Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:5]([CH3:11])=[C:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)=[CH:2][CH2:3][CH3:4].CCOCC.[C:17]([C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][C:27]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:29]=3)[CH2:24][C:23]=2[C:22]=1[Li])([CH3:20])([CH3:19])[CH3:18].C1C(=C)C=CC=1>CCCCC>[CH3:11][C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])([CH:6]1[CH:7]=[CH:8][CH:9]=[CH:10]1)[C:33]1[C:32]2[CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[C:27]([C:34]([CH3:35])([CH3:36])[CH3:37])[CH:26]=3)[C:31]=2[CH:23]=[CH:22][C:21]=1[C:17]([CH3:19])([CH3:18])[CH3:20]
Reactant: [Li]c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Reactant: CCC=CC(C)=C1C=CC=C1
Agent: C=C1C=CC=C1
Solvent: CCOCC
Solvent: CCCCC
Product: C=CCCC(C)(c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2)C1C=CC=C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Another one-liter flask fitted with an addition funnel is charged with 6-butenyl-6-methylfulvene (37 g, 253 mmol) and a stir bar, and cooled to 0° C. under a nitrogen atmosphere. The ether solution of 2,7-di-tert-butylfluorenyl lithium prepared as above is added in a dropwise fashion to the fulvene at 0° C. via the addition funnel over the course of approximately one hour. The resulting dark-colored reaction mixture is warmed to room temperature and stirred overnight (at least about 12 hours) under a nitrogen atmosphere. The reaction mixture is then quenched with the slow addition of a saturated NH4Cl/H2O solution (300 mL), the organic layer extracted with ether, washed twice with H2O (500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate evaporated to dryness. The crude product obtained by this method is then dissolved in pentane and maintained at about 0° C. in a freezer, thereby affording the product as a white solid that is washed with cold pentane, dried under vacuum, and isolated and used without further purification. Further product could be isolated in smaller quantities through concentrating the mother liquors and combined washings and placing them back in freezer.
Reaction SMILES: S([O-])([O-])(=O)=O.C[NH+:7]=[C:8]([NH2:10])S.C[NH+]=C(N)S.O.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:24][NH:25][C:8]([NH2:10])=[NH:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[NH+]=C(N)S
Reactant: NOCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: N=C(N)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 30.0 g. (0.12 moles) of S:methylthiouronium sulfate in 200 ml. of H2O there is added a solution of 24.6 g. (0.20 moles) of benzyloxyamine in 250 ml. of 95% ethanol. The mixture is stirred for 72 hours at room temperature. The clear solution is heated at reflux for two hours under a stream of nitrogen. the solvents are removed in vacuo and the residue is treated with 300 ml. of isopropanol. The solid is removed by filtration and dissolved in 300 ml. of water. The solution is made basic with 90 ml. of 10% aqueous sodium hydroxide. The precipitate is collected, washed with water and dried to give benzyloxyguanidine, m.p. 105°-50° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH:27]=[C:26]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:24]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH:27]=[C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:24]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A mixture of ethyl 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-3-phenyl-1H-pyrazol-4-yl]propionate (900 mg), 1N aqueous sodium hydroxide solution (3.4 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (860 mg, yield: 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 85–86° C.
Reaction SMILES: CC(NC(C)C)C.C([Li])CCC.[CH3:13][CH:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15].[CH3:28][C:29]1([CH3:42])[C:39]2[C:40]3[C:35]([CH:36]=[CH:37][CH:38]=2)=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]1=[O:41]>O1CCCC1.O>[OH:41][C:30]1([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:19]=2[C:17]([N:16]([CH:25]([CH3:27])[CH3:26])[CH:14]([CH3:13])[CH3:15])=[O:18])[C:31]2=[C:40]3[C:35](=[CH:34][CH:33]=[CH:32]2)[CH:36]=[CH:37][CH:38]=[C:39]3[C:29]1([CH3:42])[CH3:28]
Reactant: CC(C)N(C(=O)c1ccncc1)C(C)C
Reactant: CC1(C)C(=O)c2cccc3cccc1c23
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)N(C(=O)c1ccncc1C1(O)c2cccc3cccc(c23)C1(C)C)C(C)C
Temperature: -80 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Preparation of: ##STR30## To a cooled (-80° C.) and stirred solution of 5.25 g of N-(1-methylethyl)-2-propanamine in 500 ml of dry tetrahydrofuran there were added 20 ml of butyl lithium (2.5M in hexane) and, after stirring for 1 hour at -80° C., 10.3 g of N,N-bis(1-methylethyl)-4-pyridinecarboxamide (prepared as described in Tetr. Lett. 21, 4739, 1980). Stirring at -80° C. was continued for 3 hours and then there were added 9.3 g of 2,2-dimethylacenaphthylen-1(2H)-one. The whole was stirred for 18 hours at room temperature and was then poured into water. The product was extracted with ether and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5). The eluent of the desired fraction was evaporated, yielding 4.2 g (20.9% ) of (±)-3-(1,2-dihydro-1-hydroxy-2,2-dimethyl-1-acenaphthylenyl)-N,N-bis(1-methylethyl)- 4-pyridinecarboxamide (comp. 5.006)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-].[Ca+2:8].[OH-]>>[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Ca+2:8].[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:1](=[O:6])=[O:5]
Reactant: C=C(C)C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Product: C=C(C)C(=O)[O-]
Product: O=C=O

Procedure:
U.S. Pat. No. 3,839,437, describes a process of preparing methacrylic acid by employing calcium hydroxide to form the metal salt of the acid, calcium methacrylate, and neutralization with CO2 at low pressure to give the acid and the insoluble calcium carbonate in the presence of a water immiscible organic solvent, such as an ether, to extract the methacrylic acid from the aqueous phase. Continuous passage of carbon dioxide with ether extraction gave only 10.6 and 41.3 percent methacrylic acid recovery in 1 and 4 hours respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]([OH:22])=O)[C:14]=3[CH:13]=[CH:12][N:11]=2)=[N:7][CH:8]=1.NC1C2C=CC=C(C([NH:36][C:37]3[CH:42]=[C:41]([C:43](=[O:55])[NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=4)[CH:40]=[CH:39][C:38]=3[CH3:56])=O)C=2C=CN=1.NC1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]([NH:36][C:37]4[CH:42]=[C:41]([C:43](=[O:55])[NH:44][C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=5)[CH:40]=[CH:39][C:38]=4[CH3:56])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[N:7][CH:8]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(N)nccc12
Reactant: COc1ccc(Nc2nccc3c(C(=O)O)cccc23)nc1
Solvent: Nc1ccccc1
Product: COc1ccc(Nc2nccc3c(C(=O)Nc4cc(C(=O)Nc5cccc(C(F)(F)F)c5)ccc4C)cccc23)nc1
Yield: 33 %

Procedure:
The procedures of Example 1 were repeated, except for using 1-((5-methoxypyridin-2-yl)amino)isoquinoline-5-carboxylic acid obtained in Step (3) of Example 19 and 3-amino-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide obtained in Example 3 instead of carboxylic acid and aniline in Step (3) of Example 1 to obtain the title compound (24 mg, 33%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CC([O:29]O)(C)C.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:29])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: CC(C)(C)OO
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 30 h
Yield: 37 %

Procedure:
At room temperature, 1.307 g of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole, 0.059 g of tetrabutyl ammonium bromide as an interphase transfer catalyst, and 0.157 g of Mo(acac)2 oxidation catalyst were mixed in 15 ml of IPA. Next, 1.36 g of TBHP (70% aqueous solution) was added into the mixture in about 5–10 minutes. The reaction was carried out for about 30 hours, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 37% (HPLC purity>96%).
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=O)[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.Cl.[NH2:25]O>C(O)C.CCOCC.CCCCCCC.[Zn]>[NH2:25][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[NH:8][C:9](=[O:10])[C:4]3[CH:3]=[C:2]([CH3:1])[S:23][C:5]=3[N:6]=2)[CH:16]=1
Reactant: NO
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: CCCCCCC
Solvent: CCOCC
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CN)c(C(F)(F)F)n3)nc2s1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
A solution of 1-((6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (2.92 mmol, 1 g) and hydroxylamine hydrochloride (3.21 mmol, 0.223 g) in ethanol (7 mL) was heated to 80° C. and this temperature was maintained for 3 h. The reaction mixture was allowed to cool to room temperature & diluted with ether and heptane before the resulting precipitate was collected by filtration. The resulting solid was taken up in acetic acid (5 mL) and zinc (7.79 mmol, 0.510 g) and the whole was stirred at room temperature for 3 days with occassional agitation by sonication. The reaction mixture was filtered through celite and the pad washed with MeOH before the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and applied to an SCX cartridge that had been equilibrated with the same solvent before being eluted with 2N NH3/MeOH to give a light yellow solid (271 mg, 0.79 mmol, 50.6%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:41](Cl)=[O:42])=[N:29][N:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[CH:31]=1)[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=3)[N:29]=2)=[O:42])=[CH:18][C:17]=1[F:23]
Reactant: CCOc1cn(-c2cccc([N+](=O)[O-])c2)nc1C(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Product: CCOc1cn(-c2cccc([N+](=O)[O-])c2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X3 was prepared from A2 and 4-ethoxy-1-(3-nitrophenyl)-1H-pyrazole-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. MS (ES) C29H24N5O7 requires: 573. Found: 574 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH:9][C:10]([C:12]2[C:13]([S:22][CH2:23][CH3:24])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=O)=[CH:7][C:6]([C:25]([F:28])([F:27])[F:26])=[CH:5][N:4]=1.CN(C=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:23]([S:22][C:13]1[C:12]([C:10]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:25]([F:28])([F:27])[F:26])[CH:7]=[C:8]3[N:9]=2)=[CH:17][CH:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]=1)[CH3:24]
Reactant: CCSc1nc(C(F)(F)F)ccc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCSc1nc(C(F)(F)F)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 703 mg of 2-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 630 mg of p-toluenesolufonic acid-hydrate, 2.5 ml of DMF and 0.5 ml of toluene was heated and stirred at 150° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane, and then dried to obtain 616 mg of 2-(2-ethylsulfanyl-6-trifluoromethylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 4).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[Cl:16].[H-].[Na+].CC1C=CC(S(O[CH2:30][C:31]2([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:30][C:31]2([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:5]=[CH:4][C:3]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(Br)n1
Reactant: COC1(COS(=O)(=O)c2ccc(C)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(CN(C(=O)OC(C)(C)C)c2ccc(Cl)c(Br)n2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 6-bromo-5-chloropyridin-2-ylcarbamate (140 mg, 0.455 mmol) in DMF (2 ml) under nitrogen was added NaH (60%, 30 mg, 0.774 mmol). The resulting mixture was stirred at ambient temperature for one hour. A solution of (4-methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (intermediate O, 164 mg, 0.546 mmol) in DMF (1.5 ml) was then added to the preceding mixture. The resulting mixture was then stirred overnight at about 85° C. The stirred mixture was diluted with 30 ml of ethyl acetate, washed with water (20 ml×3) and dried. After concentration the resulting residue was purified by silica gel chromatography using a 12 g column, eluting with 5-20% ethyl acetate in hexane to yield the desired compound “P” as a viscous oil (92 mg), which solidified upon standing overnight. LCMS (m/z): 437.0 [M+H]+; Retention time=1.158 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH:29]([CH3:31])[CH3:30])=[N:11]2)=[CH:6][C:5]=1[NH:32][CH:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1)(=[O:3])[NH2:2].C(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH:29]([C:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:32][CH:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[CH:6]=2)[N:11]=1)([CH3:31])[CH3:30]
Reactant: CC(C)c1nn(-c2ccc(C(N)=O)c(NC3CCN(C(=O)OC(C)(C)C)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NC3CCNCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
Tert-butyl 4-{2-carbamoyl-5-(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenylamino}piperidine-1-carboxylate (0.704 g) was dissolved in trifluoroacetic acid, followed by stirring at room temperature for 1 hr. The reaction solution was distributed between chloroform and saturated sodium bicarbonate water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain (76) (0.600 g, 99%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([F:23])([F:22])[C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])=[CH:13][N:12]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][N:12]=1)([F:23])[F:22]
Reactant: COC/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of (E)-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(3-methoxyprop-1-en-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (48; 80 mg, 0.18 mmol) in EtOH (10 mL) was added 10% Pd/C (8 mg), and the mixture was stirred under hydrogen atmosphere for 1 h. The reaction mixture was filtered through a pad of Celite®, the Celite® cake was washed thoroughly with EtOAc (3×30 mL) and then the filtrate was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 45-50% EtOAc/hexanes) afforded 50 (65 mg, 0.14 mmol, 77%) as a semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.36 (s, 1H), 7.87 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.38-7.33 (m, 1H), 6.77-6.73 (m, 1H), 6.67-6.63 (m, 1H), 5.56 (d, J=14.5 Hz, 1H), 5.09 (d, J=14.5 Hz, 1H), 3.37-3.34 (m, 2H), 3.33 (s, 3H), 2.75 (t, J=7.0 Hz, 2H), 1.90-1.85 (m, 2H). MS (ESI): m/z 426 (M+H)+. HPLC: 97%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:7][CH2:8]4)=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22]
Reactant: CCc1coc(-c2ccc(O)c(OC)c2)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(CC)co4)cc3OC)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of [(1S-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45) (93.4mg, 0.274 mmol) and 4-(4-ethyl-1,3-oxazol-2-yl)-2-methoxyphenol (40.0 mg, 0.182 mmol) (Example 172) in DMF (4 mL) was added Cs2CO3 (118.9 mg, 0.365 mmol) and water (4 drops). The reaction mixture was stirred at rt for 16 h, then filtered, and the filtrate concentrated under reduced pressure. Purification by preparative HPLC (acetonitrile/water (v/v)=1:1 to 9:1 gradient) gave 73.6 mg (84%) of the title compound as an off-white solid. 1H NMR (400 MHz, CD2Cl2) δ 7.57 (d, 2H), 7.41 (s, 1H), 7.05 (d, 1H), 6.98 (d, 1H), 6.80 (s, 1H), 6.72 (d, 1H), 4.25 (t, 2H), 4.17 (m, 4H), 3.93 (s, 3H), 3.51 (m, 1H), 2.85 (m, 2H), 2.71 (dd, 1H), 2.62 (q, 2H), 2.40 (m, 2H), 2.31 (t, 2H), 1.76 (m, 1H), 1.29 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(OCl)(C)(C)C.[CH3:22][S:23][CH2:24][C:25](OCC)=[O:26].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:5]([C:4]1[CH:13]=[CH:14][CH:15]=[C:2]2[C:3]=1[CH:24]([S:23][CH3:22])[C:25](=[O:26])[NH:1]2)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CCOC(=O)CSC
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2cccc(C(=O)c3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 30.6. (0.152 mole) of 3-aminobenzophenone in 160 ml. of methylene chloride was cooled to -78°C. in a dry ice/acetone bath and treated dropwise under a nitrogen atmosphere with a solution of 16.5 g. (0.152 mole) of t-butylhypochlorite in 60 ml. of methylene chloride. After stirring for 1 hr. after addition was complete, thin layer chromatography showed no starting material. A solution of 20.2 g. (0.152 mole) of ethyl α-(methylthio)acetate in 60 ml. of methylene chloride was added dropwise and stirring continued at -78°C. for 2.5 hr. A solution of 15.4 g. (0.152 mole) of triethylamine in 60 ml. of methylene chloride was added dropwise at -78°C. and the reaction mixture allowed to warm to room temperature while stirring for 16 hr. (overnight). The dark brown solution was treated with 100 ml. of 3N hydrochloric acid and stirred for 3 hrs. at room temperature. Precipitation of a tan solid began after 15-30 minutes. Filtration gave 18.5 g. of solid, m.p. 224°-228°C. (dec.). The layers of the filtrate were separated, the organic phase dried over magnesium sulfate, evaporated under reduced pressure, and the residue triturated in isopropyl ether (25 g.). The gummy solid was triturated in cold methanol to give 8.3 g. of product, m.p. 222°-225°C. (dec.). The total yield was 26.8 g. (62%). A 7.0 g. sample recrystallized from methanol weighed 5.6 g. and melted at 235°-237°C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH3:25]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:25])[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nccnc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nccnc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 85 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrazin-2-amine (44 mg, 0.129 mmol) and ammonia (1 mL, 37% in water) in dioxane (1 mL). The reaction mixture was stirred and heated at 100° C. for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 10% MeOH/EtOAc to give 4-(3-(6-methoxypyridin-3-ylamino)pyrazin-2-yl)-6-methyl-1,3,5-triazin-2-amine (34 mg, 0.110 mmol, 85% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.83 (s, 1H); 8.37 (d, J=2.05 Hz, 1H); 8.24 (s, 1H); 8.20 (s, 1H); 8.04 (dd, J=8.92, 2.48 Hz, 1H); 6.80 (d, J=8.77 Hz, 1H); 5.71 (s, 2H); 3.95 (s, 3H); 2.62 (s, 3H). m/z (ESI, +ve ion) 311.0 (M+H)+.