Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(=O)C(C)=O.[Na+]>>[CH:7](=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: CC(=O)C(=O)[O-]
Agent: [Na+]
Product: O=C(O)C(=O)C=Cc1ccccc1

Procedure:
Furthermore, the pyruvic acid compound (I) can also be produced, for example, in accordance with: (1) the process in which benzaldehyde and sodium pyruvate are condensed together to give benzalpyruvic acid, and the benzalpyruvic acid is then reacted with ethyl chloroformate to give ethyl benzalpyruvate, and the ethyl benzalpyruvate is then reduced [EP387058]; or (2) the process in which phenetyl bromide is reacted with carbon monoxide in the presence of a cobalt carbonyl catalyst [J. Mol. Cat., 88, 295(1994)]. The process for producing the pyruvic acid compound (I) as the starting material is not limited to these processes, either of which can be used as the production process for the starting material in the present invention.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[Cl:17]N1C(=O)CCC1=O.ClC1C=NC=C(Cl)C=1N1CCC(C(N)=O)CC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Agent: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(c2c(Cl)cncc2Br)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (100 mg, 0.35 mmol) in DMF (7.00 mL) was added N-chlorosuccinimide (94 mg, 0.70 mmol). The reaction was heated to 80° C. and stirred for 8 hours before partitioning between EtOAc and water (100 ml each), the separated organic layer was washed with water (2×75 ml), brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give a crude clear pale yellow oil (82 mg). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 98:2-84:16, biotage 25+S) followed by flash column chromatography on silica gel (CH2Cl2, EtOH, 96:4-82:18, biotage 14+M) to give a mixture of title compound and 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide by-product as a white solid (20 mg). The mixture was further purified by preparative hplc (MeOH, H2O, 9:20, 25 min) to furnish the title compound as a white solid, LC-MS (ESI, 4 min) Rt 2.46 min, m/z 320 (100%, [M+H]+); m/z (ESI) C11H13N3OClBr requires 316.9931, found [M+H]+ 318.0003.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:13])[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[F-].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CC(=O)CC>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][C:3]1[C:2]([F:1])=[C:7]([C:8]#[N:9])[C:6](=[C:5]([F:12])[C:4]=1[F:13])[C:10]#[N:11]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Reactant: Sc1ccccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1c(F)c(F)c(Sc2ccccc2Cl)c(F)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Into a four-neck flask of glass provided with a stirrer, a thermometer, a water separation tube, and a cooling tube and having an inner volume of 100 ml, 30 gr of 2-butanone, 10 gr (0.05 mol) of tetrafluorophthalonitrile, and 3.63 gr (0.062 mol) of potassium fluoride were placed and the flask was dipped in a water bath. The reaction mixture in the reaction vessel was kept stirred at room temperature and 7.6 g (0.053 mol) of 2-chlorobenzene thiol were added thereto over about 20 minutes. The reaction temperature rose to the highest level of 30° C. When the reaction was continued for additional one hour after the completion of this addition, the conversion of tetrafluorophthalonitrile reached 99.0%. The resultant reaction solution was filtered to separate a solid component. The solid component was evaporated under a reduced pressure at 50° C. to obtain about 15 g of 2-butanone by distillation. 100 ml of methanol was added to the resultant residue of the distillation to precipitate crystals. When the crystals consequently precipitated were filtered, 11.4 gr (0.035 mol, yield: 70.2 mol %) of 4-(2-chloro phenylthio)-3,5,6-trifluorophthalonitrile was obtained.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([NH:27][C:28](=[O:30])[CH3:29])[CH:21]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[S:73]1(=[O:79])(=[O:78])[CH2:77][CH2:76][CH2:75][NH:74]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:78]=[S:73]1(=[O:79])[CH2:77][CH2:76][CH2:75][N:74]1[C:2]1[N:3]=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([NH:27][C:28](=[O:30])[CH3:29])[CH:21]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])[N:8]=1
Reactant: O=S1(=O)CCCN1
Reactant: CC(=O)Nc1cc(-c2nc(I)c(-c3ncn(COCC[Si](C)(C)C)n3)o2)c(C)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(N3CCCS3(=O)=O)c(-c3ncn(COCC[Si](C)(C)C)n3)o2)c(C)cn1

Procedure:
To a solution of N-{4-[4-iodo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.33 g, 0.601 mmol) in 1,4-dioxane (4 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.055 g, 0.060 mmol), Xantphos (0.10 g, 0.18 mmol), isothiazolidine 1,1-dioxide (0.36 g, 3.01 mmol) and cesium carbonate (0.98 g, 3.00 mmol). The mixture was degassed with nitrogen and then subjected to microwave irradiation at 140° C. for 2.5 h. The mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[4-(1,1-dioxidoisothiazolidin-2-yl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide which was used directly in the next step. LCMS (FA): m/z=534.6 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[NH3:13]>[Ni]>[NH2:13][CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: N
Agent: [Ni]
Product: CC(N)c1ccc(C(=O)O)cc1

Procedure:
4-Acetylbenzoic acid (4.1 g) is dissolved in 50 mL ammonia-saturated methanol. Raney nickel catalyst (1.5 g; activity grade III) is then added and the mixture reduced under hydrogen atmosphere (4750 psi) at 80° C. for 17 hrs. After removal of the catalyst by suction filtration, the filtrate is evaporated and the residue dissolved in H2O. The solution is passed through a 2.5×15 cm column of Dowex-50X8-400 resin (H+ form) and eluted with 1N NH4OH. Evaporation of the eluate leaves a residue (2.9 g) which is recrystallized from H2O/acetone and characterized as 4-(1-aminoethyl)benzoic acid, m.p.>300° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@H:21]([C@@:39]([OH:49])([CH2:43][CH2:44][C:45]([O:47]C)=[O:46])[C:40]([O-:42])=[O:41])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(#N)C.C(N(CC)CC)C.[Br-].[Li+]>O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@H:21]([C@@:39]([OH:49])([CH2:43][CH2:44][C:45]([OH:47])=[O:46])[C:40]([OH:42])=[O:41])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCC(=O)OC)C(=O)[O-])C(=O)OC)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCC(=O)O)C(=O)O)C(=O)O)cc1
Temperature: 50 °C
Yield: 55.7 %

Procedure:
To a mixture of No. 5507802, 5-methyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-pentanedioate (18 mg, 0.0262 mmol), acetonitrile (450 μL), and water (9 μL) were added triethylamine (21.9 μL, 0.157 mmol) and lithium bromide (45.6 mg, 0.525 mmol), and the mixture was stirred at 50° C. After confirming the consumption of No. 5507802 by LCMS, 0.1 M hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by SP1 (Diol cartridge, 80% ethyl acetate/n-hexane Rf=0.6) to obtain the title compound (9.6 mg, 56% yield, white solid).
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=O)C.C=O>CO>[C:1]1([NH:7][C:8]2[S:9][C:10]3[CH2:16][NH:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1csc(Nc2ccccc2)n1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: c1ccc(Nc2nc3c(s2)CNCC3)cc1
Reaction time: 0.33 h
Yield: 382.9 %

Procedure:
A solution of 2-phenylamino-4-(2-aminoethyl)-thiazole (0.30 g, 1.37 mmol) in methanol (15 ml) was treated with acetic acid (0.02 ml, 0.35 mmol) and formaldehyde (0.11 ml of a 37% aqueous solution, 1.37 mmol). After 20 minutes, the reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo to provide a glassy solid (0.31 g, 1.34 mmol, 98% yield) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH:56]=[CH:57][C:58]=1[CH3:59])[C:45]([NH:47][CH2:48][CH2:49][C:50]1[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=1)=[O:46]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:57]5[CH:56]=[C:44]([CH:43]=[CH:42][C:58]=5[CH3:59])[C:45]([NH:47][CH2:48][CH2:49][C:50]5[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=5)=[O:46])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1ccc(C(=O)NCCc2cccnc2)cc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)NCCc4cccnc4)ccc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and 3-bromo-4-methyl-N-(2-pyridin-3-yl-ethyl)-benzamide (62 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methyl-N-(2-pyridin-3-yl-ethyl)-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-304) as a pale brown powder (22 mg, 32%).
Reaction SMILES: Cl.Cl.[OH:3][C:4]1[C:9]([NH2:10])=[C:8]([NH2:11])[N:7]=[C:6]([NH2:12])[N:5]=1.S[CH2:14][CH2:15][OH:16].II.[I-].[K+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].C(O)=O.CO>[CH3:14][C@H:15]([OH:16])[C@H:4]([OH:3])[C:9]1[N:10]=[C:9]2[C:4]([N:5]=[C:6]([NH2:12])[NH:7][C:8]2=[N:11][CH:8]=1)=[O:3]
Reactant: OCCS
Reactant: Nc1nc(N)c(N)c(O)n1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: Cl
Agent: II
Solvent: O=CO
Solvent: CO
Solvent: O
Product: C[C@H](O)[C@H](O)c1cnc2[nH]c(N)nc(=O)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Hydroxy-2,5,6-triaminopyrimidine 2HCl (18.0 g, 0.084 mol) was suspended in a mixed solution (540 ml) of methanol and water (3:2), to which was added dropwise mercaptoethyl alcohol (1.0 ml) and then a solution of the crude phenylhydrazone (18.9 g) as previously prepared in a mixed solution (200 ml) of methanol and water (3:2) was poured into the suspension. The mixture was stirred in an argon atmosphere at room temperature for 1 hour and then stirred under heat at 60°-70° C. for 40 minutes. The reaction solution was cooled to -10° C. and into the solution was poured over a period of 10 minutes a solution of iodine (40 g, 0.158 mol), potassium iodide (66 g, 0.398 mol), potassium ferricyanide (40 g, 0.122 mol) and 80% formic acid (40 ml) in water (1 lit.). After air was bubbled into the solution at 0° C. for 1.5 hours, the reaction solution as concentrated in vacuo, the residue was extracted with 10% ammonia water (1 lit.), insoluble matter was filtered off, the filtrate was concentrated, the residue was again dissolved in 2% ammonia water (2 lit.) and separated by ion-exchange resin column chromatography (DOWEX 1×8; 10 cm×40 cm; 0.15 N ammonium formate buffer solution (pH 9)). The effluent was concentrated in vacuo, the residue was dissolved in 10% ammonia water (240 ml) and decolorized by activated charcoal. The solution was concentrated in vacuo to 1/3 of the total amount, left to stand overnight under ice-cooling, the precipitated pale yellow solid was washed with ice water and ethanol and dried in vacuo (80° C., 6 hrs.) to give 5.00 g (0.021 mole) of l-biopterin.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2].[C:34]([O:38][C:39]([CH2:41][CH2:42][C:43]#[CH:44])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:44]#[C:43][CH2:42][CH2:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2]
Reactant: C#CCCC(=O)OC(C)(C)C
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CCCC(=O)OC(C)(C)C)cc2C(F)(F)F
Yield: 82 %

Procedure:
The title compound (34.9 mg, 82%) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole of Example 48 (40.9 mg, 0.0720 mmol) and 4-t-butoxycarbonyl-1-butyne by the procedure similar to that described in Reference Example 21.
Reaction SMILES: S1CCS[C:2]21[C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH:8]([NH:14][CH:15]=[O:16])[CH2:7][CH2:6]2.O.C(=O)([O-])[O-:19].[Ca+2]>C(#N)C>[O:19]=[C:2]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]([NH:14][CH:15]=[O:16])[CH2:7][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: O=CNC1CCC2(SCCS2)c2sccc21
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Product: O=CNC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a stirred mixture of N-(5,6-dihydrospiro[benzo[b]thiophen-7(4H), 2'-[1,3]dithiolan]-4-yl)formamide (1.5 g), acetonitrile (20 ml) and water is added calcium carbonate (1.65 g) and mercuric chloride (3.0 g). The mixture is stirred at room temperature for 35 minutes and acetonitrile is added. The solid is filtered and washed with acetonitrile. The filtrate (100 ml) is evaporated to dryness to afford the title compound.
Reaction SMILES: Br.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Br:13])=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15].[Cl-].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Zn+])=[CH:23][CH:22]=1>C(OCC)(=O)C.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>[BrH:13].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Br:13])=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: COC(=O)c1cc(Br)c2ccccc2c1N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c2ccccc2c1N
Temperature: 90 °C

Procedure:
Methyl 1-amino-4-bromo-2-naphthoate hydrobromide was prepared as described in Example 1. To a round bottom flask containing methyl 1-amino-4-bromo-2-naphthoate hydrobromide (3.50 g, 9.69 mmol) under an atmosphere of nitrogen was added 4-methoxybenzylzinc chloride (97.0 mL, 0.5 M in THF, 48.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mol %). The mixture was heated at 90° C. for 7 h, cooled to rt, and diluted with 50 mL of ethyl acetate and 50 mL of water. The mixture was partitioned and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, to provide methyl 1-amino-4-(4-methoxybenzyl)-2-naphthoate that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 322.0 for [M+H]+. A solution of the above prepared compound (1.41 g, 4.39 mmol) in N,N-dimethylformamide dimethylacetal (1.76 mL, 13.2 mmol) was heated at 100° C. for 4 h. Additional N,N-dimethylformamide dimethylacetal (0.44 mL, 3.3 mmol) was added and the solution was heated at 100° C. for 1 h. The mixture was cooled to rt, concentrated in vacuo to provide methyl 1-{[(1E)-(dimethylamino)methylene]amino}-4-(4-methoxybenzyl)-2-naphthoate that gave a mass ion (ES+) of 377.0 for [M+H]+. To a solution of the above prepared compound (0.040 g, 1.1 mmol) in 0.5 mL of acetic acid was added 3-amino-5-methylpyrazole (10.7 mg, 1.10 mmol). The mixture was heated at 100° C. for 6 h and then cooled to rt and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a mass ion (ES+) of 433.1653 for [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[C:11]2[S:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-].O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[C:11]2[S:20][C:21]2[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)c(Sc2ccc([N+](=O)[O-])cc2)n1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(N)cc2)c(Sc2ccc(N)cc2)n1
Yield: 77.9 %

Procedure:
Ethyl 1-(4-nitrophenyl)-2-[(4-nitrophenyl)thio]-1H-imidazole-4-carboxylate (3.00 g) was suspended in ethanol (120 mL), iron powder (4.05 g), anhydrous calcium chloride (0.81 g) and water (20 mL) were added and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool and filtered, saturated aqueous sodium hydrogen carbonate solution was added to the obtained filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanol (30 mL) was added to the residue, and crystals were collected by filtration to give the title compound as pale-yellow crystals (yield 2.00 g, yield 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[NH2:11][C@@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([NH2:22])=[O:21])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(N[C@H](Cc2ccccc2)C(N)=O)nc1Cl
Yield: 85.9 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (86 mg, 0.494 mmol), D-phenylalaninamide (81 mg, 0.494 mmol) and DIEA (0.130 mL, 0.747 mmol) in DMF (2 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-phenylpropanamide (128 mg) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[Li+].[OH-].Cl>C1COCC1.CO>[Cl:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:15])=[O:2])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 77.6 %

Procedure:
4,5-Dichloro-2-nitrobenzoic acid piperidine amide. A solution of 4,5-dichloro-2-nitrobenzoic acid methyl ester (0.29 g, 1.16 mmol) in 1:1 THF/methanol (4 mL) was stirred as 1 N aqueous LiOH (2 mL) was added. After 1 h, the mixture was acidified with 1 N HCl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to provide crude 4,5-dichloro-2-nitrobenzoic acid as a light yellow solid (0.26 g, 0.90 mmol, 77%). The acid was refluxed in 4 mL thionyl chloride for 2 h, and the crude reaction mixture was concentrated in vacuo. Residual thionyl chloride was removed by the repeated addition and in vacuo stripping of DCM. The acid chloride was placed under high vacuum for 10 min, and then taken up in dry DCM (5 mL). The mixture was cooled in an ice bath. Piperidine (0.46 g, 5.4 mmol, 0.53 mL) was added, and the reaction mixture was allowed to stand at 0° C. overnight. The mixture was diluted with DCM, washed with 1 N HCl (2×), 5% aqueous NaHCO3 and brine, and dried (MgSO4). Filtration and concentration provided 0.32 g of the desired amide, which could not be separated from an impurity (10%) that corresponded to the product of displacement of a chlorine by an additional equivalent of piperidine. HPLC (reversed-phase): RT=9.35 min (90%), 10.58 (10%). MS (ESI): major m/z 303 [M+H]+, minor m/z 352 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)C=C.Cl[C:17]1[CH:22]=CC=C[C:18]=1Cl>>[CH2:22]([C:10]1[CH:9]=[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:6][C:5]=1[OH:4])[CH:17]=[CH2:18]
Reactant: C=CCOc1ccc(CC(=O)OC)cc1
Reactant: Clc1ccccc1Cl
Product: C=CCc1cc(CC(=O)OC)ccc1O

Procedure:
A solution of methyl 4-alloxyphenylacetate (3.1 grams) in dry ortho-dichlorobenzene (50 mL) was refluxed for 25 hours. The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, 50% methylene chloride in hexane) to afford the tittle compound.