Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)=[O:6])[CH:2]=C.I([O-])(=O)(=O)=[O:39].[Na+].[BH4-].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:21]=[CH:22][C:17]([N:12]3[CH:11]=[N:10][C:9]4[C:13]3=[N:14][CH:15]=[N:16][C:8]=4[NH:7][C:5]([NH:4][CH2:1][CH2:2][OH:39])=[O:6])=[CH:18][CH:19]=2)=[CH:28][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCNC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-n2cnc3c(NC(=O)NCCO)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.4 %

Procedure:
In a mixed solution of 3 mL of tetrahydrofuran and 1 mL of water, 50 mg (0.09 mmol) of 1-allyl-3-(9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)urea was dissolved, and 19 μL of a 0.1 M osmium tetraoxide aqueous solution and 81 mg (0.19 mmol) of sodium periodate were added thereto and the mixture solution was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was dissolved in 2 mL of ethanol, and 5 mg (0.13 mmol) of sodium borohydride was added thereto and the mixture solution was stirred at room temperature for one hour. The reaction solution was concentrated, and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 5 mg (13%) of a target product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O-])([O-])=O.[Na+].[Na+].[C:19](ON1C(=O)CCC1=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>O1CCOCC1>[C:19]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:2]=1[Br:1])([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NCc1ccc(C(=O)O)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(C(=O)O)cc1Br)OCC1c2ccccc2-c2ccccc21
Temperature: 10 °C
Yield: 66.8 %

Procedure:
To a solution of 2-bromo-4-carboxybenzylamine (20 g, 0.086 mol) in dioxane (250 mL), was added an aqueous solution of Na2CO3 (10%, 350 mL) with stirring. The reaction mixture was cooled to 10° C., added Fmoc-OSu (32 g, 0.096 mol) in portions and allowed to stir at RT for 8 h. The solid precipitate was filtered off and washed with diethyl ether (2×200 mL). The solid was acidified with 3N HCl and filtered under suction. The crude solid was recrystalised from methanol/diethyl ether to give N-(Fmoc)-2-bromo-4-carboxybenzylamine (26 g, 67%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH2:12][C@H:13]([OH:25])[CH2:14][P:15]([CH2:18][CH:19]2[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]2)(=[O:17])[OH:16])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH2:12][C@H:13]([OH:25])[CH2:14][P:15]([CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)(=[O:16])[OH:17])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(NC[C@H](O)CP(=O)(O)CC1CC=CCC1)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: CC(NC[C@H](O)CP(=O)(O)CC1CCCCC1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h

Procedure:
20 mg of 5% palladium-on-carbon are added to a solution of 0.125 g of 3-{N-[1-(3,4-dichlorophenyl)ethyl]amino}-2-(S)-hydroxy-propyl-(cyclohex-3-enylmethyl)-phosphinic acid in 5 ml of ethanol and hydrogenation at room temperature and normal pressure for 15 minutes. The catalyst is filtered off through Celite® and the filtrate is adjusted to pH 1 with ethanolic hydrochloric acid. Removal of the solvent and recrystallisation from isopropanol yield 3-{N-[1-(3,4-dichlorophenyl)ethyl]amino}-2(S)-hydroxypropyl-(cyclohexylmethyl)-phosphinic acid, m.p. 173°-178°.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li]CCCC.[CH:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccccc1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethylacetal (Tet. Lett., 22, 5027 (1981)) (130 g) in THF (2.0 L), cooled to -78° C., was added dropwise a solution of n-BuLi (210 ml, 1.91M) in hexane. After 15 min., a solution of benzaldehyde (48 mL) in THF (50 ml) was added dropwise. The cooling bath was removed, then the reaction mixture was warmed slowly (40 min.) to -10° C. and quenched with a saturated NH4Cl solution. The reaction mixture was diluted with Et2O (2.0L). The organic phase decanted, washed with H2O (3×), brine, dried over MgSO4 and the solvents evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 95:5 to 85:15) to give the title product as a foam.
Reaction SMILES: C[O:2][C:3](=[O:23])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)=[N:5]/[O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Li+].O>CO.C(Cl)(Cl)Cl>[Cl:22][C:14]1[CH:13]=[C:12](/[C:4](=[N:5]\[O:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)/[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reaction time: 1 h

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid methyl ester (144 mg, 0.40 mmol) was dissolved in methanol (4 mL) and cooled in an ice bath. A 2.0 N solution of lithium hydroxide in water (0.60 mL, 1.2 mmol) was added dropwise. After stirring 1 h, the reaction mixture was diluted with chloroform (50 mL) and washed with 0.1 M aqueous potassium bisulfate (25 mL). The aqueous phase was extracted with chloroform (30 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford (E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid which was used in the next step without further purification: H1-NMR (400 MHz, CDCl3) δ=1.65 (4H, m), 1.88 (4H, m), 3.31 (3H, s), 4.97 (1H, m), 7.58 (1H, dd, J=8.2 Hz, J=1.1 Hz), 7.67 (1H, d, J=1.1 Hz), 8.19 (1H, d, J=8.2 Hz).
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[OH-].[Na+].[C:24]([C:26](=[CH:32]OCC)[C:27](OCC)=[O:28])#[N:25]>C(O)C>[CH2:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[C:27]([OH:28])[C:26]([C:24]#[N:25])=[CH:32][N:8]=2)[CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 29.6 %

Procedure:
Mixed were 26.8 g of 1-amidino-4-benzylpiperazine sulfate and 133 ml of a 3% ethanol solution of sodium hydroxide, followed by an addition of 17.0 g of ethyl 2-cyano-3-ethoxyacrylate. After being refluxed for 5 hours, the reaction mixture was allowed to cool down. After distilling off ethanol from the reaction mixture, the residue was added with water and ethyl acetate. The resultant mixture was shaken. Precipitated colorless crystals of 2-(4-benzylpiperazino)-5-cyano-4-hydroxypyrimidine were collected by filtration, washed with water and then dried, thereby obtaining 7.4 g of 2-(4-benzylpiperazino)-5-cyano-4-hydroxypyrimidine (yield: 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2.I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:25][N:15]([CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[NH:33])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[C:16](=[O:24])[O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(CCCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCCN1CCCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a stirred solution of phenyl 3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)carbamate (830 mg, 2.445 mmol) in ethanol (35 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (1395 mg, 4.89 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with water and sodium carbonate (sat) and extracted with dichloromethane. The combine organics were dried, filtered and concentrated, then chromatographed in 1:1 ethyl acetate in hexanes, then ethyl acetate, followed by 5% (2M NH3 in methanol) in 1:1 ethyl acetate dichloromethane, giving the desired phenyl methyl(3-(6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (630 mg, 1.404 mmol, 57.4% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.23-7.21 (m, 1H), 7.13-7.05 (m, 3H), 6.56 (m, 2H), 6.49 (brs, 1H), 6.25 (brs, 2H), 3.50-3.45 (m, 2H), 3.38-3.32 (m, 2H), 3.23-3.19 (m, 2H), 3.06, 2.93 (2s, 3H), 2.69-2.64 (m, 2H), 1.89-1.81 (m, 4H).
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:6])[CH2:5][CH2:4]1.ClCCl.CS(O[CH2:15][CH2:16][C:17]1[N:18]=[CH:19][S:20][C:21]=1[CH2:22]OS(C)(=O)=O)(=O)=O>O>[CH3:2][C:3]1([N:6]2[CH2:15][CH2:16][C:17]3[N:18]=[CH:19][S:20][C:21]=3[CH2:22]2)[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)OCCc1ncsc1COS(C)(=O)=O
Reactant: CC1(N)CC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1(N2CCc3ncsc3C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
1-Methylcyclopropylamine hydrochloride (J. Org. Chem., 1989, Vol. 54, p. 1815) (1.89 g) was added to dichloromethane (20 ml) containing 4-(2-methane-sulfonyloxyethyl)-5-methanesulfonyloxymethylthiazole (4.46 g) under ice cooling, and the mixture was stirred overnight at room temperature. 1-Methylcyclopropylamine hydrochloride (1.89 g) was additionally added, and the mixture was stirred for 20 hours at room temperature and 5 hours under refluxing. Dichloromethane and water were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:49) to obtain the title compound (944 mg) as a pale yellow oil.
Reaction SMILES: O[C@@H]([C@H](O)C(O)=O)C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])=[CH:14][CH:13]=1>CC(C)=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C@H:19]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])=[CH:14][CH:13]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccc(F)cc1)c1ccccc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(C)=O
Product: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
(2S,3S)-2,3-dihydroxysuccinic acid (0.23 g, 1.52 mmol) was added to a suspension of (R)-quinuclidin-3-yl 2-(4-fluorophenylamino)-2-phenylacetate (1.08 g, 3.05 mmol) in acetone (140 ml). The resulting mixture was heated at reflux and then allowed to cool at room temperature.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]2[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]=2[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH3:12])[CH:5]=[CH:4][C:3]=2[C:13]2[C:14]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]=3[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[CH:35][CH:34]=1
Reactant: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3COCC[Si](C)(C)C)c(F)c1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1
Product: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3COCC[Si](C)(C)C)c(Oc2ccc(Cl)cc2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 1, Step 1, using 4-[2-fluoro-4-(methylamino)-3-nitrophenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and p-chlorophenol as the starting materials. LCMS calculated for C27H32ClN4O5Si (M+H)+: m/z=555.2. found: 555.1.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@@H:11]([CH2:13][OH:14])[CH2:10][N:9]([C:15]([O-:17])=[O:16])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH:1]1([C@H:7]2[CH2:12][C@@H:11]([CH2:13][O:14][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:10][N:9]([C:15]([O:17][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:16])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])N1C[C@H](CO)C[C@H](C2CCCCC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](COS(C)(=O)=O)C[C@H](C2CCCCC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of tert-utyl cis-3-cyclohexyl-5-(hydroxymethyl)piperidine-1-carboxylate (431.1 mg) in THF (10 ml) was added TEA (405.0 ml) and MsCl (135.2 ml) at 0° C. After stirring at 0° C. for 1 hour, the insoluble material was filtered off through celite and washed with THF. The filtrate was concentrated to give the crude tert-butyl cis-3-cyclohexyl-5-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate as a pale brown oil.
Reaction SMILES: [OH-].[Na+:2].[Na].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([OH:28])/[CH:10]=[CH:11]/[C@@H:12]1[C@H:16]2[CH2:17]/[C:18](/[O:26][C@H:15]2[CH2:14][C@H:13]1[OH:27])=[CH:19]/[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(O)C>[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([OH:28])/[CH:10]=[CH:11]/[C@@H:12]1[C@H:16]2[CH2:17]/[C:18](/[O:26][C@H:15]2[CH2:14][C@H:13]1[OH:27])=[CH:19]/[CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24].[Na+:2]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)O[C@H]2C[C@H]1O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)[O-])O[C@H]2C[C@H]1O

Procedure:
5 mg of prostacyclin methyl ester was stirred at room temperature for 8 hours in 0.2 ml of a 0.35M aqueous solution of sodium hydroxide and 0.2 ml of ethanol to prepare an aqueous solution of a sodium salt of prostacyclin.
Reaction SMILES: FC(F)(F)[C:3]1[N:16]=[C:15]2[C:17]3=[C:18]4[C:8]([N:9]=[C:10](C(F)(F)F)[N:11]=[C:12]4[CH:13]=[C:14]2Br)=[C:7](Br)[CH:6]=[C:5]3[N:4]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:7]2[C:8]3[C:18]4[C:12](=[CH:13][C:14]([C:13]5[CH:12]=[CH:18][C:17]([C:5]#[N:4])=[CH:15][CH:14]=5)=[C:15]5[C:17]=4[C:5]([CH:6]=2)=[N:4][CH:3]=[N:16]5)[N:11]=[CH:10][N:9]=3)=[CH:31][CH:30]=1)#[N:28]
Reactant: FC(F)(F)c1nc2cc(Br)c3nc(C(F)(F)F)nc4cc(Br)c(n1)c2c43
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: N#Cc1ccc(-c2cc3ncnc4c(-c5ccc(C#N)cc5)cc5ncnc2c5c34)cc1
Temperature: 101 °C
Reaction time: 48 h
Yield: 120 %

Procedure:
An oven-dried Schlenk tube was loaded with 100 mg (0.20 mmol) 2,7-bis-(trifluoromethyl)-4,9-dibromo-1,3,6,8-tetraazapyrene, 147 mg (1.00 mmol) 4-cyanophenylboronic acid, 391 mg (1.20 mmol) caesium carbonate and 15 mg (0.02 mmol) Pd(dppf)Cl2 and evacuated and refilled with argon for three times. 20 ml abs. 1,4-dioxane were added, the Schlenk tube was sealed with a glass cap and the reaction mixture was stirred at 101° C. for 48 h. The mixture was allowed to cool to room temperature, the solvent was evaporated and the solid residue was extracted with chloroform. The organic phase was washed with water and brine, dried over sodium sulphate and evaporated in vacuo. The solid was washed with methanol and pentane to yield 65 mg (0.12 mmol, 60%) of the compound as a light grey solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CO.C1COCC1>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
3-{[4-(Azetidin-1-ylcarbonyl)-2-chlorophenyl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (104 mg, 0.215 mmol) was dissolved in methanol (3 mL) and THF (3 mL). Triethylamine (65 mg, 0.644 mmol) was added and the flask evacuated and purged with nitrogen (3 times). 10% Palladium on carbon (25 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 16 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, the filtrate concentrated in vacuo and dissolved in ethyl acetate (10 mL), washed with water (2×10 mL, saturated aqueous sodium chloride solution (10 mL) and dried (MgSO4) to give the title compound (95 mg).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][C:4]=1[F:11])#[N:2].[CH:12]([C:14]1[N:15]=[C:16]([CH3:19])[NH:17][CH:18]=1)=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:15]2[C:14]([CH:12]=[O:13])=[CH:18][N:17]=[C:16]2[CH3:19])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: Cc1nc(C=O)c[nH]1
Reactant: N#Cc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ncc(C=O)n1Cc1ccc(C#N)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of 4-cyano-3-fluorobenzyl bromide, as described in Example 1, Step D, (1.26 g, 5.9 mmol) in DMF (10 mL), at 0° C., was added 4-formyl-2-methylimidazole (0.650 g, 5.9 mmol) and cesium carbonate (2.9 g, 8.9 mmol). After 2 hours, the reaction mixture was poured into EtOAc—30% hexane, washed with H2O, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the crude product. The crude material was purified by silica gel chromatography, eluting with a gradient of CHCl3—2% to 5% MeOH, to obtain the above-titled product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[N:20][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:27][O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)=[O:26])=[N:20][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCN(CCc3cccc(F)c3)C2)cn1
Solvent: ClCCl
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(CCc3cccc(F)c3)C2)cn1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (2E)-3-[5-({(3R)-1-[2-(3-fluorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylic acid (226 mg) and 2-(aminooxy)tetrahydro-2H-pyran and WSCD-HCl was stirred for 24 hours at ambient temperature. CH2Cl2 was added the mixture. The CH2Cl2 layer was washed with water and evaporated in vacuo. The residue was chromatographed on silica gel using a mixture of CHCl3-MeOH (10:1) to give (2E)-3-[5-({(3R)-1-[2-(3-fluorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (160 mg) as a solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:17])[CH2:9][CH2:8][C:7]([CH2:15][OH:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.S(OC)(O[CH3:22])(=O)=O>C1COCC1>[F:3][C:4]1([F:17])[CH2:5][CH2:6][C:7]([CH2:15][O:16][CH3:22])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C1(CO)CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(COC)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
NaH (60%, 29.4 mg, 0.736 mmol) was added to a cold (0° C.) solution of ethyl 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (109 mg, 0.490 mmol) in THF (2 mL) and the mixture was allowed to warm to rt over 30 min. Then neat dimethyl sulfate (0.070 mL, 0.736 mmol) was added and the mixture was stirred at rt overnight. Excess Me2SO4 was quenched with TEA, acidified with 1N HCl and extracted with EtOAc to afford a light brown oil which was purified by silica gel FCC (DCM) to afford ethyl 4,4-difluoro-1-(methoxymethyl)cyclohexanecarboxylate as a clear oil (47 mg). Ethyl ester was saponified as described for Cap-7 synthesis (1 N NaOH, MeOH-THF) to afford Cap-8 as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ 3.47 (s, 2H), 3.39 (s, 3H), 2.25 (br. d, J=13.1 Hz, 2H), 2.10-1.95 (m, 3H), 1.69-1.55 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]cnc12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1ncn2Cc1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500-mL round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet is charged with compound 3b (3.30 g, 30.6 mmol), potassium carbonate (8.95 g, 64.8 mmol), anhydrous DMF (200 mL) and 4-chloromethylpyridine hydrochloride (3.98 g, 24.3 mmol) and the mixture is then stirred under nitrogen for 24 h at ambient temperature. After such time the reaction is partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer is separated and extracted with ethyl acetate (6×250 mL). The combined organic extracts are dried with sodium sulfate, and the drying agent is filtered off. The filtrate is then concentrated under vacuum to give a brown solid, which is purified by column chromatography to afford compound 3c as a yellow solid.