Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][C:5]=1[CH3:15].C[C:17](C)([O-:19])C.[K+].C(S)CC.[C:26](O)(=[O:28])C>CN(C=O)C>[OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:26]([O:19][CH3:17])=[O:28])[C:7]=2[O:6][C:5]=1[CH3:15]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)O
Reactant: COc1cccc2c(CCO)c(C)oc12
Agent: CCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c(CCO)c(C)oc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
3-(2-hydroxyethyl)-7-methoxy-2-methylbenzofuran (2.34 g) was dissolved in DMF (60 ml) and potassium t-butoxide (2.71 g) and n-propanethiol (2.2 ml) were added to the solution, followed by stirring the resulting solution at 100° C. for 5 hours. The reaction mixture was cooled to room temperature and acetic acid (3 ml) was added. The reaction solution was concentrated, and poured into water layer (100 ml). The aqueous layer was extracted twice with ethyl acetate (50 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The obtained residue was dissolved in DMF (50 ml), and potassium carbonate (1.66 g ) and methyl bromoacetate (1.7 ml) were added, followed by stirring the resulting solution at room temperature for 17.5 hours. The reaction solution was concentrated and poured into water layer (100 ml), followed by extraction twice with ether (50 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1-1/1) using silica gel to obtain the desired compound (2.29 g, yield: 75%).
Reaction SMILES: [Mg:1].C(O)CCC.[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10]>C(O)(C)C>[F:7][C:8]([F:13])([F:12])[C:9]([O-:11])=[O:10].[Mg+2:1].[F:7][C:8]([F:13])([F:12])[C:9]([O-:11])=[O:10]
Reactant: [Mg]
Reactant: O=C(O)C(F)(F)F
Solvent: CCCCO
Solvent: CC(C)O
Product: O=C([O-])C(F)(F)F
Product: [Mg+2]

Procedure:
A soda lime glass substrate having a diameter of 30 mm and a thickness of 1 mm was ultrasonically cleaned in isopropyl alcohol and was then dried, whereby a glass substrate for coating was prepared. To one mass part of powdery magnesium available from Kishida Chemical Co., Ltd. and 18 mass parts of 1-butanol, 25 mass parts of trifluoroacetic acid (CF3COOH) was gradually added, whereby magnesium was completely dissolved. A solution containing completely dissolved magnesium was filtered and was then vacuum-dried, whereby magnesium trifluoroacetate was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
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: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1nc2c(C)cccc2cc1C=O
Yield: 90.1 %

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline 3-carbaldehyde (0.206 g, 1 mmol), 2-methoxyphenyl boronic acid (0.167 g, 1.1 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.058 g, 0.05 mmol, 0.05 eq), and sodium carbonate (0.530 g, 5 mmol, 5 eq) in acetonitrile (7.5 mL) and water (2.5 mL). After purification, 2-(2-methoxyphenyl)-8-methylquinoline-3-carbaldehyde (0.250 g, 90%) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.86 (1 H, s), 8.88 (1 H, s), 8.13 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=7.1 Hz), 7.56-7.74 (3 H, m), 7.22-7.30 (2 H, m), 3.78 (3 H, s), 2.80 (3 H, s) Mass Spectrum (ESI) m/e=278.0 (M+1)
Reaction SMILES: [SiH:1]([Cl:4])([CH3:3])[CH3:2].[SiH:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].[CH2:12]([Cl:16])[C:13](=[CH2:15])[CH3:14]>>[Si:1]([CH2:14][CH:13]([CH2:12][Cl:16])[CH3:15])([CH3:3])([CH3:2])[Cl:4].[Si:5]([CH2:14][CH:13]([CH2:12][Cl:16])[CH3:15])([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: C=C(C)CCl
Reactant: CC[SiH](CC)CC
Reactant: C[SiH](C)Cl
Product: CC(CCl)C[Si](C)(C)Cl
Product: CC[Si](CC)(CC)CC(C)CCl
Yield: 3.6 %
Yield: 81.1 %

Procedure:
In a 100 ml apparatus, there were combined 7.1 g (0.075 mol) of Me2SiHCl, 8.7 g (0.075 mol) of Et3SiH, and 6.8 g (0.075 mol) of methallyl chloride. Pt catalyst solution (0.01 ml) was added at 32° C., causing an exothermic reaction to 94° C. in 4 min. Distillation of the complete reaction yielded 81.1% Me2SiClCH2CHMeCH2Cl and 3.6% Et3SiCH2CHMeCH2Cl. Et3SiH does promote slightly the reaction of Me2SiHCl with methallyl chloride.
Reaction SMILES: [Zn:1].[Br:2]CCBr.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1>[Br:2][Zn:1][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: [Zn]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[Zn]Br
Temperature: 65 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A 4-L flask fitted with a condenser, temperature probe and mechanical stirrer was charged with Zn metal (180.0 g, 2.76 mol, 30-100 mesh) and THF (1.25 L). While stirring 1,2-dibromoethane (4.74 mL, 0.06 mol) was added via syringe [alternatively, TMS Cl (0.1 eq.) at room temperature for one hour may be substituted]. After inert gas purge (3N2/vacuum cycles) the suspension of zinc in THF was heated to reflux (65° C.) and maintained at this temperature for 1 hour. The mixture was cooled to 50° C. before charging tert-butyl bromoacetate (488 g, 369 mL, 2.5 mol) via 50 mL syringe and syringe pump (delivery set to 4.1 mL/min) over 1.5 hours. Reaction temperature of 50°+/−50° C. was maintained throughout the addition. The reaction mixture was allowed to stir at 50° C. for one hour after the addition was complete. Subsequently, the mixture was allowed to cool to 25° C. and the precipitated product allowed to settle. The THF mother liquor is decanted into a 2-L round bottom flask using a coarse fritted filter stick and partial vacuum transfer (20 mm Hg). This removed about 65% of the THF from the mixture. 1-Methyl-2-pyrrolidinone (NMP, 800 mL) was added and agitation resumed for 5 minutes. The reaction mixture can be filtered to remove any remaining zinc. Analysis indicated a titer of desired Reformatski reagent of 1.57 M with a molar yield of 94%. Alternatively, the solid reagent can be isolated by filtration from the original reaction mixture. The cake was washed with THF until a white solid was obtained and dried under N2 to obtain the desired product as a mono THF solvate that may be stored at −20° C. (desicated) for extended periods. Typical recoveries are 85-90%.
Reaction SMILES: [CH2:1]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([N:7]([CH2:1][C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[O:25])=[CH:19][CH:18]=1
Reactant: CN1CCC(NCc2ccco2)CC1
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)N(Cc2ccco2)C2CCN(C)CC2)cc1

Procedure:
Starting materials: 50ELH66B (0.21 g, 1.08 mmol, 1.0 eq.), 4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[Cl:10][C:11](OC(Cl)(Cl)Cl)=[O:12]>C(#N)C>[ClH:10].[C:11]([Cl:10])(=[O:12])[O:9][C@@H:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O[C@H]1CN2CCC1CC2
Solvent: CC#N
Product: Cl
Product: O=C(Cl)O[C@H]1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 151.9 %

Procedure:
To a stirred solution of (R)-3-quinuclidinol (2.5 g, 19.66 mmol) in acetonitrile (200 mL) was added trichloromethyl chloroformate (3.06 mL, 25.57 mmol) dropwise at 0° C., and the mixture was allowed to stir at 0° C. for 1 hour. The reaction mixture was then stirred at RT for 16 hours, and then the solvent was removed in vacuo to afford the title compound as a white solid (4.39 g, 98%).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1O.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Oc1ccc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Oc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (47.1 g), β-naphthol (28.8 g) and dicyclohexylcarbodiimide (45.4 g) in pyridine (400 ml) was stirred at room temperature for 24 hours. After evaporation of solvent, to the residue was added water (500 ml), and the mixture was acidified with hydrochloric acid. The resulting white crystals were dissolved in methanol (500 ml). After evaporation of methanol, the residue was recrystallized from methanol to give β-naphtyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride (49.1 g, 67.8%), m.p. 195°-202° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(OCC)(=O)C>CC(C)=O.O.[Cl-].[Na+].O>[C:22]([NH:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:7]([F:15])[CH:6]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: Nc1cc(F)c(N2CCOCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(F)c(N2CCOCC2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 0.518 g of 3,5-difluoro-4-morpholinyl-aniline and 0.432 g of sodium bicarbonate in 20 mL of acetone:water (2:1 v/v) at 0° C. was added 0.36 mL of benzyl chloroformate over 2 minutes. After 5.5 hours, the mixture was allowed to warm to ambient temperature and after an additional 2.6 hours, the mixture was added to 25 mL of ethyl acetate and 20 mL of brine. The aqueous layer was extracted with 3×25 ml of ethyl acetate and the combined organic layers were dried (MgSO4), and concentrated in vacuo to give a solid, mp=131°-133° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:2]([CH2:19][C:16]2[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][CH:17]=2)([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(Br)cc1)(Cc1ccc(Br)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Ethyl acetoacetate (0.632 mL, 5 mmol) was added to a solution containing NaH (0.493 g, 11.25 mmol) in DMF (5 mL), and the resulting mixture was stirred at 0° C. for 30 minutes. 1-bromo-4-(bromomethyl)benzene (2.788 g, 11.15 mmol) was added to the mixed liquid, and the resulting mixture was stirred at room temperature for 12 hours. The mixed liquid was then poured into a saturated aqueous solution of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried using MgSO4, and then concentrated under reduced pressure, yielding the title compound (4k) in a yield of 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([NH:34][NH2:35])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:35][NH:34][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:33])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NNC(=O)c1ccccc1
Product: O=C(NNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O)c1ccccc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and benzohydrazide employing methods similar to those described in Example 9 and was obtained as a light yellow solid: 1H NMR (d6-DMSO) δ 12.08 (1H, br s), 11.83 (1H, br s), 11.05 (1H, br s), 8.55 (1H, br s), 7.91-7.89 (2H, m), 7.60-7.49 (4H, m), 7.34-7.30 (2H, m), 7.16-7.13 (2H, m), 4.14 (2H, m); HRMS calcd for C23H17FN4O4+H+: 433.1312. Found 433.1311.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([S:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)=[CH:29][CH:28]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: Nc1ccc(Sc2ccccn2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)cc3)c(C#N)cnc2cc1F
Yield: 77 %

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 542.1 mg (2.81 mmol) of 4-(pyridin-2-ylsulfanyl)phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to provide 830 mg of 7-fluoro-6-methoxy-4-[4-(pyridin-2-ylsulfanyl)-phenylamino]quinoline-3-carbonitrile as an off-white solid, mp 231-233° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12
Reactant: c1nc[nH]n1
Product: Cc1csc2nc(-n3cncn3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[C:4]([OH:22])[N:3]=1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.Cl.[NH2:48][C@H:49]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>CN1CCCC1=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:48][C@H:49]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:19])=[CH:20][CH:21]=2)=[C:4]([OH:22])[N:3]=1
Reactant: Nc1nc(N)c(CCCCc2ccc(C(=O)O)cc2)c(O)n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCCc2c(N)nc(N)nc2O)cc1)C(=O)OCC
Reaction time: 1 h

Procedure:
A mixture of 0.47 g (1.0 eq) of 4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)butyl]benzoic acid, 0.62 g (1.5 eq) of phenyl N-phenylphosphoramidochloridate, 0.79 g (5.0 eq) of N-methylmorpholine, and 50 mL of anhydrous N-methylpyrrolidone is stirred under nitrogen at ambient temperatures for one hour. There is then added 0.75 g (2.0 eq) of diethyl L-glutamate hydrochloride and stirring is continued under nitrogen for 24 hours. The solvent is removed by vacuum distillation and chloroform was added to the residue. The chloroform solution is washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed with 1:9 methanol:chloroform to yield diethyl N-(4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)butyl]benzoyl)-L-glutamate, m.p. 75°-76° C.; IR (KBr) vmax 3320, 2920, 2915, 1845, 1720, 1580, 1529, 1427, 1368, 1326, 1192, 1093, 1021, 849 and 750 cm-1 ; 1H NMR (CDCl3) delta 11.58 (bs, 1 H (3)--NH), 7.68 (d, J=7.9 Hz, 2H, Ar), 7.33 (d, J=7.9 Hz, 1H, NH), 7.17 (d, J=7.9 Hz, 2H, Ar), 5.54 (bs, 2H (2)--NH2), 4.76-4.82 (m, 1H, CH), 4.71 (bs, 2H, (6)--NH2), B 4.23 (q, J=7.11 Hz, 2H, CO2CH2), 4.12 (q, J=6.5 Hz, 2H, CO2CH2), 2.15-2.68 (m, 8H, 2° aliphatic) 1.57-1.66 (m, 2H, 2° aliphatic), 1.35-1.45 (m, 2H, 2° aliphatic), 1.30 (t, J=7.1 Hz, 3H, CH3), 1.22 (t, J=7.1 Hz, 3H, CH3); HRMS calcd for C24H33N5O6 (M+): 487.2430; found: 487.2415; other ions at m/e 348, 313, 285, 195, 167, 139, 97, and 84.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([O:31]C)=[O:30])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([OH:31])=[O:30])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccccc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccccc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylate (92.9 mg, 0.22 mmol, 1.00 equiv) in methanol (15 mL), a solution of sodium hydroxide (44 mg, 1.10 mmol, 5.00 equiv) in water (1.5 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 85 mg (93%) of 2-phenyl-3-(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:27]1C=C(C=C[CH:34]=1)C#N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[CH:34][CH:27]=[C:23]([C:22]#[N:21])[CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Reactant: N#Cc1cccc(Br)c1
Product: Cc1ccc(Nc2cccc(C#N)c2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) in accordance with the general method of example 20 using 3-Bromobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=362.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[O:19]1[CH2:20][CH2:21][C@H:17]([C@:11]2([C:14]([N:35]3[CH2:36][CH2:37][N:32]([C:28]4[CH:27]=[C:26]([C:25]([F:39])([F:24])[F:38])[CH:31]=[CH:30][N:29]=4)[CH2:33][CH2:34]3)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)[CH2:18]1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)O)([C@H]2CCOC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
(1S,3R)-3-[(tert-Butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopentanecarboxylic acid (350.0 mg, 1.169 mmol), 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (391.1 mg, 1.286 mmol), triethylamine (0.652 mL, 4.68 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (665.1 mg, 1.754 mol) (HBTU) were mixed in dry DMF (8.0 mL). After being stirred at room temperature overnight, the reaction mixture was diluted with CH2Cl2 and washed with saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 four times. The combined organic layers were dried (MgSO4), concentrated and purified by flash chromatography (Combi-flash system, 0-50% EtOAc in hexanes, gradient elution, 40 gram column) to provide the desired product (270 mg, 45%). MS calculated for C25H36F3N4O4 (M+H) 513.3; found 513.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4](NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)[N:3]=1.[F:30][C:31]([F:53])([F:52])[CH2:32][O:33][P:34]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[C:45]([O:50][CH3:51])[CH:44]=1)(=[O:41])[O:35][CH2:36][C:37]([F:40])([F:39])[F:38].ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:49][C:46]2[CH:47]=[CH:48][C:43]([CH2:42][P:34](=[O:41])([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])[O:33][CH2:32][C:31]([F:30])([F:52])[F:53])=[CH:44][C:45]=2[O:50][CH3:51])[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1N
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1

Procedure:
This compound was prepared using the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate with Bis(2,2,2-trifluoroethyl) (4-amino-3-methoxybenzyl)phosphonate (Compound 114A) and 2,4-dichloro-5-(trifluoromethyl) pyrimidine. Purified using an ISCO Combiflash system eluting w/20-100% EtOAc in heptane and then MDP (ammonium bicarbonate basic buffer pH9). 1H NMR (DMSO-d6) δ ppm 9.73 (s, 1H), 8.69 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.90 (d, J=7.9 Hz, 1H), 4.67 (quin, J=8.5 Hz, 4H), 3.76 (s, 3H), 3.56 (d, J=22.1 Hz, 2H). MS (ES+): m/z 562.00/564.02 (100/38) [MH+]. HPLC: tR=3.86 min (ZQ3, polar—5 min).