Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:30]1[CH2:31][CH2:32][N:27]([C:22]2[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[N:23]=2)[CH2:28][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)nc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3OCc3ccccc3)CC2)c1
Yield: 51 %

Procedure:
A mixture of 2-benzyloxy-1-chloro-4-nitro-benzene (700 mg, 2.66 mmol), 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (457 mg, 2.39 mmol) and caesium carbonate (2.58 g, 7.97 mmol) in toluene (30 mL) was purged with argon gas. Palladium acetate (24 mg, 0.106 mmol) and 2-(dicyclohexylphosphino)-2′-N,N-dimethylamino)-biphenyl (42 mg, 0.106 mmol) were added. After purging again with argon gas the reaction mixture was heated at reflux for 20 h. The reaction mixture was cooled, filtered and the filter cake was washed with ethyl acetate (30 mL). The combined filtrate and washings were washed successively with water (2×50 mL), brine (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to yield a residue which was purified by flash column chromatography over silica gel (100-200 mesh) using 8-10% ethyl acetate in petroleum ether as eluent to afford 1-(2-benzyloxy-4-nitro-phenyl)-4-(4,6-dimethyl-2-pyridyl)piperazine (510 mg, 46%) as a pale yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C4CCCCO4)=[CH:20][CH:19]=3)[C:16]([C:36]([F:39])([F:38])[F:37])([O:31][Si](C)(C)C)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:40]C4CCCCO4)[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1>CO.Cl>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([CH:17]2[C:16]([C:36]([F:39])([F:37])[F:38])([OH:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:40])[CH:14]=3)[O:9][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)c2cc(OC3CCCCO3)ccc2OC(c2ccc(I)cc2)C1c1ccc(OC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(C2C(c3ccc(I)cc3)Oc3ccc(O)cc3C2(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
To a solution of {2-(4-iodo-phenyl)-6-(tetrahydro-pyran-2-yloxy)-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-4-trifluoromethyl-chroman-4-yloxy}-trimethyl-silane (15 g, 73 mmol) in MeOH (400 mL), concentrated HCl (100 mL) was added. The reaction mixture was stirred at room temperature for 4 h, concentrated, and re-dissolved in DCM (150 mL). The solution was washed (3×100 mL brine), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10/1) to afford the desired product (10 g). 1H NMR (DMSO-d6): δ 9.17 (s, 1H), 9.08 (s, 1H), 7.55 (d, 2H), 7.10 (d, 2H), 7.06-6.99 (m, 3H), 6.76-6.65 (m, 2H), 6.55-6.48 (m, 3H), 5.77 (d, 1H), 3.55 (d, 1H); LCMS: 527 (M−H)−.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH3:21])=[C:8]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:38][CH2:37][C:36]5[N:35]=[C:34]([CH2:39][CH2:40][CH3:41])[C:33]([C:42]([O:44]C)=[O:43])=[CH:32][C:31]=5[C:30]4=[O:46])[CH2:25][CH2:24]3)[CH:7]=2)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH3:21])=[C:8]([CH2:22][N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:38][CH2:37][C:36]5[N:35]=[C:34]([CH2:39][CH2:40][CH3:41])[C:33]([C:42]([OH:44])=[O:43])=[CH:32][C:31]=5[C:30]4=[O:46])[CH2:27][CH2:28]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC)CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC)CC1)CC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A 2 M aqueous sodium hydroxide solution (2 mL) was added at room temperature to an ethanol (8 mL) solution of methyl 6-(1-((6-cyclopropyl-2,4′-difluoro-3-methoxybiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (335 mg), and the mixture was stirred at 80° C. for 3 hours in a nitrogen atmosphere. Then, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was neutralized with 2 M hydrochloric acid. The deposited crystals were collected by filtration and dissolved in ethanol, and then, the solvent was distilled off under reduced pressure. The obtained residue was crystallized (hexane/ethyl acetate) and further recrystallized (hexane/ethanol) to obtain the title compound (276 mg).
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:25])[C@H:8]([CH2:17][CH2:18][CH2:19][NH:20][CH2:21][O:22][CH:23]=[NH:24])[NH:9]C(OC(C)(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:1].[ClH:1].[NH:24]=[CH:23][O:22][CH2:21][NH:20][CH2:19][CH2:18][CH2:17][C@@H:8]([C:7]([OH:25])=[O:6])[NH2:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNCOC=N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N=COCNCCC[C@H](N)C(=O)O
Temperature: 22 °C
Reaction time: 8 h
Yield: 206.3 %

Procedure:
A solution of 0.75 g (1.96 mmol) N2-(tert-butoxycarbonyl)-N5-(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride in 2 mL dioxane at 0° C. was treated with 15 mL of 4N hydrochloric acid in dioxane solution. The solution was stirred overnight at 22° C., concentrated to a crude paste, and freeze-dried from 8 mL of water. The product was freeze-dried a second time to yield 0.53 g N5-(iminomethoxymethyl)-L-ornithine dihydrochloride. The product analyzed solvated with an additional 0.2 molar hydrochloric acid, 0.1 molar water, and 0.3 molar dioxane.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([S:15]([C:18]2[CH:35]=[CH:34][C:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26][C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.O1CCCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([S:15]([C:18]2[CH:35]=[CH:34][C:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:25][CH2:26][C:20]=3[CH:19]=2)(=[O:16])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(S(=O)(=O)c3cccc(O[Si](C)(C)C(C)(C)C)c3)cc2CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(S(=O)(=O)c3cccc(O)c3)cc2CC1
Reaction time: 1 h

Procedure:
7-(3-t-Butyldimethysilyloxyphenylsulfonyl)-3-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (5.4 g, 10.5 mmol) was dissolved in a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (15 mL, 1M, 15 mmol). The solution was stirred for 1 h then diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL), and brine (100 mL), dried (MgSO4), and evaporated.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[CH3:7].[N-:9]=[N+:10]=[N-:11].[Na+]>O.C(O)(C)(C)C>[N:9]([CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[CH3:7])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCCCBr
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)OCCCN=[N+]=[N-]
Yield: 59.7 %

Procedure:
Acetic acid 3-bromo-propyl ester (6.7 g, 37 mmol) was suspended in water (50 mL) and tert-butanol (20 mL). To the resulting mixture was then added sodium azide (2.76 g, 42.6 mmol) and the reaction mixture was heated to reflux for 18 hours, then concentrated to half of its volume. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with water, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the acetic acid 3-azido-propyl ester (3.16 g) as an oil which used in the next step without further purification.
Reaction SMILES: [N:1]12C[N:5]3[CH2:6][P:7](=[O:10])([CH2:9][N:3](C3)C1)[CH2:8]2.[ClH:12]>O>[ClH:12].[ClH:12].[ClH:12].[NH2:5][CH2:6][P:7](=[O:10])([CH2:9][NH2:3])[CH2:8][NH2:1]
Reactant: O=P12CN3CN(CN(C3)C1)C2
Agent: Cl
Solvent: O
Product: NCP(=O)(CN)CN
Yield: 59.8 %

Procedure:
Following the procedure outline in Example 6, the 1,3,5-triaza-7-phosphaadamantane-7-oxide (7.92 g, 0.04 mol) was hydrolyzed with a solution of 22 g (0.22 mol) of 37.7% hydrochloric acid and 80 g of water, giving, after workup, 5.9 g (60% yield) of tris(aminomethyl)phosphine oxide trihydrochloride, dec. 239° C. without melting.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18](O)=[O:19])=[O:10])=[C:7]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]2[O:10][C:18](=[O:19])[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[C:7]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:26][CH2:25]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccncc2C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2-c2nc3ccncc3c(=O)o2)CC1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a stirring solution of 4-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoylamino]pyridine-3-carboxylic acid (0.15 g, 0.30 mmol) in DMF (5 mL) was added 1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (0.077 g, 0.39 mmol). After stirring overnight, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed twice with ice water/brine. The combined aq phase was back extracted with ethyl acetate and the combined organic phase was dried with MgSO4, filtered and concentrated in vacuo to give the title compound (0.121 g, 84%) as a light yellow foam.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[C:9]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:10][C:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([C:24](=[O:35])[NH:25][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)[CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[CH:12][CH:13]=1.Cl>C1COCC1>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:25][C:24]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][N:14]([C:11]1[N:10]=[C:9]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[C:8]([CH2:7][CH2:6][CH:2]=[O:1])=[CH:13][CH:12]=1)[CH2:23][CH2:22]2)=[O:35]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCC1OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCC=O
Temperature: 48 °C
Yield: 78.4 %

Procedure:
Compound 96A (7.58 g) was dissolved in THF (120 mL). To this solution was added 5% aq. HCl (100 mL). The reaction mixture was heated at 48° C. for 90 min. After cooling to room temperature, the reaction mixture was quenched with sat. NaHCO3 solution until no more CO2 was released. The solution was concentrated under vacuum. The residue was re-dissolved in EtOAc, and treated with water (500 mL). The organic layer was separated, and the aqueous layer was extracted with additional EtOAc (three times). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified with flash column chromatography on silica gel eluting with 7:3/Hex:EtOAc to give 5.5 g of the title compound 96B (78%): APCI (+)LC/MS: 543 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:21])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[C:7]2[C:19]#[N:20].[CH:22]([B-](F)(F)F)=[CH2:23].[K+].C(N(CC)CC)C>CC(O)C.O>[Cl:21][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH:22]=[CH2:23])[CH:3]=1)[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[C:7]2[C:19]#[N:20]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2cc(Cl)cc(Br)c21
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=Cc1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Temperature: 90 °C
Yield: 72.7 %

Procedure:
A solution of 7-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (620 mg, 1.607 mmol), Potassium vinyltrifluoroborate (237 mg, 1.768 mmol), and triethylamine (0.672 mL, 4.82 mmol) in 2-Propanol (50 mL) and Water (25 mL) was degassed with nitrogen for 10 min, then 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (66.1 mg, 0.080 mmol) was added and the reaction was sealed and heated at 90° C. for 2.5 hours. TLC indicated starting material was consumed and one major product plus byproducts were produced. The reaction was evaporated to remove most of the solvent, then the reaction was taken up in brine (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 10% ethyl acetate/hexanes to give product 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-indole-3-carbonitrile (389 mg, 1.169 mmol, 72.7% yield) as a yellow oil which crystallized to a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J=2.0 Hz, 1H), 7.60 (s, 1H), 7.42 (dd, J=17.1, 10.8 Hz, 1H), 7.33 (d, 2.0 Hz, 1H), 5.71 (dd, J=17.2, 1.3 Hz, 1H), 5.48 (s, 2H), 5.47 (dd, J=10.8, 1.3 Hz, 1H), 3.51 (app t, J=8.0 Hz, 2H), 0.90 (app t, J=8.0 Hz, 2H), −0.05 (s, 9H). LC/MS (HPLC method 4): tR=4.30 min, 333.13(MH)+.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]4[CH3:28])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:37]([CH2:39][NH2:40])[OH:38]>CN(C=O)C>[OH:38][CH2:37][CH2:39][NH:40][C:8]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[N:17]=2)=[CH:14][CH:15]=1)=[O:29]
Reactant: C[C@H]1COCCN1c1nccc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: NCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nccc(-c2ccc(NC(=O)NCCO)cc2)n1

Procedure:
(S)-phenyl(4-(2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate (intermediate 29) (100 mg, 0.26 mmol) was stirred with triethylamine (85 mg, 0.82 mmol) and ethanolamine (78 mg, 1.28 mmol) in DMF (1 ml) for 2 hours at room temperature. The crude residue was purified by flash chromatography (0-10% EtOH:MeOH) to yield the title compound. (34 mg, 8%)
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7](Br)[CH:3]([CH2:4]2)[CH2:2]1.[Mg].Cl[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.O1CCCC1>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][CH:7]2[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[CH:13][N:12]=1
Reactant: BrC1CC2CCC1C2
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: c1ccc(-c2cc(C3CC4CCC3C4)ncn2)cc1
Temperature: -15 °C

Procedure:
Into a reaction container, 2.99 g of exo-2-bromonorbornane, 0.50 g of magnesium, and 10 mL of tetrahydrofuran (THF) were put, and this reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 10 minutes so that the Grignard reagent was prepared. Then, 5.02 g of 4-chloro-6-phenylpyrimidine obtained in Step 1 and 30 mL of THF were mixed, and while the mixture was being stirred at −15° C., the obtained Grignard reagent was added thereto. Further, 30 mg of [1,2-bis(diphenylphosphino)ethane]nickel(II) dichloride (abbreviation: Ni(dppe)Cl2) was also added, and the temperature of the mixture was increased to room temperature. An aqueous solution of ammonium chloride was added to this reaction solution, and an organic layer was extracted with ethyl acetate. The obtained organic layer was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography (silica gel) using a mixed solvent of hexane and ethyl acetate as a developing solvent in a volume ratio of 5:1, to give the objective pyrimidine derivative Hnbppm (yellow oily substance, 43% in yield). The synthesis scheme of Step 2 is shown by (b-1).
Reaction SMILES: C(N[C:9]([C:11]1[C:16]([NH:17][C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])C1C=CC=CC=1.NC1C(C(O)=[O:32])=NC=CN=1.C(N(C(C)C)CC)(C)C.C(Cl)(=O)CC(C)C>CN(C=O)C>[CH3:21][CH:20]([CH3:22])[CH2:19][C:18]([NH:17][C:16]1[C:11]([C:9]([OH:10])=[O:32])=[N:12][CH:13]=[CH:14][N:15]=1)=[O:23]
Reactant: Nc1nccnc1C(=O)O
Reactant: CC(C)CC(=O)Nc1nccnc1C(=O)NCc1ccccc1
Agent: CC(C)CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(=O)Nc1nccnc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(3-Methyl-butyrylamino)-pyrazine-2-carboxylic acid benzylamide: To a solution of DMF (200 mL), 3-aminopyrazine-2-carboxylic acid (10.0 g, 71.9 mmol) and diisopropylethyl amine (25.0 mL, 144 mmol) was added isovaleryl chloride (12.4 mL, 86.3 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for two hours after which the solvent was removed under reduced pressure and the residue dried under vacuum overnight, to afford 3-(3-methyl-butyrylamino)-pyrazine-2-carboxylic acid as a solid residue. The solid residue was dissolved in acetic anhydride (200 mL) and the mixture stirred at 100° C. overnight. The excess acetic anhydride was removed by distillation under reduced pressure, leaving a residue that was then cooled to room temperature and washed with hexane to give the corresponding oxazinone compound of Formula 103, 2-isobutyl-pyrazino[2,3-d][1,3]-oxazin-4-one, which was carried forward without additional purification. A solution of chloroform (200 mL), the oxazinone of Formula 103, and benzylamine (16.0 mL, 144 mmol) was stirred at 60° C. for two hours. After the complete consumption of the oxazinone, as monitored by reverse phase HPLC, the chloroform was removed under reduced pressure and the residue purified by silica gel chromatography using hexane-EtOAc (1:2) as eluent to obtain the title bis amide, 3-(3-methyl-butyrylamino)-pyrazine-2-carboxylic acid benzylamide (4.5 g 20.0%, three steps). MS (Cl) M/E: 313.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:36])[CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:11][O:12][C:13](=[O:36])[CH2:14][CH:15]1[CH2:16][CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:25][CH:26]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
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: [K+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of 2-bromo-5-nitropyridine (0.81 g, 4.0 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (1.5 g, 4.0 mmol, 1.05 equiv) in 20 Ml DME was added 2 Ml saturated potassium carbonate solution followed by 50 mg Pd(PPh3)4 catalyst. The reaction was then heated to 80° C. over the weekend. Removal of volatiles in vacuo followed by silica gel chromatography (20% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.06 (m, 1 H) 1.00 (dd, J=12.76, 2.15 Hz, 2 H) 1.30-1.42 (m,J=12.82, 12.60, 12.60, 2.91 Hz, 2 H) 1.65 (br. S., 2 H) 1.68 (d, J=3:54 Hz, 3 H) 2.11 (d, J=6.82 Hz, 2 H) 3.46 (s, 3 H) 7.27 (d, J=8.34 Hz, 2 H) 7.98 (d, J=8.34 Hz, 2 H) 8.08 (dd, J=8.84, 0.51 Hz, 1 H) 8.47 (dd, J=8.84,2.78 Hz, 1 H) 9.27 (d, J=2.27 Hz, 1 H) (M+H)+ 355.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:3]=1.[OH-].[K+]>CO.O>[C:14]([CH2:13][O:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])([OH:16])=[O:15]
Reactant: CCOC(=O)COc1cc(Cl)ccc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
To a solution of methyl 4-chloro-2-(2-ethoxy-2-oxoethoxy)benzoate (10 g, 36.67 mmol) in methanol (250 mL) and water (50 mL) was added potassium hydroxide (4 g, 71.43 mmol). After stirring for 1.5 h at 25° C., the resulting mixture was concentrated under vacuum, dissolved in water (50 mL), adjusted to pH 6 with HCl (3N) and filtered to give 2-(carboxymethoxy)-4-chlorobenzoic acid as a white solid (7 g, 80%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>C(OC(=O)C)(=O)C>[CH2:4]([O:3][C:1]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
The above illustrated starting compound which is commercially available N-CBZ aspartic acid (205.7 g, 0.77 mol) was added to acetic anhydride (300 ml). This mixture was stirred at 75° C. for 4 hours. The excess acetic anhydride and acetic acid byproduct were distilled from the mixture under reduced pressure and the residue was recrystallised from hot dichloromethane. The product was collected by filtration, washed with hexane and dried at ambient temperature under reduced pressure to give a white fluffy solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:2].[Br:12]N1C(=O)CCC1=O>FC(C1C=CC=CC=1)(F)F.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH:1]([C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:2]
Reactant: CCc1cc(F)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: CC(Br)c1cc(F)ccc1C#N
Temperature: 100 °C
Yield: 93.5 %

Procedure:
To a solution of 2-ethyl-4-fluoro-benzonitrile (prepared according to WO 07039178, page 116) (1.14 g, 7.6 mmol) in trifluoromethyl-benzene (30 mL) was added N-bromosuccinimide (1.63 g, 9.1 mmol, 1.2 eq.) followed by azobisisobutyronitrile (0.025 g, 0.15 mmol, 0.02 eq.). The mixture was heated to 100° C. for 18 hr under an atmosphere of nitrogen and then cooled to room temperature. The mixture was filtered and filtrate partitioned with aqueous sodium sulphite solution (1M, 20 mL). The organic phase was washed with water (20 mL) and then evaporated under reduced pressure to give the title compound as a beige solid (1.62 g, 93%).