Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[NH:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2.Cl.N1C=CC=CC=1>O.C([O-])(O)=O.[Na+]>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[N:30]=[C:29]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[NH:28][N:27]=5)[CH2:22][CH2:21]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:3](=[O:2])[C:4]=3[CH:5]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1nccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 5-methoxy-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridine (725 mg, 1.31 mmol) and pyridine hydrochloride (6.9 gm, ˜60 mmol) was heated at 150° C. for ten minutes. The cooled residue was dissolved in the minimum amount of water and neutralized with aqueous NaHCO3. The precipitated solid was collected by filtration and purified by column chromatography on silica gel eluting with 1-14% methanol/ethyl acetate (sat'd NH4OH). The isolated product was digested in methanol/acetonitrile to give pure product. 1H NMR (500 MHz, DMSO-d6): 11.58 (1H, d, J=4.8 Hz), 8.68 (1H, br s), 8.39 (1H, s), 8.03 (1H, d, J=7.3 Hz), 7.50 (2H, t, J=6.5 Hz), 7.31-7-33 (5H, m), 7.24-7.25 (4H, m), 6.79 (2H, d, J=7.3 Hz), 3.50 (2H, s), 2.84 (2H, br d, J=10.5 Hz), 2.72 (1H, m), 2.08 (2H, br t, J=1 Hz), 1.95 (2H, br d, J=11.6 Hz), 1.77 (2H, m). m/e (m+1): 540.3, 270.9 [(m+2)/2].
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31]([CH2:32][C:33]2([NH2:36])[CH2:35][CH2:34]2)=[CH:30][CH:29]=1.FC(F)(F)C([O-])=O>>[OH:25][CH:19]([C:16]1[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=1)[CH2:20][NH:36][C:33]1([CH2:32][C:31]2[CH:37]=[CH:38][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH2:35][CH2:34]1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: COc1ccc(CC2(N)CC2)cc1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(CC2(NCC(O)c3ccc(O)c(CO)c3)CC2)cc1

Procedure:
Prepared according to general method 5 from 344 mg (1 mmol) methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 177 mg (1 mmol) 1-(4-methoxy-benzyl)-cyclopropylamine. Yield: 123 mg (27%, trifluoroacetate); mass spectroscopy: [M+H]+=344.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([CH2:29][CH2:30][CH:31](O)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])#[N:28]>>[NH2:28][CH2:27][CH2:29][CH2:30][CH:31]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CCCC(O)CCC#N
Reactant: Oc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)CCCC(CCCN)Oc1cccnc1

Procedure:
Hex-5-enoic acid is first converted to the corresponding epoxide with e.g. m-chloroperbenzoic acid and esterified with diazomethane to the methyl ester which is then condensed with acetonitrile in the presence of lithium diisopropylamide (LDA) to yield methyl 7-cyano-5-hydroxy-heptanoate. Condensation with 3-hydroxypyridine in the presence of triphenylphosphine and reduction of the nitrile yields methyl 8-amino-5-(3-pyridyloxy)-octanoate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.C[Mg]Br.[CH2:15]1COC[CH2:16]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: C1CCOC1
Agent: C[Mg]Br
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 Methyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0° C. and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 2 N HCl and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).
Reaction SMILES: [CH2:1]([N:4]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:7]2[CH:22]=[C:23](Br)[S:24][C:6]=2[C:5]1=[O:26])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:75]1[CH2:80][CH2:79][O:78][CH2:77][CH2:76]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:1]([N:4]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:7]2[CH:22]=[C:23]([N:75]3[CH2:80][CH2:79][O:78][CH2:77][CH2:76]3)[S:24][C:6]=2[C:5]1=[O:26])[CH:2]=[CH2:3]
Reactant: C1COCCN1
Reactant: C=CCN1C(=O)c2sc(Br)cc2C(c2ccc(Cl)c(Cl)c2)C1C(=O)OC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=CCN1C(=O)c2sc(N3CCOCC3)cc2C(c2ccc(Cl)c(Cl)c2)C1C(=O)OC
Temperature: 100 °C
Yield: 63.6 %

Procedure:
A mixture of methyl 6-allyl-2-bromo-4-(3,4-dichlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (0.63 g, 1.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (64.7 mg, 0.0706 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (80.7 mg, 0.139 mmol) and cesium carbonate (1.30 g, 3.98 mmol) was evacuated and filled with argon, followed by addition of 1,4-dioxane (37 mL) and morpholine (0.347 mL, 3.98 mmol). The mixture was heated in a sealed microwave tube at 100° C. for 10 h. The mixture was dry loaded on silica gel and purified by chromatography to afford the product as a white solid (0.398 g, 62%). LCMS: (AA) ES+: 481, 483, 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=8.3 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.3, 2.1 Hz, 1H), 5.71 (s, 1H), 5.36-5.22 (m, 1H), 5.00-4.90 (m, 2H), 4.78 (dd, J=15.2, 4.9 Hz, 1H), 4.55 (s, 1H), 4.12 (t, J=3.0 Hz, 1H), 3.85-3.77 (m, 4H), 3.73 (d, J=8.0 Hz, 3H), 3.42-3.31 (m, 1H), 3.18 (dd, J=12.0, 7.1 Hz, 4H).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15](=[O:18])[CH2:16]Br)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[C:10]([O:14][C:15](=[O:18])[CH2:16][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: NCc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
A mixture of 4-iodobenzylamine (5.0 g, 21.5 mmol), tert-butylbromoacetate (4.19 g, 21.5 mmol), potassium carbonate (3.55 g, 21.5 mmol) in 40 mL of 1:1 toluene/water was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate (100 mL×3) and the combined organic phase was washed with brine, dried over sodium sulfate, and evaporated to give an oil. Chromatography on silica gel gave 2.3 g (31%) of N-(4-iodobenzyl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16](=[O:48])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][C:28]2[C:33]([NH:34]C(OC(C)(C)C)=O)=[CH:32][CH:31]=[C:30]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:29]=2)=[O:26])=[CH:21][CH:20]=1>ClCCl>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16](=[O:48])[NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][C:28]2[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:29]=2)=[O:26])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 mL, 12.98 mmol) was added to a flask containing pyridin-2-ylmethyl{4-[({3-[(tert-butoxycarbonyl)amino]-6-phenylpyridin-2-yl}amino)carbonyl]benzyl}carbamate (100 mg, 0.181 mmol) in dichloromethane (2 ml) and the mixture stirred at room temperature for 1 hour. The reaction was quenched by the addition of saturated sodium bicarbonate until bubbling stopped. The aqueous layer was extracted (3×) with EtOAc and dried over sodium sulfate. The organic product was purified using HPLC. LCMS of the major UV absorbant fraction indicated the presence of the desired product. 1H NMR (DMSO-d6) δ: 10.36 (s, 1H), 8.51 (d, J=4 Hz, 1H), 7.96-8.05 (m, 3H), 7.88-7.94 (m, 2H), 7.76-7.82 (m, 1H), 7.65 (d, J=8.3 Hz 1H), 7.32-7.45 (m, 5H), 7.18-7.32 (m, 3H), 5.12 (s, 2H), 5.09 (s, 2H), 4.28 (d, J=6.2 Hz, 2H) MS: cal'd 454 (MH+), exp 454 (MH+). The in vitro HDAC1 IC50 of this compound is 35 nM. The IC50 of this compound in HCT-116 cells is 560 nM. Percent Cyp inhibitions at 10 μM are 27, 47 and 24%, for Cyp3A4, 2C9, and 2D6, respectively. The inflection point for MK-499 binding is 2535 μM.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:27]1([CH2:33][CH2:34][CH2:35]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)(=O)C>CN(C=O)C.CCCCCC>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:35][CH2:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCCCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
To a solution of [3-(4-hydroxy-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (38 mg, 0.137 mmol) in DMF (1 mL) was added K2CO3 (20 mg, 0.145 mmol) and 3-phenyl-1-bromopropane (20 μL, 0.132 mmol). After stirring for 1 h at rt and 14 h at 50° C., the reaction mixture was cooled stirred for 6 h at rt. The reaction mixture was loaded directly onto silica gel. {3-[4-(3-Phenyl-propoxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester was isolated as a white solid by column chromatography (10% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2.CC1C=C2[C:27](=C([N+]([O-])=O)C=1)[NH:26][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=CC=1)=C2>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:38]3[CH2:33][CH2:25][N:26]([CH3:27])[CH2:36][CH2:37]3)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2
Reactant: Cc1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Reactant: O=[N+]([O-])c1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Product: CN1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1
Yield: 69 %

Procedure:
5-Chloro-7-nitro-2-phenyl-1H-indole (337 mg, 1.23 mmol) was reacted instead of 5-methyl-7-nitro-2-phenyl-1H-indole in Preparation 50 to give the title compound 288 mg (Yield 69%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[NH:21][C:20]1[CH:22]=[CH:23][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Nc2cc(Cl)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,5-dinitrobenzene (II-1, 0.5 g, 2.11 mmol) and p-methoxyaniline (III-2, 0.2 g, 2.11 mmol) were dissolved in 5 mL DMSO. To the solution were added K2CO3 (0.58 g, 4.22 mmol) and metal Cu in catalytic amount. The mixture was allowed to react at 115° C. for 2 hours with stirring in an atmosphere of nitrogen. The resultant was poured into ice water, stirred to precipitate a solid. The solid was filtered, washed with water several times, dried, and separated on silica gel column (petroleum ether/ethyl acetate) to obtain a bronzing solid (IV-2, 0.68 g, 67%). 1H NMR (CDCl3) δ ppm 3.88 (3H, s, OCH3), 7.02 (1H, s, ArH-6), 7.03 (2H, d, J=8.96 Hz, ArH-3′, 5′), 7.21 (2H, d, J=8.96 Hz, ArH-2′, 6′), 9.07 (1H, s, ArH-3), 9.73 (1H, s, NH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[CH:3]=1.[CH3:13][N:14]=[C:15]=[O:16]>CN(C)C=O.C(N(CC)CC)C>[CH3:13][NH:14][C:15](=[O:16])[O:8][C:6]1[CH:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1

Procedure:
A solution was prepared by dissolving 7.4 g (0.03 m) of 6-chloro-4-(trichloromethyl)-2-pyridinol in 45 ml of dry dimethylformamide. To this solution was added 1.71 g (0.03 m) of methyl isocyanate and 7 drops of triethylamine. The mixture was allowed to stand, at room temperature, for ~30 hours. The reaction mixture was then poured over ice and the resulting solids were filtered out and taken up in hexane. The above-named product was recrystallized from the hexane and recovered in a yield of 3.8 g. The product melted at 95.5°-99.5° C. The structure of the compound was confirmed by its IR spectrum. Upon analysis, the product was found to have carbon, hydrogen, nitrogen and chlorine contents of 31.90, 2.10, 9.10 and 46.26 percent, respectively, as compared with the theoretical contents of 31.50, 1.99, 9.22 and 46.50 percent, respectively, as calculated for the above-named compound (Compound 2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32]([N:34]([CH:41]([CH3:43])[CH3:42])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:33])[C:12]2=[O:44])=[CH:2]1.C([O-])=O.[NH4+]>[Pd].CCO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32]([N:34]([CH:41]([CH3:42])[CH3:43])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:33])[C:12]2=[O:44])=[CH:2]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 80 °C
Yield: 18.4 %

Procedure:
To 10% Pd/C and EtOH was added 2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (0.71 g, 1.2 mmol). An additional 25 mL of EtOH was added followed by ammonium formate (0.77 g, 12.2 mmol). The reaction mixture was heated to 80° C. for 6 hours. The catalyst was removed by filtration through Celite® and the filtrate was concentrated. The residue was dissolved in ethyl acetate and the organic solution was washed with saturated NaHCO3. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by chromatography (0% to 18% acetone/methylene chloride) to give 128 mg of 2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a racemic mixture. 1H NMR (CD2Cl2) δ 8.18 (s, 1H), 7.64 (dd, 2H), 7.55 (dd, 1H), 7.510-7.41 (m, 8H), 7.36 (dd, 1H), 7.25 (m, 3H), 7.09 (m, 2H), 7.027 (m, 1H), 6.85 (dd, 1H), 4.86 (m, 1H), 4.40 (br d, 1H), 4.04 (dd, 1H), 3.79 (m, 3H), 1.03 (dd, 6H); MS 581.4 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:28][OH:29])[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>CO>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2([CH2:28][OH:29])[CH2:26][CH2:25][C:24](=[CH:7][C:5]([O:4][CH3:3])=[O:6])[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=C1CCC(CO)(c2ccc(Br)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=C1CCC(CO)(c2ccc(Br)cc2)CC1
Yield: 86.3 %

Procedure:
To a round bottom flask containing methanol (60 ml) was added sodium hydride (0.78 g, 19.37 mmol) portion-wise at room temperature under stirring, Trimethyl phosphonoacetate (2.58 ml, 17.88 mmol) was added drop-wise and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture was then added 4-(4-bromophenyl)-4-(hydroxymethyl)cyclohexanone (4.22 g, 14.90 mmol) in several portions and stirred at room temperature for overnight. The reaction mixture was then quenched with a saturated solution of ammonium chloride and subsequently concentrated to remove excess methanol. The residue was taken in saturated ammonium chloride solution and extracted twice with EtOAc. The combined organic portion was dried over sodium sulfate and concentrated to afford a crude product. Column purification afforded the title compound as viscous oil (4.36 g, 86% yield). LC/MS, ESI-MS: non-ionizable, RT: 1.32 (Condition E).
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].CN(C)[CH:42]=[O:43]>C(OC(C)C)(=O)C>[CH2:9]([O:10][C:42](=[O:43])[CH2:3][CH2:2][CH2:34][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])[CH3:8]
Reactant: CN(C)C=O
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Solvent: CC(=O)OC(C)C
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 55 °C
Yield: 75 %

Procedure:
To a reactor was charged a solution of 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e in isopropyl acetate (19.0 kg in 59.6 L solution). Dimethylformamide (18 L) was charged and the mixture was distilled under vacuum to remove the isopropyl acetate. Ethyl-4-bromobutyrate (7.83 kg) was charged to the reactor followed by diisopropylethylamine (5.87 kg). The reactor contents were heated to 55° C. and stirred until completion of reaction. The reactor was cooled to 20° C. and isopropyl acetate (110 L) and water (96 L) were added. The mixture was agitated and the layers allowed to settle. The water layer was removed and the organic layer was washed with water (95 L). The organic layer was treated with a solution of 85% phosphoric acid/H2O (10.4 kg/152 L). The mixture was agitated, allowed to settle, and the layers were separated. The organic layer was treated with a solution of 85% phosphoric acid/H2O (2.7 kg/19 L). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous phosphate layers were combined and washed with isopropyl acetate (21 L). After layer separation, dichloromethane (109 L) was added to the aqueous layer, followed by slow addition of a solution of potassium carbonate/water (23.2 kg/29 L) while mixing. The layers were separated and the organic layer was concentrated by vacuum distillation. The solution was passed through a silica gel plug pre-conditioned with CH2Cl2 and the plug eluted using EtOH/CH2Cl2 (5 L/469 L). Appropriate portions were combined and the solution was concentrated by vacuum distillation. Ethanol (80 L) was charged to provide a concentrated stock solution of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid ethyl ester 4a (82.9 kg total, ˜17.3 kg of 4a, 75% yield) that was used in the next step. LCMS (ESI) m/z 660.2 (MH+)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:25])[C:9]1=[O:26])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][CH:35]=1>CN(C=O)C.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:25])[C:9]1=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(Cl)c3)cc2n(C)c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1c(=O)c2c(cc(-c3cccc(Cl)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 85 °C
Yield: 50 %

Procedure:
To a mixture of 3-(6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (60 mg, 0.16 mmol), K2CO3 (110 mg, 0.80 mmol) in DMF (2 ml) was added 1-chloro-4-(chloromethyl)benzene (51 mg, 0.32 mmol). The reaction was heated at 85° C. for 2 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (40 mg, 50% yield) as an oil. LCMS: MH+ 500 and TR=1.847 min. Used without further purification.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1nc(N)c2nc(CN3CCN(Cc4cccc(C(F)(F)F)c4)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added m-trifluoromethylbenzyl bromide (0.021 mL; 0.14 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 13 mg of yellow colored 3-[4-(3-Trifluoromethyl-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.