Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][CH:5]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N+:6]([O-:28])[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cc(-c2c(CC)cccc2CC)ncc1C(=O)OC
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1cc(-c2c(CC)cccc2CC)[n+]([O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester (2.1 g, 7.1 mmol) and 3-chloroperoxybenzoic acid (77%, 1.9 g) in CH2Cl2 (50 mL) is stirred at room temperature overnight. The mixture is diluted with ether (600 mL) and washed with saturated Na2CO35 then brine, and dried. Concentration at reduced pressure gives 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester N-oxide. 1H NMR (CDCl3) 8.89 (s, 1H), 7.26 (t, 1H), 7.19 (m, 3H), 3.95 (s, 3H), 3.02 (q, 2H), 2.04 (m, 2H), 2.30 (m, 2H), 1.26 (t, 3H), 1.11 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:26])(=[O:25])[N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)[C:11]([CH3:27])=[C:10]([C:28](Cl)=[O:29])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(Cl)Cl>[CH3:35][O:34][N:33]([CH3:32])[C:28]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19](=[O:25])(=[O:26])[N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[CH:17][CH:18]=2)[C:11]=1[CH3:27])=[O:29]
Reactant: CNOC
Reactant: Cc1c(C(=O)Cl)cc(-c2ccc(Cl)cc2)n1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cold (0° C.) mixture of Example 30A (1.9 g, 4.64 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.5 g, 5.11 mmol) in DCM (50 mL) was added TEA (1.62 mL, 11.6 mmol). The mixture was stirred at room temperature for five hours after which the solvents were removed under reduced pressure and the residue purified by chromatography using a mixture of DCM:methanol (95:5) to obtain the titled compound. 1H NMR (CDCl3) δ ppm 2.20 (3H), 2.47 (6H), 2.74 (3H), 3.39 (3H), 6.20 (1H), 7.33-7.42 (4H), 7.50-7.90 (5H); MS (ESI) m/z 489 (M+H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3](=[O:12])[NH:2]1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][C:3](=[O:12])[NH:2][CH2:1][C:7]=2[CH:8]=1)([O-:15])=[O:14]
Reactant: O=C1CCc2ccccc2CN1
Reactant: O=[N+]([O-])O
Product: O=C1CCc2ccc([N+](=O)[O-])cc2CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 1,2,4,5-tetrahydro-benzo[c]azepin-3-one (1 g, 6.2 mmol) was added to fuming nitric acid (3 mL) and the mixture was slowly warmed up to 25° C. during 1 h. The mixture was stirred at ambient temperature for 1 h and poured onto ice. The mixture was extracted with dichloromethane (3×50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The crude mixture was then recrystallized from dichloromethane/hexane to give 8-nitro-1,2,4,5-tetrahydro-benzo[c]azepin-3-one (0.2 g). 1H NMR (300 MHz, CDCl3) δ 8.12 (dd, 1H), 8.03 (d, 1H), 7.37 (d, 1H), 4.47 (d, 2H), 3.2 (m, 2H), 2.8 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([CH3:28])=[C:20]([CH3:29])[C:19]=2[O:30][CH3:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=[O:33].[NH+]1C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:19]([O:30][CH3:31])=[C:20]([CH3:29])[C:21]([CH3:28])=[C:22]3[C:27]=2[CH2:26][CH2:25][CH2:24][C:23]3=[O:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: COC(=O)CCCCCC(c1ccc(F)cc1)c1c2c(c(C)c(C)c1OC)CCCC2
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC(=O)CCCCCC(c1ccc(F)cc1)c1c2c(c(C)c(C)c1OC)C(=O)CCC2
Yield: 53.3 %

Procedure:
To a solution of methyl 7-(4-fluorophenyl)-7-(2-methoxy-3,4-dimethyl-5,6,7,8-tetrahydronaphthyl)heptanoate (0.4 g) in benzene (12 ml) was added a mixture of pyridinium chlorochromate (1 g) and cerite (1.8 g) and the mixture was refluxed for 5 hours. After cooling, insoluble materials were filtered off and the filtrate was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to obtain methyl 7-(4-fluorophenyl)-7-(6-methoxy-7,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-5naphthyl)-heptanoate (0.22 g) (Compound 59). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([Cl:11])[C:3]=12.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1cnc2[nH]cnc(Cl)c1-2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Cl)c2c(Cl)ncnc21
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-dichloro-1H-pyrrolo[2,3-d]pyrimidine D39 (1 g) in DMF (20 ml) at 0° C. was added sodium hydride (60% w/w in mineral oil, 255 mg, 6.4 mmol) and the mixture stirred for 20 mins. Phenylsulfonyl chloride (1.31 g, 7.4 mmol) was the added dropwise and the reaction mixture was kept in a cool bath for 15 hours. The mixture was poured into water (40 ml), and the precipitate was filtered, washed with water and Et2O, dried in a vacuum to give the desired product D40 in 1.62 g as an ashen solid. LCMS [MH+] 329.9@1.77 min (5 min run)
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[K+].[Br-]>O>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CC(O)CCCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: C#CC(CCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 1.26 g. (10.0 mmoles) of 1-octyn-3-ol, 4.85 g. (15.0 mmoles) of triphenylmethyl bromide, and 50 ml. of dry pyridine is heated at 95°C. for 60 minutes with occasional swirling. The solution is cooled, treated with water, and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on Florisil and recrystallization from petroleum ether to give white crystals, m.p. 65°-66.5°, ν max. (KBr) 3280 (acetylenic hydrogen), 1605, 1030, and 702 cm-1 (triphenylmethoxy group).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:21][C:20]=2[C:30]([O:32][CH3:33])=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>ClCCCl.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][N:18]([C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:35]=2[Cl:34])[C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:21][C:20]=2[C:30]([O:32][CH3:33])=[O:31])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(Cl)cc1Cl
Yield: 87.4 %

Procedure:
4-[(2-Methoxycarbonyl-5-phenyl-thiophen-3-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (133 mg, 0.28 mmol) was dissolved in 1,2-dichloroethane (2.8 mL) and was treated with 2,4-dichlorobenzoyl chloride (60 μL, 0.43 mmol). The solution was heated at reflux for 1 day. The solvent was then evaporated and the residue purified by silica gel column chromatography using hexanes:EtOAc as eluent to provide 4-{[(2,4-Dichloro-benzoyl)-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (0.156 g, 85% yield).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[SH:11][CH2:12][CH2:13][CH2:14][SiH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18].C(N(CC)CC)C>C1CCCCC1>[C:1]([S:11][CH2:12][CH2:13][CH2:14][SiH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: COC(OC)[SiH2]CCCS
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CCCCCCCC(=O)SCCC[SiH2]C(OC)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
Octanoyl chloride (18.0 g, 0.111 mol) is added dropwise over 30 minutes to a solution of 3-mercaptopropyldimethoxymethylsilane F with CAS number [31001-77-1] (20.0 g, 0.111 mol) and triethylamine (11.2 g, 0.111 mol) in cyclohexane (200 mL) kept at 5° C. under an inert atmosphere. The temperature of the reaction medium remains between 5 and 8° C. The reaction medium is then stirred for 15 hours at room temperature. The precipitate of triethylamine hydrochloride Et3N.HCl is filtered over celite. After evaporating the solvents under reduced pressure at 25° C., S-octanoylmercaptopropyldimethoxymethylsilane G with CAS number [828241-23-2] (32.6 g, 0.106 mol) is obtained in the form of a colourless oil with a yield of 96%.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[CH3:17][C:16]1[O:18][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(NC(=O)c1ccccc1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)oc1C
Yield: 91.5 %

Procedure:
A solution of ethyl 2-benzamido-3-oxobutanoate (13.0 g, 0.052 mol) in phosphorus oxychloride (100 mL) was heated under reflux for 1.5 h, then cooled and concentrated under reduced pressure to a brown syrup which was dissolved in dichloromethane (250 mL). The solution was washed with water, saturated Na2CO3 and brine successively, then dried over anhydrous Na2SO4 and concentrated to give ethyl 5-methyl-2-phenyloxazole-4-carboxylate as a brown oil (11.0 g, 91% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[C:10]([C:18]2[N:19]=[N:20][C:21]([NH:24][CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)=[CH:22][CH:23]=2)=[C:9]([OH:35])[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1>>[NH:48]1[CH:47]=[C:46]([C:7]2[CH:12]=[C:11]([O:13][C:14]([F:15])([F:17])[F:16])[C:10]([C:18]3[N:19]=[N:20][C:21]([NH:24][CH:25]4[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:33])([CH3:34])[CH2:26]4)=[CH:22][CH:23]=3)=[C:9]([OH:35])[CH:8]=2)[CH:50]=[N:49]1
Reactant: CC1(C)CC(Nc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC1(C)CC(Nc2ccc(-c3c(O)cc(-c4cn[nH]c4)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Yield: 45 %

Procedure:
3-Hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyl trifluoromethanesulfonate (32 mg, 0.043 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16.68 mg, 0.086 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol was obtained as a yellow solid after HPLC purification. The product was converted to the HCl salt by addition of 1 M aqueous HCl (0.1 mL, 2.3 equivalents) followed by lyophilization (10 mg, 45% yield). LCMS Rt=0.48 min [Method Q], MS (M+1)=477.3. 1H NMR (METHANOL-d4) δ 8.17 (s, 2H), 8.05 (d, J=9.6 Hz, 1H), 7.68 (d, J=9.6 Hz, 1H), 7.22-7.30 (m, 2H), 4.49 (t, J=12.1 Hz, 1H), 2.33 (dd, J=13.6, 3.5 Hz, 2H), 1.70 (t, J=12.9 Hz, 2H), 1.61 (s, 6H), 1.54 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][N:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCSc1nccc2nccn12
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCSc1nccc2nccn12

Procedure:
Using 2.23 g (10 mmol) of 5-(4-hydroxybutylthio) imidazo[1,2-c]pyrimidine, 1.53 ml (11 mmol) of triethylamine and 0.85 ml (11 mmol) of methanesulfonyl chloride, the same procedure as in Reference Example 8 was followed, to yield 5-(4-methanesulfonyloxybutylthio)-imidazo[1,2-c]pyrimidine.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][N:27]=1>>[F:32][C:31]1[C:26]([C:18]2[CH:19]=[C:20]([C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]4)[CH:21]=[CH:22][C:17]=2[F:16])=[N:27][CH:28]=[C:29]([F:33])[CH:30]=1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1cnc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c(F)c1
Yield: 66.2 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 4-fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid (71 mg, 0.28 mmol) as described in Example 7 part g), affording 5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-2-trifluoromethyl[1,8]-naphthyridine (59 mg, 68%). δH (360 MHz, CDCl3) 7.36-7.44 (2H, m), 7.55-7.62 (2H, m), 7.75 (1H, dd, J 2.3 and 6.5), 7.85 (1H, d, J 8.8), 8.48 (1H, d, J 2.1), 8.57 (1H, d, J 8.8), 9.28 (1H, d, J 4.2). m/z (ES+) 406 [MH]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[H][H]>C(OCC)(=O)C.CCO.O=[Pt]=O>[Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1
Reactant: Cc1cc(C#Cc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(CCc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Yield: 23.3 %

Procedure:
A suspension of 3-bromo-4-[(4-fluorophenyl)ethynyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (0.430 g, 1.01 mmol) in Ethyl acetate (5 mL) and EtOH (5 mL), containing PtO2 (0.015 g) was stirred in an atmosphere of hydrogen (15 psi) in a Fischer-Porter bottle for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to reduce volume. The material was purified by flash column chromatography (ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.0943 g, 22%) as a sticky semisolid after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.46 (d, 2H, J=26.4 Hz), 7.60 (d, 1H, J=8.0 Hz), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.21 (m, 2H), 6.97 (t, 2H, J=8.8 Hz), 6.24 (s, 1H), 5.43 (s, 2H), 2.93 (m, 4H), 2.31 (s, 3H); ES-HRMS m/z 401.0645/403.0603 (M+H calculated for C20H19N2OFBr requires 401.0659/403.0641).
Reaction SMILES: [CH3:1][C@:2]12[CH2:20][CH2:19][C@H:18]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH2:16][OH:17])[CH2:14][CH2:13][C@H:12]([OH:21])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:22].C[Si:24]([CH2:27]C(N)=O)([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH3:25][Si:24]([CH3:27])([CH3:26])[O:21][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH2:16][O:17][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:18]2[CH2:19][CH2:20][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C@@H:3]2[O:22][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C[C@@H](O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Reactant: C[Si](C)(C)CC(N)=O
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C[C@@H](O[Si](C)(C)C)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O[Si](C)(C)C

Procedure:
Androst-4-ene-3β,17β,19-triol is dissolved in dry pyridine and trimethylsilylacetamide added thereto. The reaction is completed at room temperature within a few minutes. The pyridine is removed under reduced pressure and the residue purified from an acetone-hexane solution to yield the desired 3β,17β,19-tri(trimethylsiloxy)androst-4-ene.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:11]1[CH2:28][O:27][C:13]2([CH2:18][CH2:17][N:16]([C:19]3[N:24]=[C:23]([Cl:25])[CH:22]=[C:21](Cl)[N:20]=3)[CH2:15][CH2:14]2)[O:12]1>C(O)CCC>[CH2:28]1[CH2:11][O:12][C:13]2([CH2:14][CH2:15][N:16]([C:19]3[N:20]=[C:21]([N:8]4[CH2:9][CH2:10][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)[CH:22]=[C:23]([Cl:25])[N:24]=3)[CH2:17][CH2:18]2)[O:27]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1cc(Cl)nc(N2CCC3(CC2)OCCO3)n1
Solvent: CCCCO
Product: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCC3(CC2)OCCO3)n1

Procedure:
After adding 2.6 ml (17.23 mmoles) of 1,4-dioxa-8-azaspiro[4,5]decane to the solution of 2.0 g (6.89 mmoles) of 2-(4,4-ethylenedioxy-1-piperidinyl)-4,6-dichloropyrimidine in 40 ml of n-butanol, the reaction mixture is boiled under reflux for 4 hours, then evaporated. The evaporation residue is distributed between 50 ml of chloroform and 5 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 10 ml of water each, then dried and evaporated. After recrystallizing the obtained product from hexane the title compound is obtained in a yield of 2.51 g (91%), m.p.: 130°-131° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[C:26]([CH:32]=O)=[CH:25]2>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:32][C:26]2[N:27]([CH3:31])[C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([F:21])=[CH:30][CH:29]=3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cn1c(C=O)cc2cc(F)ccc21
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cc2cc(F)ccc2n1C

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 5-fluoro-1-methyl-1H-indole-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 397.08 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:28](Cl)(Cl)=[S:29]>C(Cl)(Cl)Cl>[N:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:20][CH:19]=1)=[C:28]=[S:29]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2cccnc2Oc2ccc(N=C=S)cc2)ccn1
Reaction time: 8 h

Procedure:
To a 15 mL round bottomed flask was added 4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)benzenamine (0.0978 g, 0.35 mmol) and sodium carbonate (0.0823 g, 0.78 mmol) in chloroform. Thiophosgene (0.030 mL, 0.39 mmol) was slowly added and allowed to stir overnight. The solution was filtered and concentrated to give 2-(4-isothiocyanatophenoxy)-3-(2-methylpyridin-4-yl)pyridine. To the flask was then added 1,2-phenylenediamine (0.0470 g, 0.410 mmol), and N,N′-dicyclohexylcarbodiimide (0.1032 g, 0.5200 mmol) in tetrahydrofuran at 75° C. to stir overnight. Upon completion, the solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% methanol in DCM, to provide N-(4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 394.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24]1.[K+].[Br-]>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH:23]4[CH2:25][CH2:24]4)[CH2:28][CH2:29]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(CC2CC2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, yield 83%. White crystals, m.p. 254–255° C.; IR (KBr): ν 1728 (C═O) cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:11]3[N:12]=[C:13]([CH3:17])[C:14](O)=[N:15][C:10]3=[N:9][N:8]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[C:13]([CH3:17])=[N:12][N:11]2[C:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=[C:10]2[N:15]=1
Reactant: Cc1nn2c(Cc3ccc(O)cc3)nnc2nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn2c(Cc3ccc(O)cc3)nnc2nc1Cl

Procedure:
A solution of 3-(4-hydroxy-benzyl)-6-methyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-ol (170 mg, 0.62 mmol) in POCl3 (5 mL) was heated at 80° C. for 15 minutes, and then POCl3 was evaporated. The residue was purified on a silica gel column eluting with 5% methanol in dichloromethane to provide 4-(7-chloro-6-methyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (80 mg). MS (m/z) 275 [M+1].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C1COCC1>O>[CH3:25][S:26]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:7][CH2:6]2)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1c2ccc(CO)cc2CCN1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1c2ccc(COS(C)(=O)=O)cc2CCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a mixture of 1-ethyl 2-tert-butyl 6-(hydroxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (390 mg, 1.16 mmol), methanesulfonyl chloride (0.135 mL, 1.74 mmol) and THF (10 mL) was added TEA (0.243 mL, 1.74 mmol) at 0° C., and the mixture was stirred for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-ethyl 2-tert-butyl 6-(((methylsulfonyl)oxy)methyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (500 mg, 1.209 mmol, 104%) as a colorless oil.