9])=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: Cc1cccc(C#N)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(CBr)c1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
NBS (1.729 g, 9.71 mmol) was added to a solution of 2-fluoro-3-methylbenzonitrile (1.25 g, 9.25 mmol) in acetonitrile (25 mL). The obtained mixture was refluxed, and then benzoic peroxyanhydride (0.045 g, 0.18 mmol) was added. The reaction mixture was refluxed overnight, then cooled to r.t. and water was added. The aqueous phase was discarded and the organic phase was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using a gradient of EtOAc in heptane as eluent to give the title compound (1.39 g, 70% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 4.75 (s, 2 H) 7.43 (t, 1 H) 7.93 (t, 2 H); MS (EI) m/z 213 M+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1>CN(C)C=O>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[CH2:25][O:17][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[S:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCc4nc5ccccc5s4)ccc3c2s1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol and anhydrous N,N-dimethylformamide (DMF, 2 mL). The mixture was warmed until a solution was obtained. An additional amount of DMF (1 mL) was added. To this stirred orange solution was added cesium carbonate (3.0 eq.) and a solution of 2-(bromomethyl)benzothiazole dissolved in DMF (2 mL). Additional DMF (1 mL) was used to rinse the vial. The vial was capped and heated to 60° C. overnight. The reaction was monitored by HPLC. The reaction was quenched by adding the reaction mixture dropwise to water (60 mL) with stirring. A precipitate formed. The solid was collected by vacuum filtration. The solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated; the resulting solid was recrystallized from acetonitrile to provide 7-[(1,3-benzothiazol-2-yl)methoxy]-2-ethylthiazolo[4,5-c]quinolin-4-amine as a white crystalline solid, mp. 211-212° C. MS (APCI) m/z 393 (M+H)+. Anal. calcd C20H16N4OS2.0.6H2O: C, 59.56; H, 4.30; N, 13.89. Found: C, 59.66; H, 4.08; N, 13.80.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15]CC)=O)[C:8]([O:10]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2[NH2:28].C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[F:18][C:19]1[CH:27]=[CH:26][C:25]2[C:21](=[C:22]3[N:28]=[C:8]([OH:10])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:13]([OH:15])[N:23]3[N:24]=2)[CH:20]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1n[nH]c2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Oc1nc2c3cc(F)ccc3nn2c(O)c1-c1ccccc1
Yield: 78.8 %

Procedure:
14.3 g (60.2 mmol) Diethyl phenylmalonate, 9.1 g (60.2 mol) 5-fluoro-1H-indazol-3-ylamine and 25.3 mL tributyl amine were heated for 15 h at 180° C. The reaction mixture was treated with 2M sodium hydroxide and water and extracted with tert-butyl methyl ether. The organic phase was discarded and the aqueous phase was acidified with conc. hydrochloric acid. The precipitate was collected by filtration and washed with water to obtain 14 g of the desired product which is 90% pure. MS (Cl, M+1): 296
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[I:13]I.N(OC(C)(C)C)=O.O>C(#N)C.[Cu]I>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([I:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: II
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1N
Agent: [Cu]I
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O
Product: Cc1cc(F)cc([N+](=O)[O-])c1I
Yield: 46.5 %

Procedure:
A mixture of 4.4 grams (0.026 mole) of 4-fluoro-2-nitro-6-methylaniline, 13.2 grams (0.052 mole) of iodine, and 5.5 grams (0.029 mole) of copper(I) iodide in 125 mL of acetonitrile was stirred, and a solution of 4.6 mL (0.039 mole) of tert-butyl nitrite in 25 mL of acetonitrile was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 16 hours. After this time the reaction mixture was poured into 300 mL of water. Excess iodine was destroyed using sodium meta-bisulfite. The mixture was then extracted with two 250 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:3 methylene chloride: petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of 4-fluoro-2-nitro-6-methylphenyl iodide. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain more product.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29](O)=[O:30])[CH:24]=5)[CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:30])[CH:24]=5)[CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)O)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a mixture of 5′-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-3-carboxylic acid (50 mg, 0.11 mmol), methansulfonamide (7.0 mg, 0.074 mmol), DMAP (13 mg, 0.11 mmol), and CH2Cl2 (1 mL) was added EDC (28 mg, 0.15 mmol) at ambient temperature. The mixture was allowed to stir for 18 h before it was concentrated. The residue was taken up in DMF (1 mL) and was purified by reverse phase preparatory HPLC to provide 5′-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methyl-N-(methylsulfonyl)biphenyl-3-carboxamide as a white solid. ESI-MS m/z calc. 528.5, found 529.2 (M+1)+. Retention time 1.97 minutes.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:23]([C:19]1[CH:18]=[C:17]([CH3:26])[CH:22]=[CH:21][CH:20]=1)=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)NN(C(=O)c2ccccc2)C(C)(C)C)c1
Reaction time: 2 h

Procedure:
To a stirred mixture of N'-t-butyl-N'-benzoylhydrazine (1.0 g) in 15 ml toluene and aqueous sodium hydroxide (0.5 g of 50% NaOH) was added 3-toluoylchloride (0.9 g). After stirring for 2 hours, the product was isolated by filtration to give N'-t-butyl-N-(3-toluoyl)-N'-benzoylhydrazine in good yield. m.p. 111-114° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1.CO>ClCCl>[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)C(C)C)co1
Yield: 80 %

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine provided, after silica gel chromatography using a gradient of 1-4% methanol in dichloromethane, 225 mg (80%) of the desired compound. 1H NMR (DMSO-d6) δ0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.35-1.54 (m, 2H), 1.80-1.95 (m, 1H), 2.55-2.73 (m, 4H), 2.83 (s, 3H), 2.94-3.09 (m, 1H), 3.53-3.63 (m, 1H), 3.73-3.86 (m, 1H), 3.92 (t, J=8.4 Hz, 1H), 4.08-4.34 (m, 3H), 4.65 (d, J=6 Hz, 1H), 5.04 (s, 2H), 5.91 (d, J=9 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 7.06-7.27 (m, 10H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.52 (d, J=2.4 Hz, 1H). Mass spectrum: (M+H)+ =689; (M+NH4)+ =706. Anal. Calcd for C37H48N6O7 : C, 64.52; H, 7.02; N, 12.20. Found: C, 64.52; H, 7.14; N, 12.06.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[CH:27]1(Br)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: BrC1CCCCC1
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OC1CCCCC1

Procedure:
To a solution of 0.3 g (1.1 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline -2,3(1H,4H)-dione in 30 ml ethanol was added 0.7 ml triethylamine and 1.5 ml (12 mmol) cyclohexylbromide. The reaction mixture was refluxed for 7 days and then evaporated in vacuo. The residue was stirred with water to give a precipitate (0.25 g. Recrystallization (dimethylformamide-water) gave 0.17 g (44%) of 7-cyano-1-cyclohexyloxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione). M.p. 259° C. decomp. 1H-NMR (DMSO-d6): 8.0 (1H, s), 7.6 (1H, s), 4.3 (1H, m), 1.4 (8H, m).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)(OCC)=O)C.CC(C)([O-])C.[K+].C1COCC1.[CH:30]([C:32]1[S:33][CH:34]=[CH:35][N:36]=1)=O>O>[S:33]1[CH:34]=[CH:35][N:36]=[C:32]1/[CH:30]=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH:15]=1
Reactant: O=Cc1nccs1
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(/C=C/c2nccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 1.9 %

Procedure:
A mixture of 4-(diethoxyphosphorylmethyl)benzenecarboxylic acid (440 mg) produced according to JP-A 11-60537, potassium tert-butoxide (340 mg) and THF (5.5 mL) was stirred at room temperature for about 1.5 hours, and then a THF solution (1.0 mL) of 2-formylthiazole (200 mg) was dropwise added thereto. After heated overnight under reflux, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/methanol=9/1), and the resulting purified product was further purified through reversed-phase HPLC to obtain the entitled compound (7 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([NH:51]O)=[NH:50])=[CH:47][CH:46]=2)[CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]2=[O:43])(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[O:12][N:50]=[C:49]([C:48]2[CH:53]=[CH:54][C:45]([CH2:44][N:35]([CH:36]3[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]3=[O:43])[S:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)(=[O:34])=[O:33])=[CH:46][CH:47]=2)[N:51]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCCCC1N(Cc1ccc(-c2noc(COCc3ccccc3)n2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a solution of benzyloxyacetic acid (162 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.51 g (87%) N-[4-(5-benzyloxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-4-chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=581.1 (MH+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[C:17]([O:31]C)[CH:16]=2)[CH2:6][CH2:5][CH2:4]1.B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:34][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[C:17]([OH:31])[CH:16]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc(C(=O)N2CCCC(N(C)C)c3ccccc32)ccc1NC(=O)c1ccccc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3ccccc32)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
A solution of 5-dimethylamino-1-[3-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) in dichloromethane (30 ml) is added dropwise to a solution of 1M boron tribromide in dichloromethane (5.46 ml) at -45° C. After completion of the dropping, the mixture is stirred for 1 day while the temperature of the reaction mixture is gradually raised to room temperature. To the reaction solution is added water and the mixture is neutralized with sodium hydrogen carbonate, and extracted with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=500:1), and recrystallized from methanol/diethyl ether to give 5-dimethylamino-1-[3-hydroxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.33 g) as white powder, m.p. 201.5-202.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1

Procedure:
Compound A28 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), propane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 1.09 (t, 3H), 1.90 (m, 2H), 2.07 (m, 4H), 2.95 (m, 2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.57 (m, 2H), 5.67 (m, 1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C19H25N5O7S2 499.12, found 500.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C=O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:42]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@H](CNCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: C=O
Agent: [Na+]
Product: COC(=O)[C@H](CN(C)Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 656 was subjected to reductive amination as per procedure E with formaldehyde (0.010 ml, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(Biphenyl-4-ylmethyl-methyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.040 g, 80%). 1H-NMR (400 MHz, DMSOd6): 3.17 (s, 3H), 3.9 (m, 2H), 4.76 (m, 2H), 5.31 (s, 1H), 7.69 (m, 1H), 7.77 (m, 2H), 7.97 (m, 4H), 8.05 (bd, 2H), 8.19 (m, 4H), 8.27 (d, 2H), 8.40 (d, 2H), 9.5 (s, 1H); LC/MS (m/z): 533.3 (M+1).