Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([CH:18]([CH3:20])[CH3:19])[CH2:13]3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li:21]CCCC>CCCCC>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([CH:18]([CH3:20])[CH3:19])[CH-:13]3)[CH:3]=[C:2]([CH3:1])[CH:7]=1.[Li+:21]
Reactant: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1
Reactant: [Li]CCCC
Solvent: CCCCC
Product: Cc1cc(C)cc(-c2cccc3[cH-]c(C(C)C)cc23)c1
Product: [Li+]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(3′,5′-dimethylphenyl)-2-isopropylindene (5.5 g, 21 mmol) was dissolved in 80 mL of pentane. To this solution was added 8.3 ML of n-BuLi (2.5M in hexane) and the reaction was allowed to stir 4 hours at room temperature. A white solid precipitated from solution and was collected by frit filtration and washed with additional pentane. Yield was 3.3 g (60%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH2:27].O>CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:27][CH2:26][CH2:25][O:24][CH3:23])=[O:22]
Reactant: COCCN
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (100 mg) and 2-methoxyethylamine (314 mg) in N-methylpyrrolidone (1 ml) was heated at 120° C. overnight. Water (3 ml) was added thereto under ice-cooling, and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, and the residue was purified by preparative thin layer chromatography (methanoldichloromethane) to give 8-(2,6-dichlorobenzoylamino)-4-(2-methoxyethylamino)quinoline (65 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[O:6])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccc(C)cc2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(C)cc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 48 h
Yield: 33 %

Procedure:
A suspension of 3-amino-4-methoxy-N-p-tolyl-benzamide from Example 7 (0.515 g, 2.01 mmol) in methylene chloride (75 mL) was heated to the boiling point, then 3,5-dichlorophenyl isothiocyanate (0.411 g, 2.01 mmol) was added, and the reaction was allowed to stand at room temperature. After 2 days, the mixture was stripped of solvent at 40° C. and the residue triturated in warm methylene chloride. The solid was filtered off, redissolved in methylene chloride/methanol, and filtered to clarity. Evaporation of the solvent afforded the product (0.305 g); m.p. 178-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:33])[CH2:31][CH3:32].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:33]=[C:30]([CH2:31][CH3:32])[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 4 g, 19.21 mmol) was dissolved in DMF (30 mL) to which 1,1′-Carbonyldiimidazole (CDI) (4.04 g, 24.97 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-propionamidine (2.03 g, 23.05 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After completion of the reaction, additional CDI (4.04 g, 24.97 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 8 h to effect cyclodehydration. After evaporation of DMF, the residue obtained was cooled to room temperature followed by addition of water (25 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].N1C=CC=CC=1.N1CCCCC1>O>[CH:9]([C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:18][C:19]([OH:21])=[O:20])=[CH:3][CH:2]=1)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C=Cc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(C=Cc2ccccc2)cc1
Yield: 97.4 %

Procedure:
A mixture of 9.4 g of stilbene-4-aldehyde thus-obtained, 10.6 g of malonic acid, 30 ml of pyridine and 3 ml of piperidine was reacted on a steam bath at 100° C. for 4 hours. After the completion of the reaction, the mixture was poured into an exess amount of water and the precipitate thus-obtained was collected and recrystallized from acetic acid to obtain 11.0 g of p-styryl cinnamic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:26])=[CH:16][C:17]([CH:24]=C)=[C:18]([CH:23]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:26])=[CH:16][C:17]([CH:24]=[O:30])=[C:18]([CH:23]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1
Reactant: C=Cc1cc(C)c(Cc2ccc(-c3cn(C)nc3C)nc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-methyl-2-vinylbenzoate (0.18 g) in a mixed solvent of acetone (2.80 mL)-acetonitrile (2.80 mL)-water (2.80 mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodium periodate (0.53 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.18 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1cccc(O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cccc(O)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (8.10 g, 51.7 mmol) in MeOH was added NaBH4 (1.96 g, 51.7 mmol) at 0° C. The reaction was allowed to stir for 30 minutes. The reaction was then diluted with EtOAc (400 mL), washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was used in Step B without further purification.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:19](=[O:22])([O-])[O-].[Cs+].[Cs+].O1[CH2:30][CH2:29]OCC1>O>[C:1]([N:5]1[CH:9]=[C:8]([C:8]2[CH:7]=[C:19]([OH:22])[C:1]3[N:5]([N:6]=[CH:29][CH:30]=3)[CH:9]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C1COCCO1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(C)(C)n1cc(-c2cc(O)c3ccnn3c2)cn1
Temperature: 100 °C

Procedure:
To an appropriate sized microwave vial, 6-bromopyrazolo[1,5a]pyridin-4-ol (100 mg, 0.469 mmol), 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (153 mg, 0.612 mmol), cesium carbonate (459 mg, 1.41 mmol), dioxane (3.0 mL) and water (1.5 mL) were added. The mixture was degassed with nitrogen for 10 minutes. PEPPSI-iPr catalyst (32.0 mg, 0.0469 mmol) was added and the solution was heated at 100° C. for 18 h. After cooling to room temperature, the mixture was poured into water, neutralized to pH 7 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc(Br)c(N)c1
Product: CCOC(=O)C(=CNc1cc(C)ccc1Br)C(=O)OCC
Temperature: 100 °C
Yield: 84.1 %

Procedure:
A mixture of 2-bromo-5-methyl-aniline (1.0 g, 5.34 mmol) and diethyl 2-(ethoxymethylene)propanedioate (1.23 g, 5.90 mmol) was heated at 100° C. for 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified via silica gel column chromatography using 1 to 60% EtOAc in hexanes to yield diethyl 2-[[(2-bromo-5-methyl-phenyl)amino]methylene]propanedioate (1.6 g, 84%). 1H NMR (300 MHz, CDCl3) δ 11.19 (d, J=13.2 Hz, 1H), 8.48 (d, J=13.2 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.08 (s, 1H), 6.81 (d, J=8.1 Hz, 1H), 4.37-4.23 (m, 4H), 2.35 (s, 3H), 1.42-1.25 (m, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-:21].[Ca+2]>C(#N)C.O.C(OCC)(=O)C>[OH:21][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1ccc(CO)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 80.9 %

Procedure:
4-bromomethyl-4′-nitrobenzophenone (3.20 g, 10.0 mmol, 1 eq) was dissolved in a 2:1 acetonitrile/water mixture (300 mL) and calcium carbonate (3.00 g, 30.0 mmol, 3 eq) was added. The turbid mixture was stirred under reflux for 60 hr. After this time the reaction mixture was allowed to cool and the solid calcium carbonate was filtered off. The solid was washed with ethyl acetate (10 mL) and the filtrate was concentrated under reduced pressure to give an off-white solid. The solid was dissolved in ethyl acetate and washed with concentrated hydrochloric acid. The organic solution was then neutralised with sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure to give 4-hydroxymethyl-4′-nitrobenzophenone (2.08 g, 81%) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)(C)C)(C)C)[C:5]2=[N:6][CH:7]=1.[C-:18]#[N:19].[K+]>[Cu].[Pd].CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]2[C:7](=[CH:9][CH:10]=1)[NH:6][N:19]=[CH:18]2)#[N:8]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Reactant: [C-]#N
Agent: [Cu]
Agent: [Pd]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]ncc2c1

Procedure:
Compound 19 can be cyanated with, for example, KCN in heating DMF in the presence of a catalyst such as, copper or palladium to provide the 5-cyano azaindole 46.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[C:10]([CH2:17][CH3:18])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH2:17][CH3:18])[CH3:16]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1NC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1NC

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.7 g) and 1-benzyl-4-methylamino-3-ethyl-3-methyl piperidine (6 g, 24.39 mmol) in methanol (60 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-methylamino-3-ethyl-3-methylpiperidine. Yield 2.5 g (66%), C9H20N2, m/z 157 (M+1).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])(C)(C)C.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]1)=O)(C)(C)C.[NH4+].[Cl-]>CCOCC>[C:4]1([CH2:3][CH2:2][CH:28]([CH:25]2[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]2)[OH:29])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ICCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCc1ccccc1)C1CCNCC1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5 mL (34.5 mmol) of (2-iodoethyl)benzene in 100 mL of ether at −78° C. was added 42.6 mL (72.5 mmol) of t-butyl lithium. The reaction mixture was warmed to −20° C. for 20 min, then cooled to −78° C. TO this solution, was added a solution of 5.6 g (23.2 mmol) of 1-t-butoxy carbonyl-4-formylpiperidine in 50 mL of ether and the reaction mixture was stirred 15 min at −78° C. To the reaction mixture was added 150 mL of a sat'd solution of NH4Cl and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. Removal of the BOC protecting group was achieved as described in Example 233, Step 6 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([OH:32])=O.Cl.[NH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH:25]([CH3:26])[CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:7]=[C:2]([F:1])[C:3]=1[CH2:29][C:30]([N:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1)=[O:32]
Reactant: OC1CNC1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CC(O)C4)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [(2,6-difluoro-4-{2-[(1S,2R)-2-{1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (35.0 mg, 0.078 mmol) (from example 2, step B) in 1 ml anhydrous DMF at RT was added azetidin-3-ol hydrochloride salt (8.53 mg, 0.078 mmol) and N,N-diisopropylethylamine (0.041 ml, 0.234 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59.2 mg, 0.156 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-95% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 505.4 (M+H)+. GPR119 Human EC50: 0.96 nM
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].[C:9]([O-:12])(=[O:11])[CH3:10].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](Cl)=[O:24]>C1COCC1>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23]([CH2:10][C:9]([O:12][CH2:21][CH2:22][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:7][CH:5]=[CH2:6])=[O:11])=[O:24]
Reactant: CC(=O)[O-]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCCCCCCCOC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide in the amount of 79.8 mL (2.0 M, 0.160 mol) is placed into a 250 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. Roseate acetate in the amount of 14.91 g (0.075 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of 13.80 g (0.071 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (47 mL). The mixture is poured into a separatory funnel containing ether (125 mL) and water (225 mL). The aqueous layer is extracted with ether (125 mL). The combined organic layers are washed with saturated NaHCO3 solution (3×95 mL), water (2×150 mL) and brine (150 mL), dried with MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate dissolved in hexane) to give an oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[OH-:11].[Na+].[CH2:13]([O:16][C:17](Cl)=[O:18])[CH:14]=[CH2:15]>C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH2:13]([O:16][C:17]([N:10]([C:17]([O:16][CH2:13][CH:14]=[CH2:15])=[O:11])[C:8](=[NH:9])[S:7][CH3:6])=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)Cl
Reactant: CSC(=N)N
Reactant: [OH-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)N(C(=N)SC)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-methyl-2-thiopseudourea sulfate (2 g) was dissolved in sodium bicarbonate (10% soln., 20 ml. To this was added methylene chloride (20 ml) followed by sodium hydroxide solution (5N, 2.8 ml) and allylchloroformate (4.5 ml) added dropwise over 5 min. The reaction was allowed to stir at room temperature for 3 hr., diluted with methylene chloride and the organic phase was separated. The aqueous phase was extracted once with methylene chloride and the combined organic phase was washed with water, satd. NaCl, and dried over MgSO4 and evaporated to give the product (3.7 g)
Reaction SMILES: N#N.CO[N:5](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]1[NH:7][C:8](=[O:43])[C:9]2[N:10]=[CH:11][N:12]([CH:15](OC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:16][CH:17]([CH2:21][OH:22])[CH2:18][O:19][CH3:20])[C:13]=2[N:14]=1.C(Cl)(=[O:69])CCCCC.N1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>>[C:20]([O:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16][CH2:15][N:12]1[CH:11]=[N:10][C:9]2[C:8](=[O:43])[NH:7][C:6]([NH2:5])=[N:14][C:13]1=2)(=[O:69])[CH2:72][CH2:73][CH2:74][CH2:75][CH3:76]
Reactant: CCCCCC(=O)Cl
Reactant: COCC(CO)CC(OC(c1ccccc1)(c1ccccc1)c1ccccc1)n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Reactant: c1ccncc1
Agent: N#N
Product: CCCCCC(=O)OCC(CO)CCn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of N2 -monomethoxytrityl-9-(4-monomethoxytrityloxy-3-hydroxymethylbut-1-yl)guanine (0.72 g, 0.9 mmol) in pyridine (4 ml) was added hexanoyl chloride (0.38 ml, 2.7 mmol) and the solution was stirred for 20 minutes. The mixture was precipitated in water (40 ml) and the resulting precipitate was stirred in 80% acetic acid (10 ml) at 80° for 45 minutes. The solvent was removed and the residue purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (7:1, 5:1) to afford 9-(4-hexanoyloxy-3-hydroxymethylbut-1-yl)guanine (0.12 g, 38%), m p. 179°-181° C.; νmax 2960, 2930, 1730, 1690, 1630, and 1600 cm-1 : δH [(CD3)2SO] 0.84 (3 H, t, J 6.9 Hz, CH3), 1.24 (4 H, m, CH3 (CH2)2), 1.50 (2 H, quintet, J 7.3 Hz, CH2CH2CO), 1.6-1.8 (3 H, m, 2'-H and 3'-H), 2.26 (2 H, t, J 7.3 Hz, CH2CO), 3.40 (2 H, t, J 5 Hz, D2O exchange leaves d, CH2OH), 3.9-4.1 (4 H, m, 1'-H and CH2OCO), 4.60 (1 H, t, J 5.1 Hz, D2O exchangeable, 2-NH2), 7.67 (1 H, s, 8-H), and 10.49 (1 H, s, D2O exchangeable, 1-H); (Found: C, 52.63; H, 6.91; N, 18.75%; C16H25N5O4 requires: C, 54.69; H, 7.17; N, 19.93%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3][C:4]1[CH:5]=[C:6]([N:10]=[C:11]=S)[CH:7]=[CH:8][CH:9]=1.[OH:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][CH3:35])=[C:30]([NH2:36])[CH:29]=2)[CH:24]=[CH:23][N:22]=1)=[O:20]>CO>[OH:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]3[N:34]([CH3:35])[C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:14])([F:13])[F:1])[CH:5]=4)=[N:36][C:30]=3[CH:29]=2)[CH:24]=[CH:23][N:22]=1)=[O:20]
Reactant: FC(F)(F)Sc1cccc(N=C=S)c1
Reactant: CNc1ccc(Oc2ccnc(C(=O)NCCO)c2)cc1N
Solvent: CO
Product: Cn1c(Nc2cccc(SC(F)(F)F)c2)nc2cc(Oc3ccnc(C(=O)NCCO)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with 3-(trifluoromethylthio)phenylisothiocyanate (1 eq), 4-(3-amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide (1 eq), and MeOH. The reaction was maintained at rt overnight. Ferric chloride, (1.5 eq) was added and the resulting red reaction mixture was stirred overnight. The reaction was partitioned with EtOAc and water, and filtered through Celite. The layers were separated and the aqueous phase was neutralized with saturated Na2CO3 solution. The resulting aqueous phase was extracted with EtOAc and the mixture was filtered through Celite. The phases were separated and the aqueous phase was again extracted and filtered. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give a brown solid. The crude residue was purified by reverse phase HPLC. LCMS m/z 504.1 (MH+), tR=3.7 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([CH:28]([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(#N)C.O>[CH:31]([NH:34][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([CH:28]([F:29])[F:30])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:33])[CH3:32]
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: O
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 600 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-difluoromethyl-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v), is added 1.2 mL (14.0 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Trituration of the residue in ethyl acetate affords 106 mg (15% over two steps) of the product as a pale yellowish solid; LC/MS:488/490 (M+H)+; m.p.: 250-253° C.