Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:11][CH2:10]2)[C:3]=1[NH2:12].[CH2:13]([C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:12][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[N:23][C:15]=2[CH2:13][CH3:14])=[C:4]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]=[CH:6][N:7]=1
Reactant: CCc1ncccc1C(=O)Cl
Reactant: Nc1c(Cl)ncnc1NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ncccc1C(=O)Nc1c(Cl)ncnc1NC1CC1
Temperature: 0 °C

Procedure:
6-Chloro-N-cyclopropylpyrimidine-4,5-diamine (cf. Journal of Combinatorial Chemistry (2003), 5(5), 653-659) (3.0 g, 16.2 mmol) was initially charged in a mixture of methylene chloride (12.20 ml) and pyridine (3.94 ml). The suspension was cooled to 0° C., and solid 2-ethylnicotinoyl chloride (1.2 eq) was added. The reaction mixture was allowed to warm to room temperature and stirred until the reaction had gone to completion. 10 ml of methylene chloride were then added, the suspension turning into a solution. About 10 ml of semisaturated NaHCO3 solution were added to the organic phase whilst the mixture was stirred vigorously in a flask using a magnetic stirrer; poorly soluble crystals (product) precipitated and were filtered off with suction, washed 3× with a little water and 3× with n-heptane and dried.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=2[O:9][CH:8]=1)(=O)=O.[C:20]([Si](C)(C)C)#[C:21][CH2:22][CH3:23]>>[C:20]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=2[O:9][CH:8]=1)#[C:21][CH2:22][CH3:23]
Reactant: CCC#C[Si](C)(C)C
Reactant: COc1cccc2c(OS(=O)(=O)C(F)(F)F)coc12
Product: CCC#Cc1coc2c(OC)cccc12

Procedure:
The title compound was prepared from 7-methoxybenzofuran-3-yl trifluoromethanesulfonate and Intermediate 39 following General Procedure B. 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (s, 1H), 7.26 (t, 1H), 7.17 (d, 1H), 6.99 (d, 1H), 3.94 (s, 3H), 2.52-2.47 (m, 2H), 1.21 (t, 3H). LCMS: 201 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=O)[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[S:25])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C)c2c(=S)[nH]c(-c3ccccc3OCC)nn12
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
2-(2-ethoxy)-phenyl-5-methyl-7-n-propyl-3H-imidazolo[5,1-f][1,2,4]triazine-4-one (50 g (0.16 mol)), phosphorus pentasulfide (17.8 g (0.08 mol)), pyridine (250 ml) were added into a 500 ml three-neck flask with a mechanical stirrer, stirred, heated and refluxed for 6 hours, TLC tracing was performed until the reactants were totally disappeared. The solvent pyridine was removed by distilling under reduced pressure, concentrated ammonia water ((25-28%) 75 ml) and ethanol (300 ml) were added, heated and refluxed for 30 min. It was cooled, filtered, dried, and crude product (45 g) was obtained. The crude product was heated and solved into chloroform (150 ml), activated carbon (5 g) was added, stirring and reflux was performed for 30 min, it was filtered and the filtrate was washed with saturated brine and water consequently and dried with magnesium sulfate anhydrous, chloroform was removed by distilling, the obtained solid was re-crystallized with ethanol and dried, solid (38 g) was obtained with a yield of 72%.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:22])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12](O)=[O:13].S(Cl)([Cl:25])=O>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:22])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12]([Cl:25])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: C#CCOc1c(F)cc(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1c(F)cc(C(=O)Cl)cc1F

Procedure:
To 17 ml of toluene were added 1.8 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid, 1 ml of thionyl chloride and 10 mg of DMF, and the mixture was heated under reflux for 4 hours. Then, the reaction mixture was concentrated under reduced pressure to obtain 1.9 g of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride represented by the formula:
Reaction SMILES: ClCCl.[C:4]1([N:10]2[CH2:15][CH2:14][N:13]([C:16]([NH2:18])=[O:17])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][N:20]=[C:21]=[O:22]>O>[CH3:19][NH:20][C:21](=[O:22])[NH:18][C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH2:14]1)=[O:17]
Reactant: NC(=O)N1CCN(c2ccccc2)CC1
Reactant: CN=C=O
Solvent: O
Solvent: ClCCl
Product: CNC(=O)NC(=O)N1CCN(c2ccccc2)CC1
Yield: 51.5 %

Procedure:
Into 70 ml of dichloromethane, were dissolved 4.1 g of 4-phenylpiperazine-1-carboxamide and 1.2 g of methyl isocyanate. To the solution, while being stirred and cooled in ice, was added dropwise 5.2 g of stannic chloride. After 15 hours of reaction at room temperature, water was added to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate and freed from the solvent by distillation. The residue was recrystallized from ethanol to obtain 2.7 g (51% yield) of 1-(4-methylallophanoyl)-4-phenylpiperazine having a melting point of 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-])=O)=[N:8][C:4]=2[CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH2:16])=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1Sc1nc2cc(Cl)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1Sc1nc2cc(Cl)ccc2[nH]1
Reaction time: 8 h
Yield: 85 %

Procedure:
2-(5-Chloro-1H-benzimidazol-2-yl thio)nitrobenzene (0.3 g) was dissolved in dry ethanol (100 ml) with warming and the solution was hydrogenated in the presence of 10% Pd/C at 3 atmospheres pressure and 50° for 2.75 hours. The heating and stirring were stopped and the mixture was left standing under an H2 atmosphere overnight. The mixture was then filtered through a filter aid and evaporated under reduced pressure, and dried under vacuum at 50° to leave the sub-title compound as a pale greenish glassy solid (0.23 g), mp 155°-156°.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[C:29]([Cu])#[N:30].O>CN(C=O)C.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>[C:29]([C:2]1[C:3]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6])#[N:30]
Reactant: N#C[Cu]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc(Br)c1N1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)cc(C(=O)Nc2ccc(Cl)c(Cl)c2)c1N1CCCCC1

Procedure:
To a solution of 3-bromo-N-(3,4-dichlorophenyl)-2-piperid-1-yl-5-trifluoromethylbenzamide, Example 3 (620 mg; 1 eq.) in DMF (10 ml, degassed for 1 hour with nitrogen), are added CuCN (200 mg; 1.8 eq.) and Pd(PPh3)4 (58 mg; 0.04 eq.). After refluxing for 3 hours under a nitrogen atmosphere, the reaction medium is cooled and poured into 20 ml of water. The product is extracted with ethyl acetate. After washing with water and then with saturated NaCl solution, the organic phase is dried over Na2SO4 and concentrated under vacuum. The oil obtained is purified by chromatography on silica (eluent: 9/1 heptane/EtOAc). 310 mg of 3-cyano-N-(3,4-dichlorophenyl)-2-piperid-1-yl-5-trifluoromethylbenzamide are obtained (white solid: m.p.=175° C.)
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[NH:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:33][C:30]4[CH:31]=[CH:32][NH:28][N:29]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CC(C)CNc1nc2ccccc2n2c(-c3ccc(C(=O)O)cc3)cnc12
Reactant: Nc1cc[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: CC(C)CNc1nc2ccccc2n2c(-c3ccc(C(=O)Nc4cc[nH]n4)cc3)cnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
0.1 mmol 4-{4-[(2-methylpropyl)amino]imidazo[1,2-a]quinoxalin-1-yl}benzoic acid (1.0 mL, 0.1 M in NMP) (example 1.5), 0.2 mmol 1H-pyrazol-3-amine (1 mL, 0.5 M in NMP, 2 eq), 0.2 mmol HATU (1 mL, 0.5 M in NMP, 2 eq) and 0.4 mmol NMM (0.133 mL, 3 M in NMP, 4 eq) were combined, shaken at rt for 24 h and subjected to preparative HPLC to give 7.6 mg 4-{4-[(2-methylpropyl)amino]imidazo[1,2-a]quinoxalin-1-yl}-N-(1H-pyrazol-3-yl)benzamide (18%): UPLC-MS: RT=1.04 min; m/z (ES+) 426.5 [MH+]; required MW=425.5.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][N:12]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[N:12][CH:11]=1
Reactant: COC(=O)CCCCc1ncc(-c2ccccc2OC)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1cnc(CCCCC(=O)O)o1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75.3 %

Procedure:
Dissolve 5-[5-(2-methoxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.47 g, 8.54 mmol) in 40 mL of dioxane and add a solution of LiOH (1.0344 g, 43.19 mmol) in 20 mL of water to the solution. Allow the reaction to stir at ambient temperature for 21 hours. Acidify the reaction with 5N HCl and concentrate the reaction mixture in vacuo to remove the dioxane. Extract the aqueous residue with EtOAc (3×). Dry the combined organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Recrystallize the residue in EtOAc/hexanes to afford 1.7692 g of the titled product (75%): mass spectrum: m/z=276.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1>>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Clc1ccnc2ncccc12
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.304 mmol) was reacted with the product from Example 18b (83 mg, 0.304 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (29 mg, 24%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.04 (s, 3H), 2.35 (s, 3H), 6.34 (d, J=6.99 Hz, 1H), 7.17 (d, J=7.72 Hz, 1H), 7.23 (d, J=8.46 Hz, 2H), 7.28-7.34 (m, 2H), 7.49 (d, J=8.82 Hz, 2H), 7.90 (dd, J=8.46, 4.41 Hz, 1H), 8.48 (d, J=6.99 Hz, 1H), 9.11 (dd, J=8.46, 1.47 Hz, 1H), 9.17 (dd, J=4.41, 1.47 Hz, 1H), 10.04 (s, 1H), 11.12 (s, 1H); MS (ESI+) m/z 401 (M+H)+, (ESI−) m/z 399 (M−H)−.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[N+]([O-])([O-])=[O:8].[Na+]>>[Si:2]([O-:8])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[N+]([O-])[O-]
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
An aqueous solution (c-2) of silica particles was prepared in accordance the paragraphs [0012] to [0031] of the description of JP 06-16414 A. To be specific, sodium water glass JIS No. 3 was dissolved in an aqueous sodium nitrate solution, thereby producing an aqueous sodium silicate solution. The aqueous sodium silicate solution was passed through a hydrogen-type cation exchange resin column, a hydroxyl group-type anion exchange resin column, and again, the hydrogen-type cation exchange resin column in the stated order. Thereafter, an aqueous sodium hydroxide solution was added, thereby obtaining an aqueous silicic acid solution. Subsequently, the aqueous silicic acid solution in an amount equivalent to 20% was subjected to vacuum distillation for removing evaporated water, and simultaneously, the remaining aqueous silicic acid solution was continuously and gradually supplied for successively performing the vacuum distillation, thereby producing a colloidal silica sol. The colloidal silica sol was passed through a hydrogen-type cation exchange resin column, a hydroxyl group-type anion exchange resin column, and again, the hydrogen-type cation exchange resin column in the stated order. Immediately thereafter, a special grade aqueous ammonia was added, thereby obtaining an aqueous silica sol (c-2) in which the pH was 9, the average particle diameter was 4 nm, and the concentration of each of various metal oxides was lower than 500 ppm (reactive functional group: silanol group; proportion: 100 mol %).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:11][C:6]1[S:5][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1nc(C)cs1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(C)c(Br)s1

Procedure:
N-(4-Methyl-thiazol-2-yl)-acetamide (Example 17a) (4.0 g, 25.6 mmol) is dissolved in glacial acetic acid (100 ml) at room temperature. This solution is then treated portionwise with N-bromosuccinimide (4.6 g, 25.6 mmol). After 48 hours the reaction mixture is poured into water (1000 ml) and extracted with ethyl acetate (3×250 ml). The combined organic layers are washed with water (200 ml), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in toluene (100 ml) followed by the removal of the solvent in vacuo. This is repeated twice more and the resulting solid is dried in vacuo at 40° C. to give N-(5-bromo-4-methyl-thiazol-2-yl)-acetamide.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])([CH3:23])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH3:22][CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH:21]([CH3:23])[CH3:22])=[O:13])[CH3:23]
Reactant: CC(C)c1ccccc1N
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1C(C)C
Yield: 14.3 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-isopropylaniline (1.60 g, 11.6 mmol) in 13 mL of pyridine. The crude product was recrystallized twice from acetonitrile-DMF to yield 0.45 g of the title compound, mp 235-237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]([NH:47][C:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45](=[O:46])[NH:47][C:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 63 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide (Compound IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[N:15][NH:16][C:17](=[O:19])[CH2:18][CH:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[N:15][NH:16][C:17](=[O:19])[CH:18]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2=NNC(=O)CC2CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(=O)[nH]nc2CC1
Yield: 79.2 %

Procedure:
7 g 3-oxo-2,3,4,4a, 5,6,8,9-octahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester was dissolved in 70 mL toluene and 6.7 g manganese dioxide was added to the reaction mixture. It was heated at reflux for 48 h. After completion of the reaction, the reaction mixture was diluted with chloroform and filtered through celite. The filtrate was concentrated and purified by column chromatography to afford 5.5 g of the desired product. (M+H)+=266
Reaction SMILES: ClCCl.[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([OH:15])=[O:14].[F:16][C:17]([F:25])=[C:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22]O.CN(C1C=CC=CN=1)C>O>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([CH3:24])=[C:17]([F:25])[F:16])=[O:14]
Reactant: O=C(O)c1nc2ccccc2s1
Reactant: CC(CCCCO)=C(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CC(CCCCOC(=O)c1nc2ccccc2s1)=C(F)F
Reaction time: 20 h
Yield: 43.8 %

Procedure:
To 4 ml of dichloromethane were dissolved 0.24 g (1.3 mmol) of benzothiazole-2-carboxylic acid, manufactured by a method described in “J. Amer. Chem. Soc.”, page 2328 (1949), 0.17 g (1.1 mmol) of 6,6-difluoro-5-methyl-5-hexenol and 0.13 g (1.1 mmol) of dimethylaminopyridine, followed by the addition of 0.38 g (2.0 mmol) of N-ethyl-N′-3-dimethyl-aminopropylcarbodiimide (WSC) hydrochloric acid salt at room temperature and stirring at the same temperature for 20 hours. The reaction liquid was then poured in water and extracted with dichloromethane. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:6) to obtain 0.15 g (yield: 43%) of 6,6-difluoro-5-methyl-5-hexenyl benzothiazole-2-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH2:46][C:47](OC)=[O:48])[S:36]([C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[C:47](=[O:48])[CH2:46][N:35]([CH3:34])[S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(NCc2ccc(Br)cc2)cc1OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 90 %

Procedure:
Secondary aniline 2 was coupled to carboxylic acid 6 on a 0.2 mmol scale via General Procedure B to furnish 9 (167 mg, 90%): δH (400 MHz, CDCl3) 2.33 (s, 3H, CH3Ar), 2.73 (s, 3H, CH3Ar), 3.54 (s, 2H, CH2CO), 4.64 (s, 2H, CH2Ar), 4.99 (s, 2H, CH2Ar), 5.28 (s, 2H, CH2Ar), 6.50 (br s, 1H, CH (Ar)), 6.55 (dd, J=8.3 and 1.8 Hz, 1H, CH (Ar)), 6.88 (d, J=8.3 Hz, 2H, 2 CH (Ar)), 7.16-7.34 (m, 14H, 14 CH (Ar)), 7.51 (d, J=8.3 Hz, 2H, 2 CH (Ar)), 7.75 (d, J=8.3 Hz, 1H, CH (Ar)); δC (100 MHz, CDCl3) 21.4, 29.6, 36.0, 51.2, 52.4, 53.3, 66.9, 70.7, 113.9, 119.8, 120.9, 121.7, 126.9, 127.3, 127.9, 128.2, 128.5, 129.4, 130.5, 131.6, 133.1, 135.2, 135.5, 135.6, 135.7, 143.3, 144.7, 158.7, 165.2, 167.0; LRMS (ES+) Calcd for [C38H35BrN2O6S+H] 727.15 found 726.83.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[O-:27][C:28]#[N:29].[K+]>O>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:28]([NH2:29])=[O:27])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(NC(N)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a 2 ml water/4 ml acetic acid solution of 200 mg (0.567 mmol) of the compound obtained in Example 44, 377 mg (4.65 mmol) of potassium cyanate was added, and the mixture was stirred at room temperature for 3 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 126 mg (56%) of the captioned compound.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.CCO.O.[NH2:23][NH2:24]>O>[F:8][C:7]1[C:2]([NH:23][NH2:24])=[N:3][C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][CH:6]=1
Reactant: COc1cccc(COc2ncc(F)c(Cl)n2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cccc(COc2ncc(F)c(NN)n2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A 125 mL Erlenmeyer flask was charged with 4-chloro-5-fluoro-2-(3-methoxybenzyl-oxy)pyrimidine (1.50 g, 5.58 mmol) and EtOH (50 mL). Hydrazine monohydrate (900 μL, 18.5 mmol) was added, and the resulting mixture was allowed to stir at room temperature. After 22 h, the reaction was transferred to a 500 mL Erlenmeyer flask and diluted with water (200 mL), whereupon a white solid began to precipitate from solution. After stirring for 7 h, solid product was collected in a fritted funnel and rinsed with excess water. After drying on the frit, the title compound was obtained (1.23 g, 83%) as a white solid: mp 103-106° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92 (bs, 1H), 7.86 (d, J=3.6 Hz, 1H), 7.27 (t, J=8.1 Hz, 1H), 6.94-7.01 (m, 2H), 6.87 (dd, J=2.4, 7.9 Hz, 1H), 5.24 (s, 2H), 4.46 (bs, 2H), 3.74 (s, 3H); MS (ESI) m/z 265.2 (M+H)+, 263.2 (M−H)−.