Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:19][C:20]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:21](O)=[O:22])=[O:18])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH2:24]([C:20]([NH:19][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:18])([C:21](=[O:22])[NH:30][CH3:29])[CH2:26][CH3:27])[CH3:25]
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)O
Reactant: CN
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-ethylbutanoic acid and methanamine hydrochloride as starting materials, MS (EI): m/e=390.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:13]=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc([N+](=O)[O-])cc1F
Reaction time: 18 h
Yield: 199.5 %

Procedure:
A solution of 9.4 grams (0.06 mole) of 2-fluoro-4-nitroaniline in 200 mL of toluene was stirred, and 5.9 grams (0.03 mole) of trichloromethyl chloroformate was added dropwise. Upon completion of addition, the reaction mixture was warmed to reflux, where it stirred for about 18 hours. After this time the reaction mixture was cooled and concentrated under reduced pressure, yielding about 10.9 grams of 2-fluoro-4-nitrophenyl isocyanate. The reaction product was used immediately in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:21]([OH:24])(=[O:23])=[O:22])[C:5]([CH:8]=[CH:9][C:10]2[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1.S1C(C=O)=CC=C1C=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1COCC1>[S:21]1[CH:4]=[CH:5][CH:6]=[CH:7]1.[NH:1]1[C:7]2[CH:6]=[C:5]([CH:8]=[CH:9][C:10]3[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][C:13]4[NH:16][C:14]=4[CH:15]=3)[C:4]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:3][C:2]1=2
Reactant: Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=Cc1ccc(C=O)s1
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=S(=O)(O)c1cc2c(cc1C=Cc1cc3c(cc1S(=O)(=O)O)N3)N2
Product: c1ccsc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A volume of 60 ml distilled water and a few drops of 2M sodium hydroxide was required to dissolve the commercially available 4,4′-diaminostilbene-2,2′-disulfonic acid (155 mg, 0.41 mmol). After the addition of 40 ml THF, 2,5-thiophene dicarboxaldehyde (58 mg, 0.42 mmol) was added along with a catalytic amount of benzyltriethyl ammonium chloride. The red coloured solution was stirred at room temperature for two days. The solvent was removed under reduced pressure to afford the polymer as a red solid that was recrystallized from ethanol. λmax (water): 305 and 338 nm. Mw=148 094, PDI=2.3, DP=286. 1H-NMR (200 MHz, [D] DMSO): δ=8.92 (br, s, 2H), 8.21 (br, s, 2H), 7.80 (br, s, 6H), 7.39 (br, s, 2H). Anal. cald. C20H12O6N2S3Na2.7.2H2O: C, 37.06, H, 4.11, N, 4.32, S, 14.84 found C, 37.27; H, 3.90; N, 4.28, S, 14.62. The 1S0,0-0S0,0 (HOMO-LUMO) transition was calculated to be 65 kcal/mol (2.83 eV). From the absorption onset in the red region of the spectrum, a value can be calculated for the band gap of 51.3 kcal/mol (2.23 eV) for 9.
Reaction SMILES: [C:1]1([CH:7]2[C:12]3C=C(C([O-])=O)S[C:11]=3[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[O:8]2)[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[Na+].ClC1C2C(=CC=CC=2)[O:28]C(C2C=CC=CC=2)C=1C=O>CO>[O:8]1[C:9]2[C:10](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11](=[O:28])[CH2:12][CH:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: O=C([O-])c1cc2c(s1)-c1ccccc1OC2C1=CCCC=C1
Agent: [Na+]
Solvent: CO
Product: O=C1CC(c2ccccc2)Oc2ccccc21

Procedure:
Analogously, (-)-sodium 4H-4-phenyl-thieno[3,2-c][1]benzopyran-2-carboxylate, [α]43625 =-89° (c=0.5, methanol), is prepared starting from the pure enantiomeric 4-chloro-3-formyl-flav-3-ene which is obtained by chloroformylation of (-)-flavanone [(-) at 436 nm]. The preparation of (+)- and (-)-flavanone is described e.g. in Tetrahedron Lett. 26, 2305 (1970) and Acta Chim. Acad. Sci. Hung. 86, 161 (1975).
Reaction SMILES: [C:1]1(/[CH:7]=[N:8]/[C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([O-])(C)[CH3:16].[K+].ICCC>CN(C=O)C.O>[C:1]1(/[CH:7]=[N:8]/[C:9]2[N:13]([CH2:14][CH2:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: C(=N/c1ncc[nH]1)\c1ccccc1
Agent: [K+]
Solvent: CCCI
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccnc1/N=C/c1ccccc1
Reaction time: 3.5 h
Yield: 89.9 %

Procedure:
To a solution of N-[(1E)-phenylmethylidene]-1H-imidazol-2-amine (1.00 g, 5.84 mmol) in DMF (20 mL) was added KOt-Bu (0.80 g, 7.13 mmol) and 1-iodopropane (0.63 mL, 6.46 mmol). After 3.5 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptanes/EtOAc (2:1) to give 1.12 g (90%) of yellow liquid: 1H NMR (400 MHz, CDCl3) δ 9.23, 7.94, 7.47, 7.02, 6.94, 4.14, 1.83, 0.95; IR (liq.) 2966, 2935, 2876, 1612, 1576, 1509, 1477, 1450, 1313, 1282, 1150, 761, 738, 716, 690 cm−1; HRMS (FAB) calcd for C13H15N3+H 214.1344, found 214.1336.
Reaction SMILES: [C:1]([O:23]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].N(CCCC)(CCCC)CCCC.O>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH3:21][O:20][C:18]([CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:23])=[O:19]
Reactant: COC(=O)CCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: COC(=O)C1CCCCCCC=CCCCCCCCC1=O
Yield: 27.9 %

Procedure:
Under an argon stream, to a suspension of ZrCl4 (338 mg, 1.45 mmol) in CH2Cl2 (1.0 ml) were added dropwise, at 0 to 5° C., a mixed solution of dimethyl cis-9-octadecenedioate (170 mg, 0.50 mmol) and Bu3N (278 mg, 1.50 mmol) in CH2Cl2 (4.0 ml) over a period of about 1 hour by means of a microfeeder. The whole was further mixed at the same temperature for 15 minutes. Water was added to the reaction mixture and the resulting mixture was stirred and then extracted with ether. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (hexane/ethyl acetate=20/1→10/1) to obtain the aimed product (43 mg, 28%) and a by-product (34-membered ring; 6 mg, 4%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]([CH3:26])[C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][N:16]([CH3:26])[C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: CN(C)c1cccc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 60.8 %

Procedure:
6-[3-(Dimethylamino)phenyl]-5-phenyl-1,2,4-triazin-3-amine (53 mg, 60%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-(dimethylamino)phenylboronic acid (56.7 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19](F)=[CH:20][C:21]=3[O:26][CH3:27])[N:16]=2)[CH:12]=[C:11]([CH3:29])[N:10]=1.O>CS(C)=O.C(O)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:20][C:21]=3[O:26][CH3:27])[N:16]=2)[CH:12]=[C:11]([CH3:29])[N:10]=1
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COCCOc1cc(OC)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxyethanol (3 mL) in dimethyl sulfoxide (8 mL), sodium hydride (60% suspension in mineral oil, 0.40 g, 9.40 mmol) was added in portions and the reaction mixture was stirred at room temperature for 1 hour. To this reaction mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.28 g, 0.94 mmol) and the reaction mixture was stirred at 90° C. for 16 hours. Water was added, acidified to pH approximately 4-5 with acetic acid, and the precipitated solid was filtered to give crude product, which was purified by preparative HPLC, to obtain the title compound as a white solid. Yield: 0.12 g (36%). MP 228.8-230.4° C. MS (ES) m/z: 356.05 (M++1). 1H NMR (400 MHz, CDCl3): δ 10.45 (s, 1H), 7.65 (s, 2H), 6.85 (d, J=1.6 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 4.27 (t, J=4.8 Hz, 2H), 3.97 (s, 3H), 3.82 (t, J=4.8 Hz, 2H), 3.49 (s, 3H), 2.66 (s, 6H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.[CH3:10][C:11]1([CH3:20])[CH2:16][CH:15]([NH2:17])[CH2:14][C:13]([CH3:19])([CH3:18])[NH:12]1>>[CH3:10][C:11]1([CH3:20])[CH2:16][CH:15]([NH:17][C:3]2[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=2)[CH2:14][C:13]([CH3:19])([CH3:18])[NH:12]1
Reactant: CSc1nccc(O)n1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(O)n2)CC(C)(C)N1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Neat 2-methylsulfanyl-pyrimidin-4-ol (5 g, 35 mmol) and 2,2,6,6-tetramethyl-piperidin-4-ylamine (8.243 g, 52.75 mmol) were heated to 170° C. with stirring for 2 hours. After cooling, the brown solid was triturated with ether. Filtration gave 8.16 g (93%) of 2-(2,2,6,6-Tetramethyl-piperidin-4-ylamino)-pyrimidin-4-ol. This crude (8 g, 32 mmol) was suspended in 160 ml of acetonitrile. Then, 4N-HCl in dioxane (24 ml, 96 mmol) and POCl3 (7.32 ml, 80 mmol) were added successively and the suspension was heated to reflux (105° C. heat bath) for 2 hours. After that, the mixture was cooled, diluted with EtOAc and washed twice with 2N-NaOH, then brine, dried over sodium sulfate and evaporated. Chromatography on silicagel (EtOAc/MeOH/ammonia:2/1/0.02) gave (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine as a beige solid. Yield: 7.68 g (89%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27]([N+:36]([O-:38])=[O:37])=[CH:26][CH:25]=1.[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[C:47]1[C:52]([C:53]2[NH:54][CH:55]=[CH:56][N:57]=2)=[CH:51][N:50]=[C:49]([NH:58][CH2:59][CH2:60][NH:61]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:48]=1>>[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[C:47]1[C:52]([C:53]2[NH:57][CH:56]=[CH:55][N:54]=2)=[CH:51][N:50]=[C:49]([NH:58][CH2:59][CH2:60][NH:61][C:24]2[N:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27]([N+:36]([O-:38])=[O:37])=[CH:26][CH:25]=2)[N:48]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CN(C)CCOc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(C)CCOc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
(2-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro(2-pyridyloxy)}ethyl)dimethylamine was prepared from [4-(2,4-dichloro-phenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and [2-(6-chloro-3-nitro(2-pyridyloxy))-ethyl]dimethylamine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:38])[N:26]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]2)[N:25]=1.[F-].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][N:26]([C@H:39]4[CH2:40][CH2:41][C@H:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:43][CH2:44]4)[C:27]=3[CH3:38])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c2C)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (62.3 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=553.24/555.24 (100/50) [MH+]. HPLC: tR=1.71 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].[CH2:22]=O>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:22][N:19]1[CH2:20][CH2:21][N:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:17][CH2:18]1
Reactant: O=C1COc2cc(O)ccc21
Reactant: C=O
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (0.600 g, 4.00 mmol) in ethanol (4 mL) was added with 1-(methylsulfonyl)piperazine (0.657 g, 4.00 mmol), and 37% aqueous formaldehyde (0.325 g, 4.00 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 6-hydroxy-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}benzofuran-3(2H)-one (0.169 g, 12%).
Reaction SMILES: [C:1]([NH:3][CH2:4][CH2:5][N:6]([CH2:20][C@@H:21]1[CH2:25][C@@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][N:22]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])#[N:2].O.O.C(O)(=O)C(O)=[O:48]>CC(C)=O.C(OCC)(=O)C>[CH3:30][S:27]([O:26][C@H:24]1[CH2:23][N:22]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[C@H:21]([CH2:20][N:6]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[CH2:5][CH2:4][NH:3][C:1]([NH2:2])=[O:48])[CH2:25]1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN(CCNC#N)C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN(CCNC(N)=O)C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a solution of (2S, 4R)-2-[N-{2-(cyanoamino)ethyl}-N-(4-nitrobenzyloxycarbonyl)aminomethyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.52 g) in acetone (30 ml) was added oxalic acid dihydrate (1.92 g) at ambient temperature. The mixture was stirred at the same temperature for 18 hours. Acetone was removed by evaporation to give a residue. A suspension of the syrup in ethyl acetate (100 ml) was washed in turn with 1N aqueous sodium hydroxide (50 ml×2), water (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98 v/v) to give (2S, 4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[N-(4-nitrobenzyloxycarbonyl)-N-(2-ureidoethyl)aminomethyl]pyrrolidine (1.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([CH:17]=3)[NH2:16])[N:10]=2)[CH:7]=1.C(#N)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([NH:16][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[CH:17]=3)[N:10]=2)[CH:7]=1
Reactant: Nc1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A 20 mL vial is charged with 5-(6-chloroimidazo[1,2-a]pyridin-2-yl)-2-(trifluoromethyl)aniline (0.156 g, 0.5 mmol), acetonitrile (4.12 mL) and pyridine (0.081 mL). The mixture is added trimethylacetyl chloride (0.123 mL, 0.001 mol) and stirred for 20 min at 80° C. The solution is concentrated, taken into EtOAc (10 mL) and washed once with HCl (10 mL, 1M) and NaOH (10 mL, 1M). Organics are dried, concentrated purified on silica (0-100% EtOAc in Hexanes) to give the title compound (106 mg, 54% yield). LCMS m/z=396.4 [M+H]+, tR=2.54 min. (compound same as Example 81)
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[C:26]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:27]
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1Cl
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2ccccc2Cl)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:28])[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2.[Cl:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:29][CH2:30][CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:28])[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2)=[O:34]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2NC1=O
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(NC(=O)CCCCl)c2NC1=O

Procedure:
tert-Butyl (2R)-1-(8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (300 mg) was dissolved in ethyl acetate (5 mL), and 4-chlorobutyryl chloride (0.1 mL) and saturated aqueous sodium bicarbonate solution (5 mL) were added thereto. The mixture was stirred under cooling on ice for 45 minutes and then subjected to extraction with water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (377 mg) was yielded.
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][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[N:30][CH:31]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1.[CH3:34][O:35][C:36]([NH:38][C:39](=NC(OC)=O)SC)=[O:37]>C(O)(=O)C>[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][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]4[NH:33][C:39]([NH:38][C:36](=[O:37])[O:35][CH3:34])=[N:32][C:29]4=[N:30][CH:31]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: COc1cc2nccc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2cc1OC
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(c3ccnc5cc(OC)c(OC)cc35)CCO4)cc2[nH]1
Temperature: 65 °C
Yield: 55 %

Procedure:
To a solution of 5-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridine-2,3-diamine (85 mg, 0.19 mmol) in acetic acid (3 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (40 mg, 0.19 mmol). The reaction mixture was heated (65° C.) for 18 h and then concentrated. The resulting residue was dissolved in acetonitrile and purified by preparative reverse phase HPLC to provide methyl (6-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-imidazo[4,5-b]pyridin-2-yl)carbamate (55 mg, 54% yield) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ 7.93 (br, 2H), 7.93 (br, 1H), 7.78 (br, 1H), 7.59 (dd, 1h), 7.31 (s, 1H), 7.14 (dd, 1H), 7.09 (s, 1H), 6.95 (d, 1H), 4.60 (s, 2H), 4.43 (m, 2H), 3.89 (s, 3H), 3.78 (s, 3H), 3.73 (m, 2H), 3.53 (s, 3H), MS (EI) for C28H26N6O5: 527 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1.[CH2:22]([SH:24])[CH3:23].P(OC#N)(OCC)(OCC)=O.C(N(CC)CC)C>O.C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[S:24][CH2:22][CH3:23])[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1
Reactant: CCS
Reactant: COc1cc(OC)nc(Oc2ccc(N)nc2C(=O)O)n1
Agent: CCOP(=O)(OC#N)OCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCSC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
2.5 g (8.5 mmol) of 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinic acid, 0.64 g (10.3 mmol) of ethylmercaptan, 2.8 g (17 mmol) of diethyl cyano phosphate and 1.73 g (17.1 mmol) of triethylamine were added to a THF solution, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate, followed by separation, washed with water and dried. Then, the solvent was distilled off, and the residual oily product was purified by column chromatography to obtain the desired product as colorless transparent crystals.