Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.C1(C)C=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)([O-:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O.C(O)C>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:5]1[S:4][C:3]([NH2:2])=[N:7][CH:6]=1)([O-:18])=[O:17]
Reactant: Nc1ncc(Br)s1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1ncc(-c2ccccc2[N+](=O)[O-])s1
Temperature: 90 °C
Reaction time: 18 h
Yield: 2.5 %

Procedure:
In a typical run, 2-amino-5-bromothiazole monohydrobromide (Aldrich, 5.00 g, 0.0192 mol) was mixed with 40 mL of toluene, 40 mL of ethanol, and 20 mL of water. 2-Nitrophenyl boronic acid (3.2 g, 0.0192 mol) was added, along with 2.35 g of [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with CH2Cl2 (1:1) and 6.10 g of anhydrous sodium carbonate. The reaction mixture was stirred at 90° C. for 18 hours. It was then cooled to room temperature and concentrated. The resulting residue was mixed with 500 mL of EtOAc and washed with water (3×50 mL). The organic layer was filtered to remove the black precipitate. The filtrate was extracted with dilute 1N HCl. The combined aqueous layers were concentrated to near dryness. The resulting residue was purified by preparative HPLC using a mixture of aqueous acetonitrile that has been buffered with 0.1% TFA to afford 108 mg of 5-(2-nitro-phenyl)-thiazol-2-ylamine (MS, M++H=222).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>N1C=CC=CC=1>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: COC(=O)c1ccc2c(O)n[nH]c2c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
Methyl 3-hydroxy-1H-indazole-6-carboxylate (1.6 g, 8.3 mmol) was suspended in pyridine (10 mL). Ethyl chloroformate (1.0 mL, 10 mmol) was added slowly and the reaction was allowed to stir at room temperature for 2 hours. The reaction was poured into water (65 mL) and cooled in a refrigerator for 4 hours. The resulting brown precipitate was collected by filtration, rinsed with water, and dried under vacuum to give the title compound (1.35 g, 61%) as a beige solid. +ESI (M+H) 265.0; 1H NMR (400 MHz, CDCl3, δ): 8.80 (d, J=6.0 Hz, 1H), 8.01 (dd, J=8.2, 1.2 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 4.60 (q, J=7.0 Hz, 2H), 3.98 (s, 3H), 1.57 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([Mg]Br)C.[C:5]12([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[OH:23])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.[CH2:24]=[O:25].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1>[C:5]12([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH:24]=[O:25])[C:16]=3[OH:23])[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: C=O
Reactant: COc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C=O)c(O)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
Into a 500 ml reactor thoroughly purged with nitrogen, 16.50 ml of an ether solution containing 49.60 mmol of ethylmagnesium bromide and 10 ml of THF were introduced. To the reactor, a solution containing 12.31 g (47.20 mmol) of 2-(1-adamantyl)-4-methoxyphenol diluted with 50 ml of a THF was dropwise added at 0° C. over a period of 15 minutes. Then, 150 ml of toluene was added, and the system was heated to 95° C. to distill off about 40 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to 20° C., 3.43 g (114.30 mmol) of paraformaldehyde and 9.40 ml (67.50 mmol) of triethylamine were added, followed by stirring at 90° C. for 30 minutes. The reaction solution was allowed to cool to room temperature and then quenched with 32 ml of 18% hydrochloric acid. The organic layer was washed with 100 ml of water, 50 ml of a sodium hydrogencarbonate aqueous solution and 100 ml of a sodium chloride aqueous solution, and then concentrated. The resulting solid was purified by silica gel column chromatography to obtain 4.95 g (yield: 37%) of 3-(1-adamantyl)-5-methoxysalicylaldehyde.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:43])[C@@H:24]([NH:25][C:26](=[O:42])[C:27](=[N:39][O:40][CH3:41])[C:28]4[N:29]=[C:30]([NH:34]C(=O)CCl)[S:31][C:32]=4[Cl:33])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.NC(N)=S.C(=O)([O-])O.[Na+].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(O)C.O1CCCC1.ClCCl>[CH3:41][O:40][N:39]=[C:27]([C:28]1[N:29]=[C:30]([NH2:34])[S:31][C:32]=1[Cl:33])[C:26]([NH:25][C@@H:24]1[C:23](=[O:43])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[CH:18][CH2:19][S:20][C@H:21]12)=[O:42]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(NC(=O)CCl)sc1Cl
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl
Reaction time: 4 h
Yield: 78.6 %

Procedure:
To a solution of 7β-[2-methoxyimino-2-(2-chloroacetamido-5-chloro-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (330 mg) in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml) is added thiourea (152 mg), and the mixture is stirred for 4 hours. After one night, the solution is stirred with 5% aqueous sodium hydrogen carbonate solution for 10 minutes, concentrated to remove organic solvents, and extracted with ethyl acetate. The residue is subjected to silica gel chromatography to give crude 7β-[2-methoxyimino-2-(2-amino-5-chloro-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (273 mg), which is stirred with anisole (0.5 ml) and trifluoroacetic acid (0.5 ml) in dichloromethane (5 ml) under ice-cooling for 1.5 hours, evaporated and treated with ethyl ether and high porous polymer to give 7β-[2-methoxyimino-2-(2-amino-5-chloro-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (164 mg). Yield: 76.7%. This product is identical with a sample prepared by another authentic route. Similarly prepared are compounds of Table 1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=O)=O.C(N(CC)CC)C.[C:46]([O:50][CH2:51][CH3:52])(=[O:49])[CH:47]=[CH2:48].O>CN(C)C=O>[C:26]([O:25][C:23]([NH:22][CH2:21][C:11]1[C:12]([CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][C:14]2[C:9]([C:10]=1[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[CH:8][C:7](/[CH:48]=[CH:47]/[C:46]([O:50][CH2:51][CH3:52])=[O:49])=[CH:16][CH:15]=2)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: C=CC(=O)OCC
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OS(=O)(=O)C(F)(F)F)cc23)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl trifluoromethanesulfonate (1.5 g, 2.8 mmol) in N,N-dimethylformamide (10 ml) were added dichlorobistriphenylphosphine palladium (0.021 g, 0.030 mmol), triethylamine (4.2 ml, 30 mmol) and ethyl acrylate (0.65 ml, 6.0 mmol) and the mixture was stirred at 70° C. for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl (2E)-3-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]acrylate (0.87 g, yield 62%) as pale-yellow crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:13][N:14]2[C@@H:22]3[C@@H:17]([C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:19]=4[CH2:20][CH2:21]3)[CH2:16][C:15]2=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH:7]1([CH2:13][N:14]2[C@@H:22]3[C@@H:17]([C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:19]=4[CH2:20][CH2:21]3)[CH2:16][CH2:15]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CC1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CC1CCCCC1
Yield: 97.7 %

Procedure:
0.92 g (0.02412 mol) of lithium aluminum hydride was suspended in 40 ml of THF under argon. A solution of 3.78 g (0.01206 mol) of rac-cis-3-cyclohexylmethyl-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one in 40 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 2 hours. Then, 0.9 ml of water, 0.9 ml of 4N sodium hydroxide solution and 2.7 ml of water were cautiously added dropwise thereto in succession, whereupon the mixture was boiled at reflux until a complete white precipitate had resulted. After the addition of dry Na2SO4, filtration and concentration there was obtained an oil which was chromatographed over silica gel with cyclohexane/ethyl acetate 4:1. There were obtained 3.53 g (98%) of oily rac-cis-3-cyclohexylmethyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[OH:12][CH:13](O)[C:14](=O)[CH3:15].[Cl-].[NH4+]>[OH-].[NH4+]>[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:8][C:14]([CH2:13][OH:12])=[CH:15][N:9]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: CC(=O)C(O)O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccc(-c2ncc(CO)[nH]2)cc1
Temperature: 90 °C

Procedure:
A solution of 4 g 4-methylbenzamidine hydrochloride in 60 mL ammonium hydroxide was treated with 4.0 g with dihydroxyacetone and 4.8 g ammonium chloride. The reaction mixture was heated to 90° C. for 4 hours in a sealed tube. On cooling to room temperature a the solid formed was collected by filtration to yield 3.0 g 2-(4-methylphenyl)-5-hydroxymethyl-imidazole which was converted according to the procedure described in Example VII to yield 2-(4-methylphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole (Compound 133), m.p. 178°-180° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2OS(C(F)(F)F)(=O)=O)[CH2:3]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].O.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.C(OCC)(=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH:34]=[C:35]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:1])([CH3:24])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC1(C)CC(c2ccccc2OS(=O)(=O)C(F)(F)F)CC(C)(C)C1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC1(C)CC(c2ccccc2C2=CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a mixture of trifluoromethanesulfonic acid 2-(3,3,5,5-tetramethylcyclohexyl)phenyl ester (830 mg, 2.55 mmol) produced in Example (102c), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (631 mg, 2.04 mmol) (Paul R. Eastwood, Tetrahedron Lett., 2000, 41, 3705) and 1,2-dimethoxyethane (20 mL) were added tetrakis(triphenylphosphine)palladium (147 mg, 0.13 mmol) and 2N aqueous solution of sodium carbonate (3.8 mL, 7.6 mmol), followed by stirring for 8 hours at an external temperature of 90° C. under a nitrogen atmosphere. Brine was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 570 mg of the title compound as a light yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=O.Cl.O>C1C=CC=CC=1>[CH2:16]([O:15][C:9](=[O:14])[CH:10]=[C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)[CH3:13])[CH3:17]
Reactant: Nc1cccc(I)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1cccc(I)c1
Reaction time: 4 h

Procedure:
A mixture of 47.79 g 3-iodoaniline, 27.7 ml ethyl acetoacetate and 0.13 ml 37% hydrochlorid acid in 65 ml benzene is boiled under a reflux condenser fitted with a water separator. After 4 h. 4 ml of water have been collected. The solvent is removed at reduced pressure and the residual oil dried in vacuo 3-(3-iodo-phenylamino)-but-2-enoic acid ethyl ester is obtained as a light brown oil. MS (ISP): 332.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:37])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:36])[C:17]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([CH:29]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22]C(C)(C)C)=[O:12])=[C:4]([CH3:38])[CH:3]=1.Cl.C(N(CC)C(C)C)(C)C.[CH2:49](OC(ON1C(=O)CCC1=O)=O)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:37])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:36])[C:17]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([CH:29]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:12])=[C:4]([CH3:38])[CH:3]=1
Reactant: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(Br)cc2C)cc1CN(C)C(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(Br)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 28B (450 mg, 0.753 mmol) in EtOAc (6 mL), was added HCl (4N, 6 mL). The mixture was stirred rt for 2 h, and concentrated. The residue was dissolved in DMF (10 ml), N,N-diisopropylethylamine (0.525 ml, 3.01 mmol) was added, followed by N-(benzyloxycarbonyloxy) succinimide (206 mg, 0.828 mmol). The mixture was stirred rt for 1 h, quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexanes) to give 28C (376 mg, 0.595 mmol, 79% yield). MS (ESI) m/z: 631.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C@@:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([OH:7])[C@H:4]([OH:6])[CH3:5].[OH-].[Na+].O.C(#N)C>CO>[O:7]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])([CH:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: C[C@@H](O)[C@](O)(CCl)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CC(O)C1(c2ccc(F)cc2F)CO1
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of 0.28 g (1.2 mmol) of (2S,3R)-1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol ((2S,3R)/(2R,3R)=88/12) in 3 mL of methanol was cooled in ice, and 1.4 mL of a 1 M aqueous solution of NaOH was added thereto. Reaction was performed for 1.5 hours, and 10 mL of water was added to stop the reaction. Extraction was performed with ethylacetate (20 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting crude product was quantitatively analyzed by HPLC. Thereby, the title compound was obtained in a yield of 95% ((2R,3R)/(2S,3R)=88/12) (HPLC, column: CAPCELL PAK C18 TYPE MG, mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=2/8, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 28 minutes (2S,3R), 30 minutes (2R,3R)) 1H-NMR (400 MHz, CDCl3) (2R,3R) δ: 1.16 (d, 3H, J=6.1 Hz), 2.80 (d, 1H, J=4.4 Hz), 3.30 (d, 1H, J=4.4 Hz), 4.09 (q, 1H, J=6.1 Hz), 6.80-6.93 (m, 2H), 7.32-7.37 (m, 1H)).
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([O-])=[O:22])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.C(N(C(C)C)CC)(C)C.Cl.[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][C@@H:68]2[CH2:72][CH2:71][NH:70][CH2:69]2)=[CH:63][C:62]=1[C:73]([F:76])([F:75])[F:74])([O-:60])=[O:59].[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([N:70]3[CH2:71][CH2:72][C@@H:68]([NH:67][C:64]4[CH:65]=[CH:66][C:61]([N+:58]([O-:60])=[O:59])=[C:62]([C:73]([F:74])([F:76])[F:75])[CH:63]=4)[CH2:69]3)=[O:22])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(N[C@@H]2CCNC2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(N2CCN(CCCC(=O)[O-])CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(N2CCN(CCCC(=O)N3CC[C@@H](Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To as suspension of 4-[4-(4-tert-butylphenyl)-piperazin-1-yl]-butyric acid lithium salt (15 mg; 0.05 mmol, prepared in accord with Example 167) in tetrahydrofuran (1 mL) is added a solution of tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.5 mL). After 15 minutes at room temperature, diisopropylethyl amine (25 μL; 0.15 mmol) and a solution of (4-nitro-3-trifluoromethyl-phenyl)-(R)-pyrrolidin-3-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accord with Example 165) in dimethylformamide (0.5 mL) is added and the reaction mixture is stirred at room temperature for one hour. Aluminium oxide (90 active basic) is then added and stiffing is continued. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (17 mg; 0.030 mmol). The structure was confirmed using Protocol I-D. Calculated mass=562; observed mass=562; HPLC retention time=1.60 min.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1.CN[C@@H]1CCCC[C@H]1NC>CCOCC.O.[Cu](I)I.[Co].O1CCOCC1>[CH3:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([N:19]2[N:20]=[CH:21][CH:22]=[N:18]2)[N:10]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: c1c[nH]nn1
Agent: I[Cu]I
Agent: [Co]
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a 100 ml round bottom flask containing 2-chloro-6-methylnicotinic acid (3 g, 17.4 mmol), copper iodide (0.16 g, 0.5 mol %), and cesium carbonate (11.4 g, 35 mmol) was added a mixture of dioxane (20 mL) and H2O (0.1 ml, 5.25 mmol). Next triazole (2.03 mL, 35 mmol) and finally (R,R)-(−)-N,N′-dimethyl-1,2-cyclohexanediamine ligand (0.56 mL, 3.5 mmol) were added. The resulting clumpy yellow slurry was stirred until evenly dispersed. Upon heating to 100° C. the reaction mixture changed from a yellow slurry to pale green. As heating progressed the slurry became less thick and was stirred more easily. The light green slurry was stirred for 4 hr at 100° C. and left to stir at room temp overnight. At this point the reaction mixture appeared as a cobalt blue slurry which was then diluted with 20 mL ether and 20 mL H2O. The resulting solution was thoroughly stirred and transferred to a seperatory funnel then the RBF was subsequently rinsed with 20 mL ether and H2O each. The aqueous layer was separated from the organic layer and acidified to pH 1 with 6 mL conc. HCl. The now brown/lime green aqueous layer was extracted twice with EtOAc. The bright yellow organic layers were combined and dried with Na2SO4 and then conc. into a yellow powder under reduced pressure. To the yellow powder was added EtOAc to form a yellow slurry. The solids were filtered off and washed with EtOAc to give a very pale yield). The filtrate was conc. into a yellow solid and purified (FCC, 0-5% MeOH in DCM w/0.5% AcOH) to give the title product in a 20% yield. MS (ESI): mass calculated for C9H8N4O2, 204.18; m/z found 205.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.21-8.18 (m, 1H), 7.98 (s, 2H), 7.51 (d, J=7.9 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:10]([N:4]1[C:3](=[O:9])[C:2]([I:1])=[CH:7][NH:6][C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
A solution of 5-iodouracil (2 g, 8.4 mmol) in dry pyridine (20 ml) was added dropwise to a solution of benzoyl chloride (3.5 g, 25.3 mmol) in pyridine (10 ml). The mixture was stirred at room temperature for 3 hours. Water (70 ml) was added and extracted with ethyl acetate. The organic phase washed with a saturated solution of NH4Cl and then with 2% HCl (40 ml×4). The solvent was removed under vacuum and the residue was triturated with i-Pr2O to give the title compound as a white solid (2.6 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.[CH2:23]1[O:25][CH2:24]1.[OH-].[NH4+]>C(Cl)CCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Reactant: C1CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Reaction time: 0.13 h

Procedure:
A solution of 5.2 g (0.02 M) of stannic chloride in 60 ml of dry ethylene dichloride under nitrogen was treated with 2.9 g (0.0091 M) of 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. The reaction was cooled in an ice bath, and 2.6 g (0.06 M) of ethylene oxide in 10 ml of ethylene dichloride was added with stirring over an 8 min period. After 18 hr at room temperature, the solution was made basic with concentrated ammonium hydroxide and filtered. The filtrates were washed with a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of dichloromethane, methanol and petroleum ether to give the above named product as white rods, melting at 201°-203°.