Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.B(F)(F)F.[CH3:25]COCC.C(=O)(O)[O-].[Na+].[CH2:35]1[CH2:40][CH2:39]CCC1>>[C:40]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:13])[F:14])[O:9]2)=[CH:4][CH:3]=1)([CH3:39])([CH3:35])[CH3:25]
Reactant: CCOC(=O)C1=Cc2ccc(O)cc2OC1C(F)(F)F
Reactant: C1CCCCC1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1=Cc2ccc(OC(C)(C)C)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Ethyl 7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 1a, Step 1 (2.0 g, 6.94 mmole) was treated with t-butyl trichloroacetaimidate in cyclohexane at room temperature. After addition of a catalytic amount of boron trifluoride etherate (139 uL), the mixture (orange solid precipitated) was stirred at room temperature overnight. Solid sodium bicarbonate (2.33 g, 27.76 mmole) was added into the mixture. The mixture was passed through the silica plug and was washed with 6% ethyl acetate in hexane. The filtrate containing the product was evaporated to give yellow oil (1.34 g, 56%) having >90% purity: LCMS m/z 367.00 (M+Na). 1H NMR (CDCl3/400 MHz) 7.70 (s, 1H), 7.12 (m, 1H), 6.63 (s, 1H), 6.61 (m, 1H), 5.68 (q, 1H, J=7.2 Hz), 4.30 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz). This ester was of suitable purity to use without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:56][C:57]1[NH:58][C:59]2[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=2[N:61]=1>C(Cl)Cl>[NH:58]1[C:59]2[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=2[N:61]=[C:57]1[NH:56][C:13](=[O:15])[CH:12]([C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Br:1])[CH:3]=1)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: Nc1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1Br
Yield: 52.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.266 mmol), triethylamine (110 μL, 0.80 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (187 mg, 0.42 mmol), and 2-aminobenzimidazole (56 mg, 0.42 mmol) in methylene chloride (10 mL) was stirred at 25° C. for 1.5 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 chloroform/methanol) afforded N-(1H-benzimidazol-2-yl)-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (69 mg, 53%) as a white solid: mp>220° C.; EI-HRMS m/e calcd for C22H24BrN3N3OS(M+) 489.722, found 489.727.
Reaction SMILES: C(NCC)C.CC(O)(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH2:20][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: CCNCC
Product: COc1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a vigorously stirred mixture of zinc chloride (5 g, 36.6 mmol) in anhydrous toluene (200 mL) is added a mixture of diethylamine (2.82 mL, 27.5 mmol) and t-BuOH (2.61 mL, 27.5 mmol) under Argon. After 1 h, 4′-methoxyacetophenone (4.12 g, 27.45 mmol) and 2-bromoacetophenone 1 (3.64 g, 18.3 mmol) are added sequentially. The mixture is stirred for 3 days at room temperature. The mixture is washed with 5% H2SO4 (200 mL) and the organics separated. The aqueous layer is washed with ethyl acetate (2×100 mL). The organics are combined, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (hexane/ethyl acetate (5→15%)) afforded 1-(4-Methoxy-phenyl)-4-phenyl-butane-1,4-dione (1.8 g), characterized by LCMS (Obs: 269.09, Cal: 268.11) and 1H NMR.
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:10](=[O:21])[CH:9]=1.Cl.[OH:28][C@@H:29]([CH2:59]O)[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([NH:36]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:32]1.[CH:61](N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[OH:28][C:29]([CH3:59])([CH3:61])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([NH:36][C:14](=[O:16])[C@@H:13]([N:11]2[CH2:12][C:8]([O:7][C:6]3[CH:22]=[CH:23][CH:24]=[C:4]([CH2:3][C:2]([OH:1])([CH3:26])[CH3:25])[CH:5]=3)=[CH:9][C:10]2=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:32]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.3 %

Procedure:
To a solution of (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (prepared as in Example 235, 0.159 g, 0.44 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.102 g, 0.66 mmol), N,N-diisopropylethylamine (0.312 g, 2.41 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.778 g, 1.76 mmol) at 0° C. The mixture was allowed to slowly warm up to room temperature and stirred for 48 h. The mixture was then concentrated in vacuo, the residue taken up in ethyl acetate and washed with aqueous saturated ammonium chloride and brine and then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ISCO column chromatography (Silicycle 40 g, 10% to 100% ethyl acetate/hexanes) which afforded (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.060 g, 30%) as a white solid: HR-ES-MS m/z calculated for C27H38N4O5 [M+H]+ 499.2915, observed 499.2915; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83-0.97 (m, 6H), 1.06 (br. s., 12H), 1.36-1.63 (m, 2H), 1.66-1.86 (m, 1H), 2.68 (s, 2H), 3.89 (s, 2H), 4.18 (d, J=18.1 Hz, 1H), 4.37 (d, J=1.8 Hz, 1H), 4.57 (d, J=18.1 Hz, 1H), 4.68 (d, J=1.5 Hz, 1H), 4.83 (s, 1H), 4.84-4.94 (m, 1H), 6.44 (s, 1H), 7.07-7.19 (m, 3H), 7.27-7.42 (m, 1H), 7.54 (s, 1H), 10.78 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=2N)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][C:35]=2[NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.4 %

Procedure:
A solution of the product from Example 10B (62 mg, 0.331 mmol), and the product of Example 63B (120 mg, 0.331 mmol) in acetic acid (1 mL) was stirred in an oil bath preheated to 130° C. for 20 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum leaving a brown oil as the title compound (0.15 g, 92%). The compound was used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][NH:26][C:27](=O)[O:28]C3C=CC=CC=3)=[CH:23][C:22]([C:36]([F:39])([F:38])[F:37])=[N:21]2)[CH:17]=[CH:18][CH:19]=1.O>C(#N)C.CN(C1C=CN=CC=1)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][NH:26][C:27](=[O:28])[NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=3)=[CH:23][C:22]([C:36]([F:37])([F:38])[F:39])=[N:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Temperature: 25 °C
Yield: 53.7 %

Procedure:
To a solution of methyl 4-amino-2-fluorobenzoate (870 mg, 5.143 mmol) in acetonitrile was added DMAP (691 mg, 5.657 mmol) and phenyl (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (2036 mg, 5.143 mmol) at room temperature. The reaction mixture was refluxed overnight and then cooled to room temperature. The mixture was added water and extracted with EtOAC. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography to give pure methyl 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoate (1.3 g, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](N)=[O:5].N([O-])=[O:14].[Na+].[N+]([O-])=O.O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:14])=[O:5]
Reactant: Cc1cc(F)cc(Br)c1C(N)=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[N+][O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)cc(Br)c1C(=O)O
Temperature: 20 °C
Yield: 96.7 %

Procedure:
2-Bromo-4-fluoro-6-methylbenzamide (0.9 g, 3.9 mmol) was dissolved in 75% aqueous sulfuric acid (4 mL) at 80° C. sodium nitrite (0.5 g, 7.2 mmol) was carefully added in small portions during 1 hour. At the end of addition a persistent color of nitrogen dioxide appeared. The reaction mixture was chilled to 20° C. and cold water (15 mL) was added to the reaction mixture. The product was extracted with ethyl acetate (6×2 mL). The organic phase was washed with water (4×2 mL), brine (2×2 mL), dried with sodium sulfate, filtered and concentrated to give 0.879 g (97%) of pure acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11](Cl)[N:10]=[C:9]([Cl:14])[CH:8]=2)[CH2:3][CH2:2]1.[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[H-].[Na+]>O1CCCC1>[Cl:14][C:9]1[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:12]=[C:11]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:10]=1
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
6-Morpholino-2,4-dichloropyrimidine (4.6 g; 20 mmol) and 4-(2-hydroxyethyl)-morpholine (3.3 g; 25 mmol) were dissolved in tetrahydrofuran (200 mL), and chilled in an ice bath. To the solution was added sodium hydride (600 mg; 25 mmol), and it was stirred overnight at room temperature. The solvents were evaporated, and the solid was dissolved in dichloromethane (200 mL) which was then washed with water (2×100 mL). The organic layer was dried over magnesium sulfate, evaporated, and purified by column chromatography to give 4-[2-(4-Chloro-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (4.5 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].C[I:12].[C:13](OCC)(=O)C>C(O)C>[I-:12].[CH3:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[CH2:4][N+:2]([CH3:13])([CH3:3])[CH3:1]
Reactant: CN(C)Cc1cccn1C
Reactant: CCOC(C)=O
Reactant: CI
Solvent: CCO
Product: Cn1cccc1C[N+](C)(C)C
Product: [I-]
Yield: 91 %

Procedure:
Subsequently, to absolution of 2-(N,N-dimethylaminomethyl)-1-methylpyrrole (30.00 g, 217.5 mmol) obtained above in ethanol (220 ml) was added methyl iodide (16.2 ml, 260–2 mmol) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 2 hours. After stirring, ethyl acetate (220 ml) was added to the reaction mixture. The crystals precipitated were collected by filtration, washed with ethyl acetate and dried to afford (1-methylpyrrol-2-yl)methyl trimethylammonium iodide (55.34 g, yield: 91%).
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2OC(=O)c2ccccc2)c(O)c(C(C)(C)C)c1
Yield: 96 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 122.12 g (1.0 mole) of benzoic acid, 500 g of toluene and 242.86 g (2.4 moles) of triethylamine. After replacing the air in the container with nitrogen, 229.15 g (1.2 moles) of o-toluenesulfonyl chloride was added dropwise with stirring. After completion of the dropwise addition, temperature maintenance and after-treatment were carried out in the same manner as in Example 3 to obtain 426.83 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monobenzoate having a melting point of 149° to 151° C. Yield, 96%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1[C:21]([NH2:22])=[CH:20][NH:19][N:18]=1)=[O:16])[CH3:13].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:12]([O:14][C:15]([C:17]1[C:21]([NH:22][C:4](=[O:6])[C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[CH:20][NH:19][N:18]=1)=[O:16])[CH3:13]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CCOC(=O)c1n[nH]cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-difluorobenzoic acid (6.32 g, 40.0 mmol), 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester (5.96 g, 38.4 mmol), EDC (8.83 g, 46.1 mmol) and HOBt (6.23 g, 46.1 mmol) in DMF (100 ml) was stirred at ambient temperature for 6 h. The mixture was reduced in vacuo, water added and the solid formed collected by filtration and air-dried to give 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid ethyl ester as the major component of a mixture (15.3 g). (LC/MS: Rt 3.11, [M+H]+ 295.99).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[CH:12]=[CH2:13].Cl.[CH2:15]([NH2:19])[CH2:16][CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([NH:19][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:12]=[CH2:13])[CH2:16][CH:17]=[CH2:18]
Reactant: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: C=CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCNc1c([N+](=O)[O-])ccc(F)c1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To an ice-cooled solution of 1,3-difluoro-4-nitro-2-vinylbenzene (389 mg, 2.1 mmol) in DMF (8 mL) was added 3-butenylamine hydrochloride (248 mg, 2.31 mmol) and potassium carbonate (0.87 g, 6.3 mmol). The reaction mixture was stirred at RT for 2 h, and then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 2-4% EtOAc in cyclohexane) affording the title compound as an orange oil (327.6 mg, 66%). LCMS (Method B): RT 4.27 min [M+H]+ 237
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:12][N:5]2[C:6](=[O:11])[C:7]=1[N+:8]([O-])=O.C(O)(=O)C>CN(C)C=O.[C].[Pd]>[NH2:8][C:7]1[C:6](=[O:11])[N:5]2[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:19][CH:20]=3)[S:14][C:4]2=[N:3][C:2]=1[NH2:1]
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(N)nc3s2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c(N)c(N)nc3s2)cc1
Yield: 79.6 %

Procedure:
2.75 g of 7-amino-2-(4-tert-butylphenyl)-6-nitro-5H-[1,3,4] thiadiazolo[3,2-a]pyrimidin-5-one was dissolved in 200 ml of warmed dimethylformamide, and 20 ml of acetic acid and 2.0 g of 5% palladium-carbon were added to the solution. Catalytic reduction was carried out at a temperature of 40° to 60° C. After the calculated amount of hydrogen was absorbed, the catalyst was removed by filtration while hot, and the filtrate was concentrated under reduced pressure. The precipitate formed was separated by filtration to obtain 2.0 g of 6,7-diamino-2-(4-tert-butylphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as yellow needles.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].[OH2:39]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:26])[CH:13]([O:29][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:39])=[O:30])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reactant: O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution [1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (3.4 mg, 0.009 mmol) dissolved in anhydrous dichloromethane (1.0 mL) is added TsCl (1.94 mg, 0.011 mmol), DMAP (1.24 mg, 0.011 mmol) and TEA (21.3 μL, 0.015 mmol). The reaction mixture continues stirring at room temperature overnight. The next day, the reaction mixture is diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using silica gel chromatography to yield the desired product.
Reaction SMILES: [C:1]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OCC)C.[Cl:26][CH2:27][C:28]([O:30][CH2:31]/[CH:32]=[C:33](/[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])\[CH3:34])=[O:29].ClCC([O-])=O>CCCCCC>[Cl-:26].[CH3:20][N+:18]([CH3:19])([CH2:27][C:28]([O:30][CH2:31]/[CH:32]=[C:33](/[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])\[CH3:34])=[O:29])[CH2:17][CH2:16][CH2:15][NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NCCCN(C)C
Reactant: CC(C)=CCC/C(C)=C/COC(=O)CCl
Agent: O=C([O-])CCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC(=O)OC/C=C(\C)CCC=C(C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.4 %

Procedure:
A 22.76 g (0.080 mol) portion of N-dodecanoyl-N′,N′-dimethyl-1,3-diaminopropane and 120 ml of diethyl ether were put into a flask, and 18.46 g (0.080 mol) of geranyl chloroacetate was added thereto at 25° C. spending 5 minutes. The reaction mixture was stirred at 25° C. for 24 hours, and disappearance of the most part of chloroacetate was confirmed by 1H-NMR. Next, the reaction mixture was slowly added dropwise to 600 ml of hexane which was ice-cooled and vigorously stirred, spending 10 minutes, to effect precipitation of the product as a white solid. Thereafter, in the same manner as described in Inventive Example 1, the title compound (to be referred to as betaine ester (3) hereinafter) was obtained as a light yellow viscous oil. Yield 38.50 g (0.0747 mol; yield 93.4%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33]>>[CH:18]1([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: N#Cc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 96.9 %

Procedure:
The title compound (135.4 mg) was prepared as in Example 177, Steps C and D, using 203.8 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 198 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C20H24N4, 320.43. found, m/z 321.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.93 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 3.92-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.19-3.15 (m, 2H), 2.80-2.75 (m, 2H), 1.98-1.80 (m, 6H), 1.71-1.64 (m, 1H), 1.32-1.20 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=1.[OH:35]O>C(O)(=O)C.O>[CH3:34][S:33]([C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][O:24][C:4]2[CH:5]=[C:6]([CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)=[O:8])[CH:32]=[CH:31][CH:30]=1)=[O:35]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(SC)c1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of example 16 (35 mg, 0.078 mmol) was dissolved in acetic acid (2.5 ml), hydrogen peroxide (43 mg of a 30% solution in water, 0.38 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was partitioned between EA and a 1% aqueous sodium sulfite solution, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to give 36 mg of the title compound.