Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-])=O.C1(C)C(C)=CC=CC=1.P.[OH-].[Na+]>Cl[Pd]Cl.O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8]
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: P
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: C=Cc1cccc(N)c1

Procedure:
A degassed solution of 40 mmol of 3-nitrostyrene (starting material) and 40ml of xylene are placed in an autoclave (volume: 200 ml). 2.0 mmol of BINAS(in the form of 11.56 g of an aqueous solution containing 0.173 mol of BINAS/kg of solution) as phosphine and 1.92 g (48 mmol) of NaOH, 23 ml of H2O and 0.8 mmol of PdCl2 are added. The pH is from 10.0 to 10.5.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].C([O-])(O)=O.[Na+].CO.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16](Cl)[C:15]=1[N+:24]([O-])=O>[Pt].O>[CH3:2][C:1]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([NH2:24])[CH:16]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CC(=O)[O-]
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(Cl)c(N)c1
Yield: 85 %

Procedure:
A hydrogenation reactor is charged with 15 parts of sodium acetate, 60 parts of NaHCO3, 1320 parts of MeOH and 1015 parts of 1-chloro-2,4-dinitrochlorobenzene under nitrogen at 50° C. and then 11 parts of 1% Pt/C, 0.15 parts of NH4VO3 and 66 parts of water are added.The hydrogenation is carried out at 60° C. and 18 bar. The product is isolated as 3-amino-4-chloroacetanilide (785 parts, 85% of theory).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[O:22]C(=O)C)[C:8]([NH:10][N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]1=[O:18])=[O:9])(=O)C.[OH-].[K+].Cl>CO.O>[OH:4][C:5]1[CH:6]=[C:7]([C:8]([NH:10][N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]2=[O:18])=[O:9])[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: CC(=O)Oc1ccc(C(=O)NN2CCNC(=O)C2=O)cc1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1NCCN(NC(=O)c2ccc(O)c(O)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 12.13 g (34.7 mmol) of 3,4-bis(acetyloxy)-N-(2,3-dioxo-1-piperazinyl)benzamide in 290 ml of methanol and 80 ml of water was added 29 ml of 25N potassium hydroxide solution (72.9 mmol), and the mixture was stirred for 1 hour at room temperature. The pH of the solution was brought to 6.9 with dilute hydrochloric acid, the solution was then concentrated to 100 ml and the precipitate filtered off, washed with water and dried in vacuo (60°-70° C.); yield: 7.85 g, melting point 294° C.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][CH:14]([NH:23][CH:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]1=[O:38])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:9]([CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][CH:14]([NH:23][CH:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:13]1=[O:38])([OH:10])=[O:8]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)O)C1=O

Procedure:
A solution of 1-benzyloxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (isomer B of example 3, 0.9 g) in ethanol (150 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen had ceased, the catalyst was filtered off, and the solvent removed under reduced pressure to give a solid. This material was triturated with ether (8 ml) to give the title compound melting at 138°-140° and identical to the compound obtained in Example 1.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([Br:5])([Br:4])[Br:3].C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].O>C(OCC)C>[Br:3][C:2]([Br:5])([Br:4])[CH2:1][O:6][C:14](=[O:17])[CH:15]=[CH2:16]
Reactant: OCC(Br)(Br)Br
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)OCC(Br)(Br)Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
A first solution including tribromoethanol (50 g, 177 mmol) and triethylamine (19.73 g, 195 mmol) dissolved in 50 g of diethylether was prepared. A second solution comprising acryloyl chloride (17.65 g, 195 mmol) dissolved in 50 g of diethylether was added dropwise to the first solution followed by stirring for four hours at room temperature. The resulting solution was then added to water, and the organic phase was extracted. The organic phase was distilled to yield 48.38 g of TBEA (72.5% yield).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15](Cl)[N:14]([C:17](=[C:34]([CH3:38])[CH2:35][O:36][CH3:37])[C:18]([O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(CC(NC1C(Cl)N(C(=C(C)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)C1=O)=O)C1C=CC=CC=1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:17](=[C:34]([CH3:38])[CH2:35][O:36][CH3:37])[C:18]([O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1Cl
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COCC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O

Procedure:
Benzhydryl 2-(3-phenoxyacetamido-4-chloro-2-oxoazetidin-1-yl)-3-methyl-4-methoxy-2-butenoate [prepared from benzhydryl 2-(3-phenoxyacetamido-4-chloro-2oxoazetidin-1-yl)-3-methyl-2-butenoate using the general procedures described in Examples 7 and 8(A) hereinabove] (264 mg, 0.5 mmol) was dissolved in 1 ml of toluene with 0.6 mmol of tri(butyl)tin hydride and 0.6 mmol of azobisisobutyronitrile (99 mg) and heated at 62° with stirring under a nitrogen atmosphere. The reaction solvent was removed under reduced pressure to provide an impure product which was purified by preparative thin layer chromatography. (1:2/ethyl acetate:hexane). Yield --54 mg of title product.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH:6]1([NH:9][C:10](=[O:42])/[C:11](/[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:12]/[C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](OC)=[O:30])=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1>CO.C(Cl)Cl.O>[CH:6]1([NH:9][C:10](=[O:42])[C:11]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:12][C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([NH:2][OH:3])=[O:30])=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:8]1
Reactant: NO
Reactant: COC(=O)C=Cc1ccc(CNC(=O)c2ccc(/C=C(/C(=O)NC3CC3)c3ccc(F)cc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(/C=C/c1ccc(CNC(=O)c2ccc(C=C(C(=O)NC3CC3)c3ccc(F)cc3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Hydroxylamine hydrochloride (0.5 g, 7.2 mmol) in methanol (2 mL) was mixed with KOH (0.4 g, 7.2 mmol) in methanol (2 mL) at 0° C., and sonicated for 2 minutes and the white precipitate formed was filtered. The filtrate was added to methyl 3(4-((4-(1E)-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-enyl)benzamido)methyl)phenyl)acrylate (0.20 g, 0.4 mmol) in DCM (1.5 mL) and the mixture stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The ethyl acetate layers were washed with water (100 mL), dried over anhydrous Na2SO4 and concentrated to obtain a crude compound, which was triturated with DCM (15 mL) to obtain a solid which was filtered and washed with DCM (5 mL) to afford the title compound (0.050 g, 25% yield). 1H NMR (DMSO-d6) δ (ppm): 0.51-052 (2H, m, —CH2), 0.63-0.65 (2H, m, —CH2), 2.74-2.75 (1H, m, —CH), 4.43-4.44 (2H, d, CH2), 6.39-6.43 (1H, d, ═CH), 7.05-7.07 (2H, d, Ar—H), 7.16-7.22 (4H, m, Ar—H), 7.29-7.32 (3H, m, Ar—H and ═CH), 7.40-7.44 (1H, d, ═CH), 7.49-7.51 (2H, d, Ar—H), 7.68-7.70 (2H, d, Ar—H), 7.89-7.90 (1H, d, —NH), 9.00 (2H, m, NH and OH), 10.73 (1H, s, NH), MS m/z: 498.1 (M+−1).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1[C:23]2=[C:24]3[C:13]([C:14]4[C:25]5[C:22]2=[CH:21][CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]=5[C:17]([C:29](O)=[O:30])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([C:32](=N)[OH:33])[C:9]3=[C:8]([C:35](=N)[OH:36])[CH:7]=1>>[CH:15]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]4[C:32]([O:2][C:35](=[O:36])[C:8]5[C:9]=4[C:24]=3[C:23](=[CH:6][CH:7]=5)[C:22]3[C:25]=2[C:18]2[C:19]([C:26]([O:28][C:29](=[O:30])[C:17]=2[CH:16]=1)=[O:27])=[CH:20][CH:21]=3)=[O:33]
Reactant: O=S(=O)(O)O
Reactant: N=C(O)c1ccc2c3ccc(C(=O)O)c4c(C(=O)O)ccc(c5ccc(C(=N)O)c1c25)c43
Product: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Temperature: 220 °C

Procedure:
800 g of 95% strength sulfuric acid are initially taken and 200 g of 89.4% strength perylene-3,4,9,10-tetracarboxylic acid diimide are introduced at room temperature. The temperature of the mixture is then raised to 220° C. and maintained at this level for two hours. The mixture is then allowed to cool to room temperature and the precipitate which has been formed is filtered off with suction and washed first with 280 g of 80% strength sulfuric acid and then with water until it is neutral. Drying at 80° C. gives 170.9 g of crude perylene-3,4,9,10-tetracarboxylic dianhydride. This is introduced, with exclusion of light, into a solution composed of six liters of water and 140 g of 85% strength potassium hydroxide. While blanketed with nitrogen, the solution is heated to 80°-90° C. and stirring is continued for a further 90 minutes at this temperature. The mixture is then allowed to cool to 25° C., the pH is adjusted to a value of 8-9 and the solid residue is filtered off and washed with 100 ml of water. (The residue is 35.6 g of perylene-3,4,9,10-tetracarboxylic acid diimide which has been only half-saponified, i.e. perylene-3,4,9,10-tetracarboxylic acid monoanhydride-monoimide, and this is expediently added to the next batch.) 120 g of 85% strength potassium hydroxide are introduced into the filtrate, with exclusion of light, and the mixture is then blanketed with nitrogen. After a further hour's stirring at 25° C., a solution of 120 g of iron(II) sulfate and 600 ml of water is added dropwise, the mixture is stirred for a further hour at 25° C. and clarified and the filtrate is then added dropwise to 600 g of concentrated hydrochloric acid, the mixture is kept at 80°-90° C. for one hour and the precipitate is filtered off, washed with water until it is neutral and dried at 80° C. This gives 130.8 g of perylene-3,4,9,10-tetracarboxylic dianhydride having the following extinction values:
Reaction SMILES: [CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([C@H]1CC[C@H](C2CCC(=[O:40])CC2)CC1)CCCC>>[CH2:1]([C:6]1([OH:40])[CH2:11][CH2:10][CH:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=CCC([C@H]2CC[C@H](CCCCC)CC2)CC1
Reactant: CCCCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Product: CCCCCC1(O)CCC([C@H]2CC[C@H](CCCCC)CC2)CC1

Procedure:
30.4 g of 1-pentyl-4-(trans-4-pentylcyclohexyl)-cyclohexene [obtainable by reacting 4-(trans-4-pentylcyclohexyl)-cyclohexanone with pentyl-MgBr, hydrolysing the product to give 1-pentyl-4-(trans-4-pentylcyclohexyl)-cyclohexanol and dehydrating the latter], 2.7 g of liquid HCN, 0.1 g of palladium bis-[2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)-butane] and 100 ml of acetonitrile are heated at 130° for 1 hour in an autoclave. The mixture is cooled, evaporated and worked up in the customary manner to give r-1-cyano-1-pentyl-cis-4-(trans-4-pentylcyclohexyl)-cyclohexane, m.p. 28°, c.p. 63°.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][C:8]=1[CH3:9].CCN(CC)CC.OS([O-])=O.[Na+]>C(Cl)Cl>[Br:1][C:5]1[C:4]([Cl:3])=[C:8]([CH3:9])[NH:7][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
Bromine (0.56 ml, 11 mmol) was added to a solution of 1 g (5.3 mmol) of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 7) and 0.8 ml (5.7 mmol) Et3N in CH2Cl2. After stirring at room temperature for 2 h, aqueous NaHSO3 was added and the CH2Cl2 was removed and the aqueous residue was partitioned between water and EtOAc. The EtOAc was separated and washed with brine. Drying (MgSO4) and removal of solvent gave 1.5 g of product as a solid. MS (ES) (MH+): 240 for C8H9BrClNO2; NMR (d6-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.2 (q, 2H), 12.3 (s, 1H).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:27])=[N:21][C:22](Cl)=[N:23][C:24]=4[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([O:33][CH:34]([F:36])[F:35])[C:29]([F:32])([F:31])[F:30])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>O1CCCC1.[Cl-].[NH4+].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:24]([CH3:25])=[N:23][C:22]([CH2:1][CH3:2])=[N:21][C:20]=4[CH3:27])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([O:33][CH:34]([F:35])[F:36])[C:29]([F:32])([F:31])[F:30])=[CH:8][CH:7]=1
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CC[Mg]Cl
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethylmagnesium chloride (2.0 M solution in tetrahydrofuran, 0.37 mL, 0.740 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (183 mg, 0.369 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (20.0 mg, 0.0369 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture containing an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was washed with ethyl acetate/n-hexane to give the title compound as a colorless amorphous (16.5 mg, 0.037 mmol, 9%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])=[O:4].O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O

Procedure:
Characterization of sugars by GC analysis. The sugar standards, (1 mg each) rhamnose, fructose, galactose, glucose and the internal standard Phenyl-δ-D-Glucoside (E. Merck, Darmstadt) and the sugars (1 mg each) obtained from the hydrolysis of crude and pure anthocyanins (1-3) were reacted separately with 30 mg/ml Hydroxylamine HCl in dry pyridine (2 ml). The resulting oximes were then reacted with 1.0 ml hexamethyldisilazane (HMDS) and 0.1 ml trifluoroacetic acid (TFA) to yield their silyl derivatives. The samples were then analyzed by GC using an autosampler. Sugars from anthocyanins 1, 2 and 3 were identified by comparing with the retention times of sugar standards. The retention times were 6.97, 9.83, 10.58, 10.90, 19.82 minutes, respectively, for rhamnose, fructose, galactose, glucose and Phenyl-β-D-Glucoside. The GC analysis of sugars yielded from the hydrolysis of anthocyanins showed that anthocyanin 1 contained a 2:1 ratio of glucose and rhamnose. Anthocyanin 2 showed a 1:1 ratio of glucose and rhamnose and anthocyanin 3 had only glucose. Similarly, the GC analysis of sugars from the crude anthocyanin powder indicated that it contained only rhamnose and glucose at a ratio of 2:4, respectively.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1cccc(CBr)c1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1cccc(CN([C@H]2CCN(Cc3cccc(C#N)c3)C2=O)S(=O)(=O)c2ccc3ccc(OC)cc3c2)c1

Procedure:
The title compound is prepared as described in EXAMPLE 68, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 3-methoxybenzyl bromide. The crude product is purified by column chromatography eluting with 50% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20](CC2C=CC=CC=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30]>C(Cl)Cl>[ClH:30].[CH2:1]([CH:8]([CH2:13][S:14]([N:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)(=[O:16])=[O:15])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCNCC1
Yield: 81 %

Procedure:
The resultant compound from Example 6A (4.66 g, 1.12 mol) was dissolved in methylene chloride and treated with gaseous HCl. The solution was evaporated and the residue was dissolved in methanol, treated with 10% Pd/C and hydrogenated under 50 psi hydrogen. The mixture was evaporated to afford 330 g (81%) of the desired product: 1H NMR (CDCl3) δ7.37-7.13 (m, 5H), 3.68 (s, 3H), 3.42 (dd, 1H), 3.29-3.18 (m, 1H), 3.18-3.12 (m, 4H), 3.07 (dd, 1H), 2.97-2.82 (m, 6H).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[NH:9])[O:6][CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.CCOC(C)=O>[CH2:21]([O:20][C:18]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[CH2:4][CH:3]([CH3:10])[CH3:2])=[O:19])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N=C(CC(C)C)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
Ethyl 3-methylbutanimidate hydrochloride (4.0 g, 24.2 mmol) was suspended in DCM (48 mL) and the mixture was cooled to 0° C. Pyridine (10.0 mL, 124 mmol) was added and the mixture was stirred for 15 minutes. Ethyl chloroformate (5.3 mL, 48.3 mmol) was added and the solution was allowed to warm to RT and stirred for 12 h. The mixture was diluted with a mixture of EtOAc and hexanes (1:1, 200 mL) and solids were removed by filtration through a diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-3-methyl-butanimidate (4.3 g, 88%) as a colorless viscous oil. 1H NMR (400 MHz, DMSO-d6): δ 4.09 (q, J=7.1 Hz, 2H), 4.05 (q, J=7.1 Hz, 2H), 2.18 (d, J=7.4 Hz, 2H), 1.95-1.94 (m, 1H), 1.20 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H), 0.86 (d, J=6.7 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH3:9])[NH:4][C:3]=1[CH:10]=[O:11].[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:4]3[C:3]([CH:10]=[O:11])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH3:9])=[C:27]([F:33])[CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCOc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde (15.0 g, 68.5 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (25.0 g, 68.5 mmol) and potassium carbonate (9.5 g, 68.5 mmol) were dissolved in DMF (958 mL, 12.4 mol) and was stirred at room temperature for 2 hours. The reaction was quenched with water, and the mixture extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (0-30% EtOAc:hexanes) to yield intermediate (15a) (25 g). MS m/z: [M+H+] calcd for C24H24BrFN2O4, 503.3. found 503.2. 1H-NMR (CDCl3): 9.57 (1H, s), 7.80 (1H, d), 7.48 (2H, m), 7.27 (1H, s), 7.11 (1H, t), 7.01 (2H, d), 5.47 (2H, s), 4.33 (2H, q), 1.41 (3H, t), 1.24 (9H, s).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH3:13])[CH2:10][C:9](=[O:14])[NH:8][C:5]2=[N:6][CH:7]=1.[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[N:21]1[CH:25]=[N:24][N:23]=[C:22]1[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([N:11]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:22]4[N:21]([CH:16]5[CH2:17][CH2:18][CH2:19][CH2:20][O:15]5)[CH:25]=[N:24][N:23]=4)=[CH:27][CH:28]=3)[N:3]=2)[NH:8][C:9](=[O:14])[CH2:10]1)[CH3:13]
Reactant: CC1(C)OB(c2ccc(-c3nncn3C3CCCCO3)cc2)OC1(C)C
Reactant: CCN1CC(=O)Nc2ncc(Br)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CC(=O)Nc2ncc(-c3ccc(-c4nncn4C4CCCCO4)cc3)nc21
Temperature: 120 °C
Yield: 45 %

Procedure:
6-Bromo-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.1 equiv), 4-(tetrahydro-2H-pyran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole (1 equiv) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (0.05 equiv) were combined in 1,4-dioxane followed by the addition of sodium carbonate (3 equiv) in water. The solution was heated in a Biotage Emrys Optimizer microwave reactor to 120° C. for 30 min. The solution was condensed under reduced pressure and purified using column chromatography (0-10% methanol in ethyl acetate) to afford the title compound in 45% yield. MS (ESI) m/z 406.6 [M+1]+.