Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:11]/[C:12](/[NH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:13]/[NH:14][C:15]([O:17][CH3:18])=[O:16])[C:7]([O:9][CH3:10])=[O:8])=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:11][CH:12]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][NH:14][C:15]([O:17][CH3:18])=[O:16])[C:7]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: COC(=O)N/C=C(/C[C@H](NC(=O)OC)C(=O)OC)NC(=O)OC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)NCC(C[C@H](NC(=O)OC)C(=O)OC)NC(=O)OC
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of methyl (2S,4Z)-2,4,5-tris[(methoxycarbonyl)amino]pent-4-enoate CXXVII (624 mg, 1.87 mmol) in ethanol (15 mL) was added 10% Pd/C catalyst (60 mg). The mixture was placed in an autoclave and exposed to 50 atm of H2 with stirring at r.t. for 36 h. Reaction mixture was filtered through Celite and concentrated to dryness to give crude methyl (2S)-2,4,5-tris[(methoxycarbonyl)amino]pentanoate CXXVIII (540 mg). ESIMS found for C12H21N3O8 m/z 358 (M+Na).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([F:18])[C:16]=3[CH:17]=[C:9]2[C:8]2[N:19]=[C:20](Cl)[CH:21]=[CH:22][C:7]=2[O:6]1)=[N+:2]=[N-:3].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]3[CH:43]=[C:42]([N:44]([CH3:49])[S:45]([CH3:48])(=[O:47])=[O:46])[C:41](B4OC(C)(C)C(C)(C)O4)=[CH:40][C:34]=3[C:35]=2[C:36]([NH:38][CH3:39])=[O:37])=[CH:27][CH:26]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CCOC(C)=O>O1CCOCC1.O.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]>[N:1]([CH2:4][CH:5]1[N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([F:18])[C:16]=3[CH:17]=[C:9]2[C:8]2[N:19]=[C:20]([C:41]3[C:42]([N:44]([CH3:49])[S:45]([CH3:48])(=[O:47])=[O:46])=[CH:43][C:33]4[O:32][C:31]([C:28]5[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=5)=[C:35]([C:36]([NH:38][CH3:39])=[O:37])[C:34]=4[CH:40]=3)[CH:21]=[CH:22][C:7]=2[O:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN=[N+]=[N-])O4)cc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-(azidomethyl)-2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (1.4 g, 4.25 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (1.8 g, 3.73 mmol) and K3PO4.3H2O (3.4 g, 12.75 mmol) in Dioxane/water (10 mL/1 mL), Pd2(dba)3 (195 mg, 0.21 mmol) and X-Phos (200 mg, 0.42 mmol) were added. The reaction mixture was stirred at 90° C. for 2 hours under N2 protection. Then cooled to room temperature and added EtOAc, then filtered through a Celite pad. The combined organic phase was washed with water and brine, dried over Na2SO4. The solvent was concentrated in vacuo giving 5-(6-(azidomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide. The crude product was used in the next step without purification. 1H-NMR (CDCl3, 400 MHz) δ 2.73 (s, 3H), 2.97˜3.03 (d, J=4.8 Hz, 3H), 3.04˜3.15 (d, J=10.8 Hz, 1H), 3.20˜3.32 (m, 1H), 3.40 (s, 3H), 5.93˜6.02 (m, 1H), 6.33˜6.40 (m, 1H), 6.81˜6.89 (m, 1H), 7.14˜7.26 (m, 5H), 7.45˜7.53 (m, 2H), 7.67 (s, 1H), 7.93˜8.01 (m, 2H), 8.03 (s, 1H). MS (M+H)+: 670.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:13]1[CH:24]=[CH:23][C:16]([CH:17]=[C:18](C)[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>C(O)(=O)C.[Pd].[C]>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:13]1[CH:24]=[CH:23][C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(=Cc1ccc(C(C2=C(C)C(=O)C(C)=C(C)C2=O)c2cccnc2)cc1)C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C(C(c2ccc(CCC(=O)O)cc2)c2cccnc2)=C(C)C1=O
Reaction time: 2 h
Yield: 44.2 %

Procedure:
4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl-(3-pyridyl)methyl]-α-methylcinnamic acid, 0.7 g (1.75 mmol), was hydrogenated with 0.2 g of 5% Pd-carbon in 6 ml of acetic acid (the reaction completed in about 2 hours). The catalyst was filtered off, and the filtrate was concentrated, to which water was added and neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The resultant substance was extracted with ethyl acetate, and oxidized by shaking with an aqueous solution of ferric chloride. After the organic phase was washed with water and dried, the solvent was evaporated off and the residue was purified with silica gel column chromatography (ethyl acetate-ethanol (9:1)) and recrystallized from ethyl acetate, to give 0.3 g (44.2%) of 3-(4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl-(3-pyridyl)methyl]phenyl)propionic acid. The physical data are shown in Table 1.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:30][C:31]([OH:33])=O)[C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:14]=1.ON1C2N=CC=CC=2N=N1.[C:44]([O:48][C:49]([NH:51][C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30][C:31]([N:54]2[CH2:55][CH2:56][C@H:52]([NH:51][C:49](=[O:50])[O:48][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:53]2)=[O:33])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.6 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.36 g, 1.87 mmol) was added to a solution of {(4-hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid 13 (0.37 g, 1.24 mmol), 1-hydroxy-7-azabenzotriazole (0.25 g, 1.87 mmol), (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (0.35 g, 1.87 mmol) and N-methyl-morpholine (0.27 mL, 2.5 mmol) in DMF (40 mL). The reaction mixture was stirred at room temperature for 3 days and then diluted with ethyl acetate and washed with 10% hydrochloric acid (×2), brine, NaHCO3 (x 2) and brine, dried (Na2SO4) and evaporate. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/petrol (4:1)→ethyl acetate, to give the title compound as a white powder (0.419 g, 72%). 1HNMR (300 MHz) (CDCl3) δ 1.45 (9H, s), 1.8-2.25 (2H, m), 3.4-3.8 (4H, m), 4.15 (1H, m), 4.6 (1H, m), 5.3 (1H, m), 6.43 (1H, d, J=16), 6.87 (2H, d), 7.2-7.32 (7H, m) and 7.65 (1H, d, J=16 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[C:5]([OH:10])[C:4]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([OH:10])[C:4]=1[CH3:11]
Reactant: Cc1c(O)cc(=O)[nH]c1Cl
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Product: Cc1c(Cl)[nH]c(=O)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-4-hydroxy-5-methyl-1H-pyridin-2-one hydrochloride (64 g) was dissolved in sulfuric acid (325 mL) while cooling in an ice bath. Nitric acid was added dropwise over a period of 90 minutes. The reaction mixture was allowed to stir for an additional 30 minutes and then it was poured into ice water (2 L). The resulting precipitate was isolated by filtration, washed with water and then dried to provide 42.5 g of 6-chloro-4-hydroxy-5-methyl-3-nitro-1H-pyridin-2-one as a light yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16](CC=C)[C:15]([Cl:23])=[N:14][C:13]=2[N:12]([CH2:24][CH2:25][CH2:26][CH3:27])[C:11]1=[O:28])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]1([N:41]2[C:45](=[O:46])[N:44]=[N:43][NH:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1CCOCC1>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.CO.CN(C=O)C>[CH2:24]([N:12]1[C:13]2[N:14]=[C:15]([Cl:23])[NH:16][C:17]=2[C:18](=[O:19])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:44]2[C:45](=[O:46])[N:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:42]=[N:43]2)[C:11]1=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCOS(C)(=O)=O)c(=O)n2CCCC
Reactant: O=c1nn[nH]n1-c1ccccc1
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: [Cs+]
Solvent: CO
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCCn2nnn(-c3ccccc3)c2=O)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 60 h
Yield: 49 %

Procedure:
A mixture of 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butyl methanesulfonate (50 mg, 0.12 mmol), Cs2CO3 (45 mg, 0.14 mmol) and DMF (3 ml) was treated with 1-phenyl-1,2-dihydro-5H-tetrazol-5-one (23 mg, 0.14 mmol) and stirred for 60 h at 50° C. After cooling, the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (20 mg, 0.017 mmol) was added and the mixture degassed once more. Morpholine (150 μl, 1.7 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl column with the product eluting with 2% AcOH/MeOH. Further purification by MDAP gave the title compound as an off-white solid (27 mg, 51%). NB. ca. 10% O-alkylated material present.
Reaction SMILES: C1C=C[C:4]2[N:9](O)N=[N:7][C:5]=2C=1.C(N(C(C)C)CC)(C)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:34]=[CH:35]/[C:36]([OH:38])=O)[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1.Cl.NCC#N>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[C:5]([CH2:4][NH:9][C:36](=[O:38])/[CH:35]=[CH:34]/[C:24]1[CH:25]=[CH:26][C:27]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[C:22]([O:21][CH3:20])[CH:23]=1)#[N:7]
Reactant: On1nnc2ccccc21
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: Cl
Agent: N#CCN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)NCC#N)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
EDC (4.48 g), HOBT (3.14 g) and IPEA (6.76 mL) were sequentially added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (2 g) and aminoacetonitrile hydrochloride (1.08 g) in DMF (25 mL), and the reaction solution was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer washed with brine and then dried over anhydrous sodium sulfate and filtered through a silica gel pad (Chromatorex NH). The filtrate was concentrated under reduced pressure. The residue was crystallized (heptane-ethyl acetate-methanol system) to obtain 1.24 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C([N:4]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Br)=[CH:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=O)C.Cl[C:20]1[N:21]=[C:22]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[C:23]2[S:28][C:27]([CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]3)=[CH:26][C:24]=2[N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:5]([NH:4][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:20]2[N:21]=[C:22]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)[C:23]3[S:28][C:27]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]4)=[CH:26][C:24]=3[N:25]=2)=[CH:10][N:9]=1)(=[O:7])[CH3:6]
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC(=O)N(C(C)=O)c1ncc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)c2ccccc12
Temperature: 60 °C
Yield: 18.3 %

Procedure:
Following General Procedure B of Suzuki coupling, N-acetyl-N-(4-bromoisoquinolin-1-yl)acetamide (57 mg) was reacted with 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (107 mg). After reaction completion, 1 M Na2CO3 (2 mL) and 1,4-dioxane (2 mL) were added to the mixture. The suspension was heated at 60° C. for 3 h. The reaction mixture was concentrated. Water (5 mL) was added. The contents were extracted with DCM (2×10 mL). The combined DCM solutions were dried (Na2SO4). The crude was purified with reverse-phase HPLC to give 144 (20 mg, 22%). LCMS: M+H+=589. 1H NMR (400 MHz, CDCl3) δ 8.86 (2H), 8.07 (, s, br, 2H), 7.75 (t, J=7.7, 1H), 7.64 (t, J=7.6, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 5.18 (s, 1H), 4.12-4.00 (m, 4H), 3.94-3.81 (m, 6H), 2.62 (s, 8H), 2.44 (s, 3H), 1.25 (s, 6H)
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]1=[O:17])[CH:4]([CH3:6])[CH3:5]>CO.C1COCC1>[CH2:3]([N:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]1=[O:17])[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)c1ccn(CC(C)C)c(=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cn1ccc(C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 81 %

Procedure:
To a mixed solution was added a 1M aqueous NaOH solution (4.1 ml) of methyl 1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (430 mg) in CH3OH-THF (4 ml-3 ml). The solution was stirred at room temperature for 10 hours, and then concentrated under reduced pressure, and water (10 ml) was added, and subsequently 1M HCl was added thereto until pH becomes 3. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (325 mg) as white powders.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1Nc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (TEA) (17 ml, 122 mmol) slowly. The whole was stirred at room temperature (RT) overnight. Filtration gave a white solid 1 (6.5 g). The filtrate was worked up with water (300 ml), then extracted with DCM (300 ml) three times. The organic phase was collected and dried over MgSO4, concentrated and recrystallized in DCM/hexanes to give another portion of white solid 1 (10.6 g). Total amount of product 1 is 17.1 g, in 93% yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17](Cl)[N:16]=2)=[CH:11][C:10]=1[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:16]=2)=[CH:11][C:10]=1[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(Cc1ccccc1)Cc1ccccc1
Reactant: C1COCCN1
Product: FC(F)(F)c1cc(-c2cc3ncccc3c(N3CCOCC3)n2)ccc1N(Cc1ccccc1)Cc1ccccc1
Yield: 26 %

Procedure:
A solution of dibenzyl-[4-(5-chloro-[1,6]naphthyridin-7-yl)-2-trifluoromethyl-phenyl]-amine, 3, (100 mg, 0.20 mmol, 1 eq) in morpholine (1.25 mL, 14 mmol, 70 eq) was heated up at 100° C. overnight under Ar(g). Once cooled down, the solution was partitioned and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:3-0:1) to yield the product as a pale yellow solid (29.1 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:3]=C[C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.BrC1C=CC(F)=C[N:19]=1>>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:19][CH:3]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Product: Fc1cnc(-n2cnc3cnccc32)nc1

Procedure:
Intermediate 6 was prepared in a manner analogous to Intermediate 1, substituting 2-bromo-5-fluoropyrimidine for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C10H6FN5, 215.06. m/z found 216.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)(C)(C)C.[ClH:25]>ClCCl.O1CCOCC1>[ClH:25].[ClH:25].[CH3:23][O:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][NH2:7])[CH:21]=1
Reactant: COc1cc(NCCCNC(=O)OC(C)(C)C)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(NCCCN)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of [3-(4-methoxyquinolin-2-ylamino)propyl]carbamic acid tert-butyl ester (3.10 g, 9.35 mmol) in anhydrous dichloromethane (20 ml) was treated with 4N HCl in 1,4-dioxane (10 ml). It was stirred at ambient temperature for 2 hours then was evaporated under reduced pressure to give N′-(4-methoxyquinolin-2-yl)propane-1,3-diamine dihydrochloride (2.81 g, 99%) as a white solid. [M+H]+ 232.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Br.[CH3:53][O:54][C:55](=[O:69])[CH2:56][CH2:57][C:58]1[O:62][N:61]=[C:60]([CH:63]([NH2:68])[CH2:64][CH:65]([CH3:67])[CH3:66])[CH:59]=1>C(Cl)Cl.O>[CH3:53][O:54][C:55](=[O:69])[CH2:56][CH2:57][C:58]1[O:62][N:61]=[C:60]([CH:63]([NH:68][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH2:64][CH:65]([CH3:67])[CH3:66])[CH:59]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: COC(=O)CCc1cc(C(N)CC(C)C)no1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCc1cc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a stirred solution of [4-(3-o-tolyl-ureido)-phenyl]-acetic acid (305 mg, 1.07 mmol), DIEA (1.3 ml), HOBT (120 mg, 0.89 mmol) and EDCI (170 mg, 0.89 mmol) in CH2Cl2 (8 ml) at room temperature was added a solution of 3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-propionic acid methyl ester hydrobromide (272 mg, 0.85 mmol) in CH2Cl2 (12 ml). After stirring for 16 h at room temperature the mixture was diluted with CH2Cl2 (20 ml) and poured into water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (20 ml×3). The combined organics were dried over MgSO4; filtered; and concentrated under reduced pressure. The residue was purified by Flash 40 chromatography using a silica gel column and eluting with 65% EtOAc/hexane to give 220 mg of the title compound as a white amorphous solid. MP 153-4° C.; MS [+1]+507.2; 1H nmr (400 MHz, CDCl3) δ0.88 (d, J=6.4 Hz, 6H), 1.53-1.66 (m, 3H), 2.21 (s, 3H), 2.66 (t, J=7.6 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 3.49 (s, 2H), 3.68 (s, 3H), 5.15 (dt, J=6.2 and 8.7 Hz, 1H), 5.85 (s, 1H), 6.11 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 7.00 (s, 1H), 7.05-7.24 (m, 7H), 7.53 (d, 1H); Anal. calcd. for C28H34N4O5: C (66.39), H (6.76), N (11.05). Found: C (66.29), H (7.11), N (11.11).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2/[CH:8]=[CH:7]/[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: Nc1ccccc1C=Cc1ccncc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2ccncc2)cc1
Yield: 21.1 %

Procedure:
Using 4.93 g of 2-[2-(4-pyridyl)ethenyl]aniline and 5.70 g of p-methoxybenzenesulfonyl chloride, the reaction and after-treatment procedure of Example 1 was otherwise carried out to give a crystal crop. This crystal crop was recrystallized from ethanol to provide 1.94 g of the title compound (light yellowish white prisms). m.p. 207-209° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].O.[N+:7]([C:10]1[CH:19]=[C:18]2[C:13]([NH:14][C:15](=[O:21])[C:16](=[O:20])[NH:17]2)=[CH:12][C:11]=1[S:22](Cl)(=[O:24])=[O:23])([O-:9])=[O:8]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:22]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[N+:7]([O-:9])=[O:8])[NH:17][C:16](=[O:20])[C:15](=[O:21])[NH:14]2)(=[O:23])=[O:24]
Reactant: COCCN
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: O
Product: COCCNS(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 59 %

Procedure:
To a solution of 3.76 g (0.05 mole) of 2-methoxyethylamine in 15 ml of water 6.11 g (0.02 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added at room temperature, under stirring. The mixture is stirred at room temperature for 6 hours and then allowed to stand for 16 hours. The separated crystals are filtered off, washed successively with water and acetone, filtered again, dried and dissolved in a slight amount of hot dimethyl sulfoxide. The product is precipitated from this solution with water. Thus 4.05 g (59%) of 1,2,3,4-tetrahydro-N-(2-methoxy-ethyl)-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 320-321° C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@H:29]([NH2:31])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[C:40]([O:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41]>ClCCl.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@H:29]([NH:31][C:49](=[O:50])[CH2:48][NH:47][C:45]([O:44][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:46])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](NC(=O)CNC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 104.7 %

Procedure:
Triethylamine (1.13 mL), 1-hydroxybenzotriazole (1.04 g), and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.56 g) were added to a solution of cis-4-amino-N-tert-butoxycarbonyl-L-proline methyl ester (Compound D102 (C), 1.65 g) and N-tert-butoxycarbonylglycine (1.42 g) in dichloromethane (100 mL) at 0° C. The mixture was stirred at room temperature for 19 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 10% citric acid, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (2.84 g) as a colorless foam.