Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].[F:11][C:12]1[CH:24]=[C:23](F)[C:22]([F:26])=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:23]2[C:22]([F:26])=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([F:11])[CH:24]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a solution of (5,6-dichloropyridin-3-yl)methanol (275 mg, 1.55 mmol) in DMSO (5 mL) were added tert-butyl 2,4,5-trifluorobenzoate (Preparation 97, 300 mg, 1.30 mmol), and potassium carbonate (535 mg, 3.88 mmol) and the mixture stirred for 18 hours at room temperature under a nitrogen atmosphere. Water (10 mL) was added and the mixture extracted with EtOAc (3×20 mL). The combined organics were washed with water (20 mL) and concentrated in vacuo to yield the title compound (490 mg, 96%).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][OH:13])=[CH:10][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[CH3:20][N:21]([CH2:26][CH2:27][O:28]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:22](=[O:25])[CH2:23]Cl.C(OCC)(=O)C>C(O)(C)(C)C.CN(C)C=O.O>[OH:28][CH2:27][CH2:26][N:21]([CH3:20])[C:22](=[O:25])[CH2:23][O:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[S:6][C:2]([F:1])=[CH:3][C:4]=2[CH:10]=1
Reactant: OCCc1ccc2sc(F)cc2c1
Reactant: CN(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CN(CCO)C(=O)COCCc1ccc2sc(F)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
In a mixture of 4.8 mL of tert-butanol and 1.2 mL of N,N-dimethylformamide is dissolved 0.60 g of 2-(2-fluorobenzo[b]thiophen-5-yl)-1-ethanol, to which are added, at an ice-cooled temperature, 0.45 g of potassium tert-butoxide and 1.81 g of N1-methyl-N1-[2-(trityloxy)ethyl]-2-chloroacetamide. The resulting mixture is stirred at the same temperature as above for 30 minutes and then at ambient temperature for 2 hours. Ethyl acetate and water are added to the reaction mixture, and the organic layer is separated. The solvent is distilled off under reduced pressure. To the residue are added 6 mL of ethanol, 0.6 mL of water and 0.29 g of p-toluenesulfonic acid monohydrate, and the resulting mixture is stirred at ambient temperature overnight. Ethyl acetate and water are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=50:1 to 30:1). Thus, 0.74 g of N1-(2-hydroxyethyl)-N1-methyl-2-[2-(2-fluorobenzo[b]-thiophen-5-yl)ethoxy]-acetamide is obtained as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:21][CH3:22])[C:16](OCC)=[O:17])[C@@H:9]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:10]([C@@H:15]([CH2:21][CH3:22])[CH2:16][OH:17])[C:11](=[O:14])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](CC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 3 g (6.9 mmol) of (S)-ethyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate (Example 9, Step A) in 45 mL of Et2O was added lithium tetrahydroborate (0.334 g, 13.81 mmol) at 0° C. After being stirred at 0° C. for 50 min, the reaction was quenched (ice cold 10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: 30% to 60% EtOAc/Hexanes, gradient elution) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:26]=[CH:25][C:13]([C:14]([NH:16][NH:17][C:18]4[C:23]([Cl:24])=[N:22][CH:21]=[CH:20][N:19]=4)=O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.C(Cl)(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.C(P(CC)CC)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:26]=[CH:25][C:13]([C:14]4[N:19]5[CH:20]=[CH:21][N:22]=[C:23]([Cl:24])[C:18]5=[N:17][N:16]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(NNc1nccnc1Cl)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Agent: CCP(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1ccc2nc(Nc3ccc(-c4nnc5c(Cl)nccn45)cc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a solution of 4-(6-chlorobenzo[d]thiazol-2-ylamino)-N′-(3-chloropyrazin-2-yl)benzohydrazide (63B) (6.17 g, 14.31 mmol) in a mixed solvent of CCl4 (60 mL), THF (80 mL) and CH2Cl2 (120 mL) cooled to 0° C. under argon was added DIPEA (18.49 g, 143 mmol), followed by dropwise addition of triethylphosphine (8.45 g, 71.5 mmol). After addition, the reaction mixture was stirred at 0° C. for 1 h, and then quenched by addition of water (100 mL). The precipitate was isolated by filtration and air dried to yield the first crop of the title compound as a dark brown solid (3.92 g). The filtrate was extracted with ethyl acetate (2×). The combined organics were washed with water (1×100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The obtained residue was triturated with CH3OH/CH2Cl2 (35 mL/5 mL) to yield the second crop of the title compound (0.95 g) (total 4.87 g, 82% yield). HPLC/MS (Method C): retention time=2.61 min, [M+H]+=413.3. 1H NMR (500 MHz, DMSO-d6): δ 10.98 (s, 1H), 8.68 (d, J=4.95 Hz, 1H), 8.05 (d, J=8.25 Hz, 2H), 7.98 (s, 1H), 7.96 (d, J=825 Hz, 2H), 7.77 (d, J=4.95 Hz, 1H), 7.63 (d, J=8.25 Hz, 1H), 7.37 (d, J=8.80 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C.C(#N)C.CS(C)=O>[F:24][C:23]([F:26])([F:25])[C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Yield: 33 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 130 mg, 0.604 mmol), 4-chloro-6-(trifluoromethyl)pyrimidine (165 mg, 0.906 mmol) and DIPEA (0.211 mL, 1.208 mmol) in N-methyl-2-pyrrolidone (2 mL) were stirred at 150° C. for 1 hour in the microwave. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure to give a brown oil. This oil was dissolved in a mixture of acetonitrile and DMSO (1:1) (2.7 mL) and purified by MDAP (3 injections). Fractions containing the suspected product were combined and concentrated under reduced pressure to give the title compound as a pale brown solid (72 mg);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:12]=[O:13])=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].CC(=CC)C.[Cl-].[Na+].[O:21]1CCOCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:21])=[O:13])=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: C1COCCO1
Reactant: CCc1cc(C=O)sc1C(=O)OC
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C(=O)O)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-Ethyl-5-formyl-thiophene-2-carboxylic acid methyl ester (1.22 g, 6.15 mmol) in dioxane (30 ml) was added 2-methyl-2-butene (8 ml) and a solution of Na2ClO2 (3.42 g, 37.8 mmol) and NaH2PO4 (3.25 g) in water (8 ml). The mixture was stirred at rt for 2 h. The solution was saturated with sodium chloride, then successively extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (1.48 g, 100% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH3:11][Si:12]([CH3:17])([CH3:16])[CH2:13][CH2:14]O.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl.Cl>[CH3:11][Si:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][O:9][C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]1)=[O:10]
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)C1CCCC(=O)C1
Yield: 99.8 %

Procedure:
3-oxo-cyclohexanecarboxylic acid (2.00 g, 14.1 mmol), 2-trimethylsilylethanol (2.5 mL, 17.4 mmol), 4-dimethylaminopyridine (148 mg, 1.21 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.44 g, 17.9 mmol) in methylene chloride (14 mL) was stirred for 18 h. The solution was diluted with 10% aqueous hydrochloric acid and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield 3.41 g (100% yield) of 3-oxo-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester as a clear oil.
Reaction SMILES: [P:1]([CH2:5][N:6](CC(O)=O)[CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].C1(C=CC(O)=CC=1)O>O>[P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: O
Product: O=C(O)CNCP(=O)(O)O

Procedure:
The process of the present invention involves contacting N-phosphonomethyliminodiacetic acid in a slurry or solution with a water soluble salt or a salt complex of selected metals in the presence of a quinone or hydroquinone. The mixture or solution is contacted with a peroxide while heating the reaction mass to a temperature sufficiently high to initiate and sustain the oxidation reaction of N-phosphonomethyliminodiacetic acid to produce N-phosphonomethylglycine.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[C:12]2[C:7]1=[N:8][C:9]([C:24]1[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[N:25]=1)=[N:10][CH:11]=2.C([SiH](CC)CC)C.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[F:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:26]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:32]2[C:24]([C:9]2[N:8]=[C:7]3[C:12]([N:13]([CH2:16][C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])[C:14](=[O:15])[NH:6]3)=[CH:11][N:10]=2)=[N:25]1
Reactant: COc1ccc(Cn2c(=O)n(CC(F)(F)C(F)(F)F)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1CC(F)(F)C(F)(F)F
Yield: 85.1 %

Procedure:
471 mg (0.60 mmol) of the compound from example 85A were dissolved in 15 ml of trifluoroacetic acid, 698 mg (6.01 mmol) of triethylsilane were added and the mixture was heated to reflux for 18 h. The reaction mixture was admixed with water and ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum, and purified by means of preparative HPLC (eluent: methanol/water with 0.1% trifluoroacetic acid, gradient 30:70→90:10). 252 mg of the title compound were obtained (85% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:74]1[CH:83]=[CH:82][C:77]2[O:78][CH2:79][CH2:80][O:81][C:76]=2[CH:75]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[O:78]1[C:77]2[CH:82]=[CH:83][C:74]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:75][C:76]=2[O:81][CH2:80][CH2:79]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: Ic1ccc2c(c1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc2c(c1)OCCO2
Temperature: 25 °C

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenylbenzoate 0.10 g, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 2.3 mg, palladium acetate 0.8 mg and cesium carbonate 0.24 g was added 2,3-dihydro-6-iodobenzo[1,4]dioxin 0.24 g, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 2.3 mg and palladium acetate 0.8 mg were added, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((2,3-dihydrobenzo[1,4]dioxin-6-yl)amino)-4-phenylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:31])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][CH:23]=[C:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:30])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[H][H]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:31])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][CH2:23][CH:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:30])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OCC=C2SC(=O)NC2=O)C1
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OCCC2SC(=O)NC2=O)C1

Procedure:
Hydrogenation of the compound 5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}ethylidene)thiazolidine-2,4-dione, mentioned in Example Example XXII, with hydrogen gives the compound 5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-oxy}ethyl)thiazolidine-2,4-dione:
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:10][CH:11]([CH3:15])[C:12](Cl)=[O:13]>N1C=CC=CC=1.O1CCCC1>[CH2:1]([O:9][C:12](=[O:13])[CH:11]([Cl:10])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: CC(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)C(C)Cl
Reaction time: 24 h

Procedure:
Racemic 2-chloropropionate octyl ester was prepared by reacting 130 gm (1.0 mol) of n-octanol with 127 gm (1.0 mol) of 2-chloropropionyl chloride in 240 ml of pyridine and 50 ml of tetrahydrofuran. The reaction was carried out for 24 hours after which the solution was washed with 100 ml of 1 N HCl and 100 ml of distilled water. 500 ml of ether was added, then washed with 3×500 ml of saturated solution of NaHCO3 and 500 ml of saturated solution of NaCl. The organic phase was finally dried over MgSO4. The total weight of 2-chloropropionate octyl ester obtained was 248 gm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH:23](=[C:25](C(OC)=O)[C:26](OC)=[O:27])[CH3:24]>CO>[CH2:14]([N:13]1[C:26](=[O:27])[CH2:25][CH:23]([CH3:24])[N:21]=[C:12]1[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:22])[CH:9]([CH3:11])[CH3:10])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Reactant: CC=C(C(=O)OC)C(=O)OC
Solvent: CO
Product: CC1CC(=O)N(Cc2ccccc2)C(C(NC(=O)OC(C)(C)C)C(C)C)=N1
Temperature: 110 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
To a solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (7.08 g, 23 mMol) in MeOH (15 mL) was added Dimethyl ethylidenemalonate (3.64 g, 23 mMol). The reaction was slowly heated to 110° C. allowing the MeOH to distill off. The reaction was stirred for 5 h at 110° C. then allowed to cool to RT. Purification by flash chromatography (25% EtOAc, hexane) gave the title compound (6.37 g, 64%) as an oil: ˜(3:1) mixture of diastereomers by LCMS; MS (ES) m/e 432.2 and 432.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:21]([C:18]1[C:19](=[O:20])[N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:3][CH:4]=3)[CH:9]=2)[C:15]2[N:31]=[CH:30][CH:29]=[CH:28][C:16]=2[N:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[3-(4-aminophenyl)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (94 mg) and triethylamine (0.04 ml) in dichloromethane (3 ml) was added methanesulfonyl chloride (0.04 ml). The mixture was stirred at room temperature for 30 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (35% ethyl acetate in hexane) and crystallized from ethanol to give 2-benzyl-4-[3-(4-methylsulfonylaminophenyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (53 mg).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[N:44]1([C:50](=[O:52])[CH3:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:50]([N:44]1[CH2:49][CH2:48][N:47]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:46][CH2:45]1)(=[O:52])[CH3:51]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), 1-(piperazin-1-yl)ethanone (59 mg, 0.46 mmol, 3.00 equiv), potassium iodide (12.7 mg, 0.08 mmol, 0.50 equiv), and potassium carbonate (42.4 mg, 0.31 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 54.8 mg (34%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): 8.94-8.92 (d, J=4.2 Hz, 1H), 8.66-8.64 (d, J=6.6 Hz, 1H), 8.43 (s, 1H), 8.14-8.09 (m, 3H), 7.88-7.87 (m, 1H), 7.79-7.54 (m, 7H), 4.72 (s, 2H), 4.47 (s, 2H), 3.82 (s, 3H), 3.65-3.62 (t, J=4.2 Hz, 1H), 3.33-3.29 (m, 5H), 2.15 (s, 3H), 2.04-2.01 (t, J=5.2 Hz, 4H), 1.82-1.81 (d, J=5.2 Hz, 1H). MS (ES, m/z): 699 [M+H]+.
Reaction SMILES: [C:1]1([N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=2[OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Cl>C(OCC)C>[C:1]1([N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=2[O:21][CH:40]2[O:41][CH:39]2[CH3:37])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CC)c1ccc(C=NN(c2ccccc2)c2ccccc2)c(O)c1
Reactant: ClCC1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Product: CCN(CC)c1ccc(C=NN(c2ccccc2)c2ccccc2)c(OC2OC2C)c1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A mixture of the 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone (10.0 g, 27.82 mmol, prepared as described above), 85% powdered potassium hydroxide (3.7 g, 0.05 mol), and anhydrous sodium sulfate (1.4 g, 11.13 mmol) in 35 ml of epichlorohydrin (commercially obtained from Aldrich, Milwaukee, Wis.) was stirred vigorously at 30–35° C. until the 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone disappeared (2.5 hours, as determined by thin layer chromatography (TLC)). After termination of the reaction by cooling the mixture to room temperature, the mixture was diluted with diethyl ether, and washed with copious amounts of water until the washed water reached a pH value of 7. The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. The diethyl ether and unreacted epichlorohydrin were removed by evaporation under a vacuum. The crystals formed upon standing at room temperature were filtered off and washed with 2-propanol to give 9.0 g (77.6%) of the desired compound. The melting point was found to be 86–87° C. (recrystallized from 10:1 v/v of 2-propanol:ether mixture). The 1H NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 8.0 (d, 1H, 6-H of 1,2,4-subst. Ph); 7.8–7.0 (m, 11H, CH═N, Ph); 6.45 (d, 1H, 5-H of 1,2,4-subst. Ph); 6.1 (s, 1H, 3-H of 1,2,4-subst. Ph); 4.35–3.75 (m, 2H, OCH2); 3.35 (q, 4H, CH2); 3.05 (p, 1H, CH); 3.65 (t, 1H, one of CH2 of oxirane); 2.45 (dd, 1H, one of CH2 of oxirane); 1.15 (t, 6H, CH3). Elemental analysis yielded the following values in weight percent C, 74.95; H, 6.88; and N, 9.92; which compared with calculated values for C26H29N3O2 in weight percent of C, 75.15; H, 7.03; and N, 10.11.