Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([N:22]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O.NN.C(Cl)Cl>C(Cl)Cl.C(O)C>[CH:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)s3)s2)cc1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N)s3)s2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
A solution of Example 24F (0.48 g, 0.98 mmol) in CH2Cl2/ethanol (1:1, v/v, 12 mL) was treated with hydrazine hydrate (0.476 mL, 9.79 mmol). The reaction was stirred at 25° C. for 5 hours and was concentrated under reduced pressure on a rotary evaporator to provide a residual oil. The concentrate was treated with CH2Cl2 (15 mL) and a white suspension formed. The suspension was filtered and the filtrate was concentrated on a rotary evaporator to provide 0.32 g of a pale yellow oil. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 98:1:1 to 97:2:1 CH2Cl2/CH3OH/NH4OH to provide 0.09 g (25%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.46 (d, J=3.68 Hz, 1H) 7.38 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.96 (dd, J=3.68, 0.74 Hz, 1H) 4.63 (heptet, J=5.88 Hz, 1H) 4.17-4.29 (m, 1H) 1.35 (d, J=6.62 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (APCI) m/z 362 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:26][CH2:27][NH2:28])=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:25][CH2:26][CH2:27][NH:28][C:9](=[O:11])[C@@H:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:20][CH:19]=1
Reactant: CC(C)C[C@H](NC1CCCCC1)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC1CCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (108 mg, 0.51 mmol) and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (151 mg, 0.51 mmol) in dry DMF (4 mL) was treated with Triton® B (0.92 mL, 2.0 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.), then sonicated for a few seconds, a clear solution was obtained. The clear solution was concentrated in vacuo to remove most of the methanol, then cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.19 g, 0.51 mmol) was then added. After stirring at 0° C. for 20 minutes the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (60% EtOAc in hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 150 mg (60%) of the pure titled compound as a white foam; mp 75-85° C. APCI-MS m/z 457.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)OCC(C)(C)O3)cc1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (69 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then was evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 112 as a white solid (40 mg, 59%). LCMS: RT=2.73 min, [M+H]+=344. 1H NMR (400 MHz, CDCl3): δ 8.28 (2H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.22 (1H, broad s), 3.90 (2H, s), 3.87-3.78 (8H, m), 2.19 (3H, s), 1.46 (6H, s)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=O)[CH:6]=[CH:7][CH:8]=1.Cl.CSC1C=C(N)C=CC=1.C1(S)C=CC=CC=1>C(O)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:6]([CH:12]=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[N:9]2)=[CH:7][CH:8]=1
Reactant: CSc1cccc(NC=C(C=O)[N+](=O)[O-])c1
Agent: CSc1cccc(N)c1
Agent: Cl
Agent: Sc1ccccc1
Solvent: CC(=O)O
Product: CSc1ccc2cc([N+](=O)[O-])cnc2c1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
To a refluxing mixture of 3-[(3-methylthiophenyl)amino]-2-nitroprop-2-enal (2.3 g, 9.6 mmol) and the HCl salt of 3-methylthiophenylamine (2.7 g, 19.3 mmol) in acetic acid (25 mL) was added thiophenol (0.2 g, 1.9 mmol). After being refluxed for 18 h, the mixture was cooled to room temperature and the acetic acid was removed under reduced pressure. To the remaining dark colored solid EtOAc (50 mL) was added with stirring. Filtration gave a yellow/green solid and a dark filtrate. The product crystallized from the EtOAc solution upon standing. Filtration and rinsing with cold EtOAc gave 330 mg crystalline product. The yellow/green solid was washed with 3×250 mL portions of dichloromethane. The dichloromethane washes were concentrated to give an additional 150 mg of product (23%). LC/MS (m/z): 221.1 (MH+), Rt 2.54 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH:25]=O)[CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][CH2:25][CH2:24][CH2:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:11]1
Reactant: O=CCCc1cccnc1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc(CN2CCC(NCCCc3cccnc3)CC2)cc1Cl
Yield: 25.6 %

Procedure:
The title compound was prepared from 1-(3,4-dichlorobenzyl)piperidine-4-amine (free base 187 mg), 3-(3-pyridinyl)propanal (125 mg), sodium triacetoxyborohydride (70 mg), and 0.02 ml acetic acid, stirred together for 2 hrs in dichloromethane (10 ml). Water was added, the mixture neutralised with sodium bicarbonate and the organic phase separated, dried and chromatographed on silica with ethyl acetate/methanol (9:1) as eluant, to give the title compound (70 mg) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I:15]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[I:15][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: COc1ccc(NC(C)=O)cc1OC
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(I)c(NC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of N-(3,4-dimethoxyphenyl)acetamide (6.3 g, 32.0 mmol) in DCM (100 mL) and AcOH (6.5 mL) was added a solution of iodine monochloride (6.3 g, 39 mmol) in DCM (50 mL) dropwise. The reaction mixture was stirred at r.t. for 16 h. Aqueous sat. Na2S2O3 (500 mL) was added. The organic fraction was separated, washed with water (2×250 mL), then brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 50% EtOAc/hexanes) gave the title compound (7.5 g, 72%) as a dark solid. LCMS (ES+) 321.8 (M+H)+, RT 2.67 minutes (Method 4).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:31])[CH:6]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH2:18][OH:19])=[CH:9][C:8]=1[F:20])[CH3:3].CN(C=O)C.C(N(CC)CC)C.[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH2:2]([O:4][C:5](=[O:31])[CH:6]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[N:30][C:51](=[O:52])[NH:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH2:18][OH:19])=[CH:9][C:8]=1[F:20])[CH3:3]
Reactant: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(OCC)c(OCCO)cc1F
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C(N)=NC(=O)Nc2ccccc2)cc1)c1cc(OCC)c(OCCO)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
The (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester hydrochloride (456 mg) described in example 1.6 was dissolved in THF (3 ml). DMF (3 ml), triethylamine (106 mg) and phenylisocyanate (131 mg) were added and the mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated and purified by column chromatography (hexane/ethyl acetate) to give 380 mg of (RS)-[4-(Amino-phenylcarbamoylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester as a colorless foam. MS: 539 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:19]=[C:18]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=3[O:25][CH3:26])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]1[CH:29]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[C:32]([F:34])[CH:33]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:12][C:11]([NH:13][C:14]4[CH:19]=[C:18]([S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:17]=[CH:16][C:15]=4[O:25][CH3:26])=[N:10][CH:9]=3)[CH:3]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(F)cc(F)c1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Br)c3)o2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(-c4cc(F)cc(F)c4)c3)o2)c1
Temperature: 100 °C
Yield: 63 %

Procedure:
In a pyrex sealed tube, a mixture of the title compound of Example 100 (123 mg, 0.28 mmol), 3,5-difluoro(tributylstannyl)benzene (400 mg, 1 mmol), tetrabutylammonium chloride (170 mg, 0.61 mmol), and tetrakistriphenylphosphine palladium(0) (20 mg, 0.017 mmol) was suspended in dry acetonitrile (10 mL) and stirred at 100° C. After the reaction was determine to be complete by TLC analysis, the reaction was cooled and diluted with ethyl acetate (50 mL), quenched with 1M aqueous potassium fluoride solution (20 mL), and stirred for 3 h. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (1:1) to afford the title compound (83 mg, 63%) as a solid white powder. 1H NMR (400 MHz, d6-DMSO): δ 9.72 (s, 1H), 8.74 (d, J=2.2, 1H), 7.91 (s, 1H), 7.60–7.64 (m, 3H), 7.42–7.53 (m, 4H), 7.23 (d, J=8.6, 1H), 3.94 (s, 3H), 3.16 (q, J=7.3, 2H), 1.07 (t, J=7.3, 3H). MS (ES+, m/z)=471 (m+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][NH2:41]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([NH:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)CCCN
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(NCCCN(C)C)ccc1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in Example 15, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with 3-dimethylaminopropylamine to give the title compound; NMR Spectrum: (DMSOd6) 1.6-1.72 (m, 2H), 2.12 (s, 6H), 2.22-2.28 (m, 5H), 3.2-3.25 (m, 2H), 3.5-3.54 (m, 4H), 3.69-3.73 (m, 4H), 6.65-6.68 (m, 2H), 7.04 (d, 1H), 7.2 (d, 1H), 7.25 (d, 1H), 7.29 (t, 1H), 7.68 (d, 1H), 8.84 (s, 1H), 8.0 (d, 1H), 8.26 (d, 1H), 9.82 (s, 1H), 10.34 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[C:17]([CH3:20])(C)C)[CH:3]=1.Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][NH2:31])=[CH:26][CH:25]=1.[CH3:32]C([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])=[C:4]([C:16](=[N:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:17][CH2:20][CH3:32])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: NOc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCC(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 10.1 %

Procedure:
A solution of N-[4-chloro-2-(2,2-dimethylpropionyl)phenyl]trifluoromethanesulfonamide 29C (300 mg, 0.87 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (173 mg, 0.96 mmol) and anhydrous NaOAc (80 mg, 0.96 mmol) in EtOH (20 mL) was stirred for 40 hours at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:7) and the solvent removed under reduced pressure. The residue was purified by recrystallization from CH2Cl2/PE to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)butyl]phenyl}trifluoromethanesulfonamide 182 (40 mg, 10%), as a yellow solid. M.p. 69-70° C. 1H n.m.r. (200 MHz, CDCl3) δ 7.52, d, J=8.8 Hz, 1H, 7.43, dd, J=2.2 and 8.8 Hz, 1H, 7.25, d, J=9.2 Hz, 2H, 7.18, d, J=2.2 Hz, 1H, 7.01, d, J=9.2 Hz, 2H, 6.43, br s, 1H, 1.33, s, 9H.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:17].[OH-].[Na+].[OH-].[K+]>O=P(Cl)(Cl)Cl>[C:1]([C:4]1[CH:13]=[C:12]([Cl:17])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2]
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)cc(C(=O)O)nc2c1
Temperature: 130 °C
Yield: 49.2 %

Procedure:
To 20 mL POCl3 was added 2-carboxy-7-methyl-4-hydroxyquinoline (2.5 g, 12.3 mmol) and PCl5 (11.5 g, 55 mmol). The mixture was heated to 130° C. for 3 hours. The reaction mixture was cooled and poured onto ice. The solution was neutralized with solid NaOH and adjusted to pH 11 with solid KOH. The tan precipitate was filtered, slurried in 250 mL water and adjusted to pH 2 with concentrated HCl. The resultant solid was filtered and dried to afford 2-carboxy-7-methyl-4-chloroquinoline (1.34 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.[CH:11]1([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2/[CH:25]=[CH:26]/[CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C.C(OCC)(=O)C>[CH:11]1([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2/[CH:25]=[CH:26]/[CH:27]2[CH2:32][CH2:31][N:30]([CH2:9][C:4]3[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=3)[CH2:29][CH2:28]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1nccnc1C=O
Reactant: C(=C/C1CCNCC1)\c1ccccc1OCC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1nccnc1CN1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
After dissolving 131 mg of 3-methoxypyrazine-2-carboxaldehyde and 236 mg of (E)-4-[2-[2-(cyclohexylmethyloxy)phenyl]vinyl]piperidine in 3 ml of 1,2-dichloroethane, 0.07 ml of acetic acid and 276 mg of sodium triacetoxyborohydride were added and the mixture was stirred overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (255 mg, 77% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](Cl)(Cl)Cl)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1.C([O-])(O)=[O:33].[Na+].O>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:33])[NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][C:26]4=[O:31])=[CH:23][CH:24]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc2[nH]c(C(Cl)(Cl)Cl)nc12
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(N4CCOCC4=O)cc3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 69.4 mg (0.236 mmol) methyl-2-trichloromethyl-1H-benzoimidazole-4-carboxylate in 2 mL THF were slowly added to a mixture containing 50 mg (0.26 mmol) 4-(4-amino-phenyl)-morpholin-3-one, 220 mg (2.62 mmol) NaHCO3, 8 mL THF and 3 mL H2O. The mixture was stirred vigorously for 3 h at room temperature, diluted with 50 mL CH2Cl2 and washed with 30 mL of a saturated NaHCO3-solution. The aqueous solution was extracted with 50 mL CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give a brown solid, which was pure enough for the following reactions.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([CH2:21][OH:22])[O:12]3)[N:9]=[CH:10][C:3]=12.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:22][CH2:21][C@@H:13]1[C@H:14]2[O:18][C:17]([CH3:19])([CH3:20])[O:16][C@H:15]2[C@H:11]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH:1][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:3]3[CH:10]=[N:9]2)[O:12]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ncc2c(N)ncnc21
Reactant: O=C(Cl)c1ccccc1
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ncc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
Compound 22.2 (4.20 g, 13.66 mmol) in pyrdine (40 mL, 0.33 M) was cooled to 0° C. and treated with benzoyl chloride (12.68 mL, 109.3 mmol) The mixture was warmed to room temperature and stirred for 16 h. The solvent was removed in vacuo and the residue was treated with 2.5 N KOH (40 mL) in pyridine (40 mL) and stirred for 20 min. The mixture was cooled to 0° C. and AcOH was added (6 mL). The solvent was removed in vacuo and the residue was dissolved in EtOAc (150 mL) and washed with H2O (100 mL), saturated NaHCO3 (2×100 mL), and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford compound 22.3 (2.74 g, 49% yield) as a white solid: 1H NMR (CDCl3, 300 MHz) 9.02 (br s, 1H), 8.80 (s, 1H), 8.55 (s, 1H), 7.97 (d, J=7.5 Hz, 2H), 7.62 (app t, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 2H), 6.65 (s, 1H), 5.25 (m, 1H), 5.07 (d, J=6.0 Hz, 1H), 4.99 (br s, 1H), 4.53 (m, 1H), 3.91 (m, 1H), 3.77 (m, 1H), 1.61 (s, 3H), 1.35 (s, 3H); MS (ESI) m/z 412 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)CCC([O-])=O.C([O-])(O)=O.[Na+].[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O>[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47]([NH:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: Cc1cccc(C)c1OCC(=O)Cl
Agent: O=C([O-])CCC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane×0.5 succinate (111.9 g, 0.25 mol) was charged to a 2L, 3-necked round-bottomed flask with mechanical stirring. NaHCO3 (106 g, 1.26 mol), 600 ml H2Q and 600 ml EtOAc were added and stirred vigorously until all solids were dissolved (15 minutes). Stirring was slowed and a solution of the 2,6-dimethyl-phenoxyacetyl chloride and EtOAc (100 ml) was added in a narrow stream via addition funnel. After 30 min of stirring, starting materials were consumed (HPLC analysis) and the layers were separated. The aqueous layer was extracted With EtOAc, the organic layers were combined and washed with 200 ml of 1 M NaOH, 200 ml of 10% HCl, 200 ml of brine, dried over MgSO4 filtered and concentrated to provide the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].C1C=CC2N=CNC(=O)C=2C=1.[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][N:7]1[C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8]1
Reactant: ClCCCCI
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cnc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(CCCCCl)c(=O)c2cc1OC

Procedure:
3-(4-chlorobutyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared starting from 6,7-dimethoxy-4(3H)-quinazolinone (1.65 g, 8 mmol). The quinazolinone was combined with 1-chloro-4-iodobutane (1.08 mL, 8.8 mmol), an excess of potassium carbonate (10 g) and stirred in 30 mL DMF overnight. The salts were filtered off and the reaction mixture was diluted with water. The solid that formed was collected via vacuum filtration, washed with water and dried, 1.55 g (65%); gray solid; m.p. 117° C., MS: 296.8 (M+H)+