Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([F:15])[F:14])[CH:10]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:8]=2)[CH:6]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[F:14][CH:13]([F:15])[C:11]1[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.7) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.64 mmol) according to the general procedure VI. Obtained as a yellow solid (0.031 g, 7%). MS (ISP) 433.3 [(M+H)+]; mp 253.5° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:25])[O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:38])=[CH:18][C:17]=1[F:23])[CH3:2]
Reactant: CCNC(=O)Oc1cn2ncnc(Oc3ccc(N)cc3F)c2c1C
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: ClCCl
Product: CCNC(=O)Oc1cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl ethylcarbamate (10 mg, 0.029 mmol) in CH2Cl2 (1 mL) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate (2 mL, 0.25 M in dichloroethane). The reaction was stirred at room temperature for 1 h, LC/MS analysis indicated consumption of starting carbamate. The mixture was concentrated in vacuo and the residue was suspended in methanol and filtered to give the title compound. The filtrate was purified by flash chromatography to provide more of the title compound as a pale yellow solid (combined yield 5.9 mg, 40%). 1H NMR (CDCl3) 10.63 (s, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.67 (dd, 1H, J=12.1, 2.2 Hz), 7.28 (m, 4H), 7.10 (m, 2H), 3.73 (s, 3H), 3.36 (m, 2H), 2.48 (s, 3H), 1.26 (m, 3H); MS(ESI+) m/z 525 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:20][CH:19]([O:21][CH3:22])[CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:6]1[CH2:7][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH:19]([O:21][CH3:22])[CH2:20]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:26])[CH3:24]
Reactant: COC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1CN(C(=O)c2coc(N3CC(SC(C)=O)C3)n2)C1
Temperature: 80 °C
Reaction time: 6 h
Yield: 61.7 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (580 mg, 1.75 mmol) (obtained as described in Reference Example 73(3)) in dimethylformamide (30 ml) was added potassium thioacetate (1.20 g, 10.5 mmol) at room temperature and the mixture was stirred in an oil bath (80° C.) for 6 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (97:3) as the eluant to afford 3-acetylthio-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (336 mg, yield 62%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1conc1-c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: OCc1conc1-c1ccc(Cl)cc1
Temperature: -10 °C
Yield: 46.1 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-isoxazole-4-carboxylic acid (40.0 g, 178.9 mmol) in THF (370 mL) at −10° C. was added triethylamine (25.1 mL, 179 mmol) and then a solution of ethylchloroformate (17.4 mL, 179 mmol) in THF (111 mL) added keeping the temperature below −5° C. After 1 h the mixture was filtered and the filtrate cooled to −10° C. and a suspension of sodiumborohydride (17.6 g, 447 mmol) in water (111 mL) added over 15 minutes keeping the temperature below −5° C. The mixture was then allowed to warm up to room temperature over 2 h and diluted with aqueous sodium hydroxide (1 N, 648 mL) and extracted with tert-butylmethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1) afforded the title product (17.3 g, 46%) which was obtained as a light green solid. MS: m/e=210.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2([C:20]([OH:22])=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])=[C:6]([CH:23]=[C:24]([CH3:26])[CH3:25])[C:5]([CH3:27])=[CH:4][CH:3]=1.[C:28](O)(=[O:30])[CH3:29]>[Pd]>[C:28]([NH:1][C:2]1[C:7]([C:8]([NH:10][C:11]2([C:20]([OH:22])=[O:21])[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19]2)=[O:9])=[C:6]([CH:23]=[C:24]([CH3:25])[CH3:26])[C:5]([CH3:27])=[CH:4][CH:3]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: CC(C)=Cc1c(C)ccc(N)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Agent: [Pd]
Product: CC(=O)Nc1ccc(C)c(C=C(C)C)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Yield: 86 %

Procedure:
To a solution of (225) (48 mg, 0.1 mmol) in acetic acid (10 mL) is added the catalyst, Pd—C (5 wt. % Pd, 21 mg, 1% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 55 psi, 90° C., overnight. The catalyst is removed by filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined organic solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (226) as white solid (35 mg, 86%).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1.Br[C:21]1[CH:26]=[CH:25][C:24](/[C:27](/[C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)=[CH:28]/[CH2:29][O:30][C:31]2[CH:42]=[CH:41][C:34]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[C:33]([CH3:43])[CH:32]=2)=[CH:23][CH:22]=1.[C:51]([C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=1)#[CH:52].C(NC(C)C)(C)C>O1CCCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:50][C:47]1[CH:48]=[CH:49][C:44](/[C:27](/[C:24]2[CH:25]=[CH:26][C:21]([C:52]#[C:51][C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=3)=[CH:22][CH:23]=2)=[CH:28]\[CH2:29][O:30][C:31]2[CH:42]=[CH:41][C:34]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[C:33]([CH3:43])[CH:32]=2)=[CH:45][CH:46]=1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(Br)cc2)cc1C
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(C#Cc3ccc(C)cc3)cc2)cc1C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
In nitrogen atmosphere, bis(benzonitrile)palladium(II) chloride (14.6 mg, 0.038 mmol), copper(I) iodide (12.1 mg, 0.064 mmol) and 0.15 M solution of tri(tert-butyl)phosphine in cyclohexane (0.60 mL, 0.090 mmol) were added to a degassed solution of methyl (E)-[4-[3-(4-bromophenyl)-3-(4-chlorophenyl)allyloxy]-2-methylphenoxy]acetate (383 mg, 0.763 mmol), 4-ethynyltoluene (115 mg, 0.990 mmol) and diisopropyl amine (0.50 mL, 3.57 mmol) in dry tetrahydrofuran (6 mL). In atmosphere of nitrogen, the reaction mixture was stirred at 60° C. for 4 h, cooled down and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 12:1) yielding methyl (Z)-[4-[3-(4-chlorophenyl)-3-[4-(4-methylphenylethynyl)phenyl]allyloxy]-2-methylphenoxy]acetate as brownish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[N+]([C:15]1C=CC=C[C:16]=1[OH:21])([O-])=O.C(OC(=O)C)(=O)C>C(O)(=O)C.O=[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:16](=[O:21])[CH3:15])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared from the commercially available 2-fluoro-4-nitrophenol according the procedure of Burckhalter, J. H. et al. (J. Am. Chem. Soc. 1948, 70, 1363). Nitrophenol (5.73 g, 36.5 mmol) and acetic anhydride (3.72 g, 36.5 mmol) were dissolved in acetic acid (20 mL) and PtO2 (150 mg) was then added. The reaction mixture was shaken under H2 atmosphere (50 psi) at RT for 24 h. The precipitate which formed was collected by vacuum filtration and the filter paper was washed with acetic acid (25 mL). The combined filtrate and washing was concentrated in vacuo to give the title compound (2.0 g). The solid that remained on the filter paper was treated with MeOH to dissolve the product and the Pt2O filtered off. The filtrate was concentrated in vacuo and the solid obtained was triturated with 1:1 EtOAc/hexanes (200 mL) to give a second crop of the title compound (1.8 g, 62% overall). 1H NMR (DMSO-d6) δ 9.83 (s, 1H), 9.51 (s, 1H), 7.50 (dd, 1H, J=13.6, 2.5 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (dd, 1H, J=9.3, 9.3 Hz), 1.98 (s, 3H); MS (ESI+) m/z 170.23 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][CH2:6][C:7](O)=[S:8].OS(O)(=O)=O.ClC(Cl)C.[NH2:23][OH:24].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][CH2:6][C:7]([NH:23][OH:24])=[S:8]
Reactant: NO
Reactant: OC(=S)CCc1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: ONC(=S)CCc1ccc(Cl)c(Cl)c1
Yield: 75 %

Procedure:
20.2 g (0.08 mol) of 3,4-dichlorobenzylthioacetic acid are esterified with 10 ml of methanol, 0.6 ml of concentrated H2SO4 and 100 ml of dichloroethane. The mixture is heated under reflux for 4 hours, washed with water and with dilute bicarbonate solution, and dried. The mixture is evaporated in vacuo. The oily residue, in methanol, is treated with a solution of hydroxylamine (0.1 mol) in the presence of 0.18 mol of sodium methylate. After leaving the reactants in contact overnight, the mixture is evaporated to dryness in vacuo, the residue is taken up in water, the mixture is filtered over charcoal and the filtrate is precipitated with 3 N HCl, the product is extracted with ether, the extract is dried and evaporated and the product is crystallised in diisopropyl ether. 15 g of the stated product are obtained (yield 71%). Melting point: 75°-76° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][O:20][CH2:21][CH3:22]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) in N,N-dimethylformamide (4.5 mL) was added cesium carbonate (1324 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. 1-Bromo-2-ethoxyethane (1016 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (120 mL×3). The organic layer was washed with saturated brine (100 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (697 mg) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[NH:41][CH:42]=[C:43]([CH2:45][C:46]([F:49])([F:48])[F:47])[N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[NH:41][CH:42]=[C:43]([CH2:45][C:46]([F:49])([F:47])[F:48])[N:44]=5)=[O:59])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nc(CC(F)(F)F)c[nH]4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nc(CC(F)(F)F)c[nH]4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-(2,2,2-trifluoroethylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (79 mg) in dichloromethane (10 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-(2,2,2-trifluoroethylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (60 mg) (Compound 344) as yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:24](Cl)(=[O:26])=[O:25])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:28][NH2:29]>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([S:24]([NH:29][CH3:28])(=[O:26])=[O:25])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Cl)nc(S(=O)(=O)Cl)n1COCC[Si](C)(C)C
Reactant: CN
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 4-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonyl chloride (0.341 g, 0.72 mmol) in acetone (4.5 mL) and THF (2.5 mL) was added to a 0° C. solution of methylamine (3.6 mL of a 2M solution in THF, 7.2 mmol) in THF (2 mL). The reaction mixture was stirred at RT for 1 h and evaporated. The residue was taken up in EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered evaporated, and purified by silica gel chromatography (0-25% EtOA/hexanes) to give the title compound (0.23 g, 68%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.85 (br. s., 1H), 5.73 (s, 2H), 4.75 (s, 2H), 3.59-3.68 (m, 2H), 2.86 (d, J=5.1 Hz, 3H), 0.93 (d, J=8.4 Hz, 2H), 0.89 (s, 9H), 0.10 (s, 6H), −0.01 (s, 9H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[C:40](O)(=O)[CH2:41][OH:42].C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C.C(O)(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:40]([CH2:41][OH:42])[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)CO
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OCc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-4 (5 g, 13 mMol), HOBT (1.9 g, 14.3 mMol), and glycolic acid (1.2 g, 15.6 mMol) in anhydrous DMF (100 mL) was added EDC (2.7 g, 14.3 mMol). The solution was stirred overnight at ambient temperature. The solution was then treated with 5 mL of glacial acetic acid and was heated to 80° C. in an oil bath for 2 hours. Upon cooling to room temperature, the reaction was diluted with ethyl acetate and washed with NaHCO3 (aq), water, and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to yield 14-1 as a red solid. LC/MS (M+1) calculated: 425.5; observed: 425.6
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH2:7]([N:10]=[C:11]=[S:12])[CH2:8][CH3:9].NC1N(C(NCCC)=S)N=CN=1>CN(C)C=O>[NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:11]([NH:10][CH2:7][CH2:8][CH3:9])=[S:12])[N:3]=1
Reactant: Nc1nc[nH]n1
Reactant: CCCN=C=S
Agent: CCCNC(=S)n1ncnc1N
Solvent: CN(C)C=O
Product: CCCNC(=S)n1cnc(N)n1
Yield: 35 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (4.00 g), dimethylformamide (30 ml) and n-propyl isothiocyanate (5.7 ml) were used as reagents. After the reaction, the reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3.07g of a 1:1 mixture of 5-amino-1-[n-propylamino(thiocarbonyl)]-1H-1,2,4-triazole and 3-amino-1-[n-propylamino(thiocarbonyl)]-1H-1,2,4-triazole as a white solid (yield 35%). The solid was applied to high performance liquid chromatography (acetonitrile-water) and recrystallization from hexane-ethyl acetate to give colorless transparent thin film crystals.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH2:36][O:37][Si](C(C)(C)C)(C)C)=[CH:29][C:28]=2[CH:45]([CH3:47])[CH3:46])=[O:25])[C:6]1=[O:48])[CH2:2][CH2:3][CH3:4].O>CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:28]([CH:45]([CH3:46])[CH3:47])=[CH:29][C:30]([CH2:36][OH:37])=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])=[O:25])[C:6]1=[O:48])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CO[Si](C)(C)C(C)(C)C)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Solvent: CO
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CO)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Yield: 89 %

Procedure:
A solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2,6-diisopropyl-4-(tert-butyldimethylsilyloxymethyl)phenyl]urea (6.75 g, 10.1 mmol) in methanol containing 15% HCl (100 ml) is stirred at room temperature for 3 hours. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water (once) and an aqueous sodium hydrogen carbonate solution (once). The solvent is concentrated under reduced pressure, and the residue is purified by silica gel chromatography to give the title compound (5.0 g, 8.99 mmol) as colorless amorphous.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:10]([C:20]#[N:21])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.CCN(CC)CC.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:29][N:30]([CH3:35])[S:31](=[O:33])(=[O:32])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH:8]=[CH:9][C:10]=2[C:20]#[N:21])=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(Cn2cncn2)cc1-c1ccc(O)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)Oc1ccc(-c2cc(Cn3cncn3)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a white suspension of 19 (0.075 g, 0.271 mmol) and NEt3 (0.292 mL, 2.71 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. under an inert atmosphere was added to a colourless solution of N,N-dimethylsulfamoyl chloride (0.408 mL, 3.80 mmol) in anhydrous CHACl2 (3 mL). The resulting white suspension was left to stir under an inert atmosphere at room temperature for 70 h forming a clear orange/brown solution. The reaction mixture was diluted in CH2Cl2 (30 mL) and washed with distilled H2O (30 mL×3) and brine (30 mL). The organic fraction was separated, dried (MgSO4), filtered and solvent removed in vacuo to leave yellow residues. Column chromatography (CH2Cl2/acetone 75:25) eluted 21 as a viscous yellow oil (0.093 g, 90%); 1H NMR δH (270 MHz, CDCl3) 3.00 (s, 6H), 5.44 (s, 2H), 7.28-7.33 (m, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.76 (d, J=7.9 Hz, 1H), 8.00 (s, 1H) and 8.18 (s, 1H); LCMS (APCI−) m/z (rel intensity) 382 (100, [M−H]+; HRMS (ES+) m/z calcd. for C18H18N5O3S [M+H]+: 384.1125, found 384.1143.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([OH:8])[CH:7]=1.[C:18]1([N:24]2[CH2:27][CH:26](O)[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:7]=1)[O:8][CH:26]1[CH2:27][N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25]1
Reactant: Oc1cc(Br)ccc1OCc1cccc(F)c1
Reactant: OC1CN(c2ccccc2)C1
Product: Fc1cccc(COc2ccc(Br)cc2OC2CN(c3ccccc3)C2)c1

Procedure:
Prepared by the procedure of Example 163 using 5-bromo-2-(3-fluoro-benzyloxy)-phenol and 1-phenyl-azetidin-3-ol. MS (ESI): mass calcd. for C22H19BrFNO2, 427.1; m/z found, 428.2 [M+H]+. 1H NMR (CDCl3): 7.34-6.47 (m, 12H), 5.11-5.03 (m, 3H), 4.36-4.28 (m, 2H), 3.98-3.91 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].C(O)C>O>[C:28]([NH:32][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CC(C)(C)Nc1c([N+](=O)[O-])cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-5,7-dinitro-2-trifluoromethylbenzimidazole (5.0 grams) was mixed with 1.6 grams of triethylamine and 1.2 grams of tert-butylamine in a small amount of ethanol. The resulting reaction mixture was refluxed over a weekend, then poured into water and the resulting aqueous mixture acidified and filtered to separate the expected 4-tert-butylamino-5,7-dinitro-2-trifluoromethylbenzimidazole product. It was recrystallized from ethanol as an orange solid, m.p., 195°-97° C. Elemental analysis confirmed the identity of the product. A second crop melted at 177°-88° C.