Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29](=[O:55])[N:30]([C@H:40]3[CH2:45][CH2:44][C@H:43]([O:46][CH2:47][C:48]4([C:52]([NH2:54])=[O:53])[CH2:51][CH2:50][CH2:49]4)[CH2:42][CH2:41]3)[C:31]3[N:32]([N:37]=[CH:38][N:39]=3)[C:33]=2[CH2:34][CH2:35][CH3:36])=[CH:23][CH:22]=1)#[N:14]>C(OCC)(=O)C>[O:55]=[C:29]1[C:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]3[NH:3][C:4](=[O:7])[O:5][N:14]=3)=[CH:26][CH:25]=2)=[C:33]([CH2:34][CH2:35][CH3:36])[N:32]2[N:37]=[CH:38][N:39]=[C:31]2[N:30]1[C@H:40]1[CH2:41][CH2:42][C@H:43]([O:46][CH2:47][C:48]2([C:52]([NH2:54])=[O:53])[CH2:51][CH2:50][CH2:49]2)[CH2:44][CH2:45]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(N)=O)CCC3)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(N)=O)CCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 1-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]methyl}cyclobutanecarboxamide (0.37 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.26 g, 64%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:11]\[OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O/N=C\c1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
To a suspension of 4-fluoro-benzaldehyde (30.4 g, 0.24 mol) in water (50 mL) was added at 0-5° C. within 5 minutes a solution of hydroxylamine hydrochloride (17.7 g, 0.25 mol) in water (30 mL) and the resulting mixture stirred for 15 minutes at 0-5° C. The mixture was then treated at 15-25° C. within 15 minutes with 32% NaOH (24.44 mL, 0.26 mol) and the resulting suspension was stirred for one additional hour and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL) and subsequently concentrated to dryness to afford 31.9 g (95%) of the title oxime as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:9]([CH:22]([CH3:24])[CH3:23])[CH:8]=1)(=O)=O.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C:10]1[CH:11]=[CH:12][C:7]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:8][C:9]=1[CH:22]([CH3:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1C(C)(C)O[SiH2]C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C#C[Si](C)(C)C)ccc1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 95 °C
Yield: 23.6 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenyl 1,1,1-trifluoromethansulfonate (Intermediate 150, 970.0 mg, 2.35 mmols) in triethylamine (2 mL) and 6 mL DMF was sparged with argon for 15 minutes. Trimethylsilyl acetylene (1.00 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (66.0 mg, 0.09 mmol). The resulting reaction mixture was heated to 95° C. for 20 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound (200.0 mg, 78%) was isolated by chromatography (0-25% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[C:9]([I:23])[CH:8]=2)=[C:5]([CH3:24])[O:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.I[CH2:37][CH3:38]>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([N:16]([CH2:37][CH3:38])[C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])=[C:9]([I:23])[CH:8]=2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: CCI
Reactant: Cc1noc(C)c1-c1cc(I)c(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C(=O)C(F)(F)F)c1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of N-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-2,2,2-trifluoroacetamide (2.2 g, 4.83 mmol), cesium carbonate (3.94 g, 12.08 mmol) and N,N-Dimethylformamide (100 ml) was stirred at room temperature under argon. To the mixture was added iodoethane (3.77 g, 24.17 mmol) and reaction was heated to 45° C. overnight. Crude mixture was diluted in EtOAc and water and extracted 3 times with EtOAc. Organics were washed with water, aq LiCl, then brine, dried over sodium sulfate and evaporated to dryness under reduced pressure to afford crude N-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-N-ethyl-2,2,2-trifluoroacetamide as a dark oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][C:29]([C:32]5[NH:36][C:35](=[O:37])[NH:34][N:33]=5)=[CH:30][CH:31]=4)=[CH:25][CH:26]=3)C(=O)OC(C)(C)C)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][C:29]([C:32]5[NH:36][C:35](=[O:37])[NH:34][N:33]=5)=[CH:30][CH:31]=4)=[CH:25][CH:26]=3)[CH2:9][CH2:10][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ccc(-c3n[nH]c(=O)[nH]3)s2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-c2ccc(-c3ccc(NCC4(c5ncccc5F)CCC4)nn3)s2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To tert-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridazin-3-yl)carbamate (86 mg, 0.16 mmol) in DCM (6 mL) was added TFA (2 mL) at rt. The reaction mixture was stirred at rt for 2 hr followed by concentration to dryness. The crude mixture was purified by reverse phase chromatography to provide the title compound as a pale yellow solid (73.6 mg, quantitative). LRMS (M+H+) m/z 424.2.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[C:19]1([C:25]2[O:26][CH:27]=[CH:28][C:29]=2B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:19]1([C:25]2[O:26][CH:27]=[CH:28][C:29]=2[C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:3]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccoc1-c1ccccc1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccoc1-c1ccccc1
Temperature: 80 °C
Yield: 6.7 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (300 mg, 0.940 mmol), (2-phenylfuran-3-yl)boronic acid (265 mg, 1.41 mmol), Na2CO3 (299 mg, 2.82 mmol) and Pd(PPh3)4 (54.3 mg, 0.047 mmol) in DME (3.6 mL) and water (1.1 mL) was heated to 80° C. for 4 h under Ar atmosphere. The mixture was diluted with water, extracted with AcOEt, washed with NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=80/20 to 0/100) and recrystallized with AcOEt/heptane to yield the title compound (23.9 mg, 7% yield) as a pale yellow solid: mp 159-163° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.63 (1H, d, J=8.0 Hz), 6.99 (1H, d, J=1.9 Hz), 7.32-7.43 (3H, m), 7.54-7.60 (2H, m), 7.69-7.76 (2H, m), 7.78-7.82 (1H, m), 7.85 (1H, d, J=1.9 Hz), 7.85-7.92 (1H, m), 8.96 (1H, d, J=8.0 Hz). Anal. Calcd for C21H13F3N2O2.0.3H2O: C, 65.05; H, 3.54; N, 7.22. Found: C, 65.20; H, 3.63; N, 7.29.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[OH-:24].[K+].[C:26](#[N:28])[CH3:27]>>[CH3:1][C:2]1([NH:28][C:26](=[O:24])[CH3:27])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][CH2:3]1
Reactant: CC#N
Reactant: [OH-]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(O)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)NC1(C)CCCN(c2c([N+](=O)[O-])cnn2C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
4-Methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (610 mg, 2.40 mmol) was dissolved in acetonitrile (4 mL) and cooled to 0° C. before concentrated sulphuric acid (2.1 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 hr before being poured onto ice (150 g), basified with KOH and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (20 mL), passed through a phase separation cartridge and concentrated under reduced pressure to give N-(4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide as a yellow solid (660 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 8.05-7.98 (m, 1H), 5.31 (s, 1H), 3.81-3.73 (m, 3H), 3.35 (ddd, J=14.2, 9.3, 2.2 Hz, 1H), 3.22 (t, J=5.9 Hz, 2H), 3.09 (ddd, J=14.2, 7.6, 2.5 Hz, 1H), 2.43-2.31 (m, 2H), 2.05-1.95 (m, 3H), 1.89-1.74 (m, 4H), 1.53-1.36 (m, 3H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24])#[N:20]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=[CH:18][C:9]=1[N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:19]#[N:20])=[O:24])[CH2:6][CH:5]2[CH2:1]1
Reactant: N#Cc1ccccc1C(=O)O
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: N#Cc1ccccc1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-cyano-benzoic acid. MS (ESI): mass calculated for C22H19N5O, 369.43; m/z found 370.3 [M+H]+.
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][P:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13])C1C=CC=CC=1.C>CO.C1C=CC=CC=1.[Pd]>[ClH:1].[NH2:9][CH2:10][P:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13]
Reactant: COP(=O)(CNCc1ccccc1)OC
Agent: [Pd]
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: COP(=O)(CN)OC

Procedure:
Dimethyl N-benzyl-aminomethylphosphonate hydrochloride (80.0 g) in methanol (800 ml) is hydrogenated at 40 psi with 10% palladium on powdered charcoal (4.0 g). The catalyst is removed by filtration through a pad of super cel. Evaporation of the methanolic filtrate gives a clear residue which is taken up in benzene. Removal of the benzene in vacuo affords crystalline dimethyl aminomethylphosphonate hydrochloride.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:20])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][N:8]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:7]1)=[O:5])C>O1CCOCC1.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:11]([C@H:10]2[CH2:9][N:8]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:20])=[CH:14][CH:15]=1
Reactant: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1C[C@H](C(=O)O)[C@@H](C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
Compound 39d (0.9 g; 2.4 mmol) is dissolved in a mixture of 1,4-dioxane/water (1:1; 15 ml). LiOH monohydrate (0.302 g; 7.2 mmol) is added as a solid and the mixture is stirred for 18 at 25° C. The mixture is evaporated to dryness and dissolved in ethyl acetate and the product is extracted with saturated aqueous Na2CO3 solution. The aqueous phase is cooled to 10° C. and acidified with 25% aqueous HCl solution until pH=1. The product is extracted several times with ethylacetate (3×100 ml). The combined organic phases are washed with brine and dried over Na2SO4. After filtration the organic phase is evaporated to dryness. Yield: 0.7 g (84.1%), ESI-MS: m/z=345 [M−H]−, Cl-pattern
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][NH:5]1)#[N:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[C:47](Cl)(=[O:49])[CH3:48]>>[C:47]([N:5]1[CH2:6][CH2:7][C:8]2[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:12][C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[N:10][C:9]=2[CH:4]1[CH2:3][C:1]#[N:2])(=[O:49])[CH3:48]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3CC#N)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)C3CC#N)cc1
Reaction time: 4 h

Procedure:
1-(4-(8-(Cyanomethyl)-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (0.100 g, 0.230 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) was added N,N-Diisopropylethylamine (0.120 mL, 0.689 mmol) followed by Acetyl chloride (0.0246 mL, 0.346 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was concentrated and chromatographed through silica gel (12 g, 0-5% MeOH in dichloromethane). LC/MS-m/z+478.5 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[N:5]=1.[I:10][CH3:11]>CN(C)C=O.O1CCCC1>[I-:10].[CH3:9][N+:6]1[N:5]=[C:4]([CH:3]=[N:2][OH:1])[N:8]([CH3:11])[CH:7]=1
Reactant: Cn1cnc(C=NO)n1
Reactant: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1c[n+](C)nc1C=NO
Product: [I-]
Temperature: 35 °C
Reaction time: 96 h

Procedure:
A solution formed of 3.0 grams of the 3-(hydroxyimino)methyl-1-methyl-1,2,4-triazole made above in 20 ml of dry dimethylformamide was treated with 2.96 ml of iodomethane in 40 ml of dry tetrahydrofuran. After stirring under exclusion of light for four days at 35° C., the mixture was filtered to provide 5.41 grams of 1,4-dimethyl-3-(hydroxyimino)methyl-1,2,4-triazolium iodide as a colorless solid melting at 187° C. with decomposition. This salt was ion exchanged in Amberlite Cl- anion exchange resin to give the chloride salt melting at 201°-202° C. with decomposition.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[C:20]([Br:21])=[CH:19][N:18]([CH3:22])[N:17]=2)[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:21][C:20]1[C:16]([C:12]2[CH:11]=[C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH:15]=[CH:14][CH:13]=2)=[N:17][N:18]([CH3:22])[CH:19]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3cccs3)c2)n1
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To thiophene-2-carbonyl chloride (11 μL, 0.09 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (25 mg. 0.09 mmol) and triethylamine (14 μL, 0.09 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (24 mg, 68%), m.p. 127.8-128.6° C. (EtOAc/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[K+].BrBr>CC(O)=O.O>[NH2:13][C:12]1[S:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(C(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-aminobenzoic acid (1.37 g, 14 mmol) in AcOH (16 mL) may be added with potassium thiocyanate (3.9 g, 40 mmol) and may be stirred for 15 minutes. A solution of bromine (0.5 mL, 10 mmol) in AcOH (6 mL) may then be added slowly into the reaction mixture in water bath, where the temperature may be maintained at about 25° C. The resulting mixture may be stirred overnight. The mixture may then be filtered, and the pale yellow precipitate may then be further recrystallized with the minimal volume of aqueous hydrochloric acid (6 M). A pale yellow product of formula (2) may be collected with the following characterization: 1H NMR (CD3OD, 500 MHz): δ 4.96 (2H, brs), 7.58 (1H, d, J=8.0 Hz), 8.14 (1H, dd, J=8.5 Hz and 1.5 Hz), 8.47-8.47 (1H, m); 13C NMR (CDCl3): δ 12.1, 23.7, 54.6, 85.0, 85.1, 122.5, 123.9, 127.9, 128.3, 132.7, 151.9, 155.3, 168.0, 178.7.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].[C:14]([CH:16]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]=[CH:40][N:41]([CH3:43])[CH3:42])(=[O:38])=[O:37])=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]>CC(C)=O>[C:14]([CH:16]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]=[CH:40][N:41]([CH3:42])[CH3:43])(=[O:38])=[O:37])=[CH:26][CH:25]=1)[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: CCOC(=O)C(C#N)NCc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1)C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.53 g of potassium carbonate and 3.33 ml of valeryl chloride were added to a solution of 1 g of the product of Stage C in 200 ml of dry acetone. After stirring for 20 hours at ambient temperature, the solution was filtered and dried. Purification was carried out by chromatography with dichloromethane-ethyl acetate 85-15 to obtain 11.6 g of the expected product as a white solid with a
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.N>>[CH2:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:7]=[C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1)[CH2:15][CH2:16][CH3:17]
Reactant: C1CCNCC1
Reactant: CCCCNc1nc(N)nc(NCCCC)n1
Agent: N
Product: CCCCNc1nc(NCCCC)nc(N2CCCCC2)n1

Procedure:
The same procedures were repeated as in the N-substituted melamine (C1), except that piperidine was employed in place of the aqueous ammonia to obtain 2,4-bis(monobutylamino)-6-piperidino-1,3,5-triazine which is in powder-state.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=2)[O:26][CH2:27][C:28]([O:30]CC)=[O:29])=N[C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+].Cl.[CH2:39]1COCC1>CO>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]1[CH:39]=[C:13]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=2)[O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:12]=[CH:11][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C1CCOC1
Reactant: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(OCC(=O)O)c3)cc2CC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(3-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)phenoxy)acetate (102 mg) in THF (3.0 mL) and methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (0.97 mL), and the mixture was stirred at 80° C. for 30 min. To the reaction mixture was added 1N hydrochloric acid (1.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (83 mg) as a colorless oil.
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:14]=2[CH:42]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:18]([C:16]1[N:15]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:14]2[CH:42]=[C:10]([NH:9][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:11]=[CH:12][C:13]=2[N:17]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)N1CCCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2ccc(NC(=O)N3CCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
2.0 g (15 mMol) of pyrrolidinocarbonyl chloride are placed in 50 ml of dry chloroform and 2.3 g (6 mMol) of tert.-butyl 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate dissolved in 50 ml of dry pyridine are added dropwise for one hour. The reaction solution is stirred for a further 24 hours and then concentrated by rotary evaporation. The oily residue is distributed in ethyl acetate and 10% sodium hydrogen carbonate solution, the organic phase is separated off and, after drying with magnesium sulphate, concentrated by rotary evaporation. Purification is carried out using a silica gel column (particle size: 0.063-0.2 mm), eluting with petroleum ether/ethyl acetate=3:7. The corresponding column fractions are concentrated by rotary evaporation and dried in vacuo at 50° C.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH2:13][CH2:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22]1(=O)[CH2:25][CH2:24][CH2:23]1>[Cl-].[Cl-].[Zn+2]>[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH2:13][CH2:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22]2([C:5]#[N:6])[CH2:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(CCCc2nccs2)nc1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Zn+2]
Product: N#CC1(Nc2ccc(CCCc3nccs3)nc2)CCC1
Yield: 94.3 %

Procedure:
TMSCN (0.13 mL, 0.96 mmol) was added to a mixture of compound 139 (70 mg, 0.32 mmol), cyclobutanone (0.15 mL, 1.92 mmol) and ZnCl2 (4 mg, 0.03 mmol) with stirring. The reaction mixture was stirred at room temperature for 5 h, and concentrated in vacuo. The residue was diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 141 (90 mg) as a light yellow oil. The crude product was used directly for the next step without purification.