Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](C2C=CC=C(CSCCO)C=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:13]2[CH:12]=[CH:17][CH:16]=[C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:14]=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2cccc(CSCCO)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester (1.95 g, 6.16 mmol, 1 eq.) in anhydrous THF was treated with phenol (0.75 g, 8.01 mmol, 1.3 eq.), triphenylphosphine (2.10 g, 8.01 mmol, 1.3 eq.), and diisopropyl azidocarboxylate (1.62 g, 8.01 mmol, 1.3 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH3:16])[CH2:12][CH:13]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:17]([F:20])([F:18])[F:19]
Reactant: CCCN1CC=C(c2ccc(F)c(C(F)(F)F)c2)CC1
Agent: Cl
Product: CCCN1CCC(c2ccc(F)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(4-Fluoro-3-trifluoromethylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine, the titled compound was recovered by the procedure described in Preparation 6: m.p. 195-197° C. (HCl), MS m/z (rel. intensity, 70 eV)) 289 (M+, 4), 261 (15), 260 (bp), 177 (7), 70 (13).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][C:46]([NH2:48])=[O:47])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][CH2:45][C:46]([NH2:48])=[O:47])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NC(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(N)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3-piperazin-1-yl-propionamide (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2928.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1C=O
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Sodium hydride (60% dispersion in oil, 12 mg, 0.32 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (70 mg, 0.29 mmol) in THF (1.5 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude, prepared in accordance with example 11, step 2, ˜0.32 mmol) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (30×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 66 mg (59%) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CCN(C(C)C)C(C)C.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:22][C:23]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(OC(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred solution of 3-hydroxy-1-Boc azetidine (21; 350 mg, 2.023 mmol) and DIPEA (1.3 ml, 7.080 mmol) in THF (5 ml) at 0° C. was slowly added triphosgene (898 mg, 3.034 mmol). The resulting mixture was stirred for 2 hr at RT. After completion of the reaction, the reaction mixture was filtered and washed with fresh THF to get rid of inorganic salts. The filtrate was concentrated under reduced pressure to get crude product 61 in 55% yield. The crude product, thus obtained, was immediately used for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1>>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[CH3:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:10]1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: CN(C)c1cccc(N(C)C)c1
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(C)c1

Procedure:
In a manner similar to that of part B of Example 1 condensation of 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (25 g.) and N,N,N',N'-tetramethyl-m-phenylenediamine (13.2 g.) in contact with acetic anhydride (75 g.) and recrystallization of the resulting product afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)phthalide (I: X = (CH3)2N, Y2 = CH3, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = H) in a first crop from toluene (m.p. 204°-206° C.) and in a second crop from a mixture of toluene and hexane (m.p. 191°-195° C.).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:23])[CH3:24])[C:12]([C@H:25]([C:34]3[CH:35]=[CH:36][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=3)[OH:26])=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Product: CC(C)c1ccc([C@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC2(CCC2)C3)cc1

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 4-isopropylphenylmagnesiumbromide.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28]CC)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([CH:36]=[N:37][CH:38]2[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>C1COCC1>[O:28]=[C:26]1[C:23]2([CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:25][CH2:24]2)[CH:36]([C:35]2[CH:41]=[CH:42][C:32]([Cl:31])=[CH:33][CH:34]=2)[N:37]1[CH:38]1[CH2:39][CH2:40]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccc(C=NC2CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(C1CC1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Cool to 0 to −10 C, a solution of diisopropylamine (6.0 mL) in THF (10 mL) and add n-butyllithium (2.5 M, 16.6 mL) dropwise. After 1 h, the reaction mixture was cooled to −78 C. Add a solution of ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate (1) (10 g) in anhydrous THF (20 mL) dropwise, and stir the resulting solution at −78 C for 1.5 h. Add 4-chlorobenzylidene cyclopropylamine (8) (6.69 g) in THF (40 mL) and stir for 1 h. Warm the reaction mixture to room temperature and stir overnight. Quench the reaction mixture with saturated ammonium chloride solution and extract with EtOAc. Partition the EtOAc solution with IN HCl, then salt solution. Concentrate the dried (MgSO4) EtOAc solution in vacuo to give an amber oil (13.83 g). Absorb the amber oil (12.8 g) on Purasil 60A 230-400 mesh (˜30 mL), place in a syringe cartridge, and elute onto a Redi Sep Normal Phase Disposable Column (330 g, ISCO). Elute with hexane (one column volume) then hexane/EtOAc gradient (0% to 55% EtOAc) at 65 mL/min. Collect the title compound and concentrate the fractions in vacuo to give the title compound (9) (3.49 g).
Reaction SMILES: [H-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[O:19][CH3:20])[NH:15][C:14](=[O:21])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[O:19][CH3:20])[N:15]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](=[O:21])[CH2:13][CH2:12]3)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2CC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a mixture of 95% dry sodium0 hydride (24 mg, 1.00 mmol) in anhydrous N,N-dimethylformamide (8 mL) at room temperature was added a solution of 6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (7) (110 mg, 0.38 mmol) in N,N-dimethylformamide. The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl bromoacetate (390 mg, 2.00 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature until majority of the starting material was converted (as shown by LCMS), then it was quenched by addition of methanol (10 mL). The mixture was concentrated under reduced pressure, anhydrous toluene (10 mL) was added to the residue, and the solvent removed under reduced pressure, to afford crude (tert-butyl 2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:18][CH2:19][CH2:20][OH:21]>C(Cl)Cl>[Br:18][CH2:19][CH2:20][O:21][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCOC1CCCCO1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
12 ml of dihydropyran and 20 mg of paratoluenesulphonic acid are added to a solution of 3.7 ml of 2-bromoethanol dissolved in 100 ml of methylene chloride. After stirring for 3 hours at 20° C., the reaction medium is washed with water and then with saturated aqueous sodium chloride, and evaporated to dryness. The residue is distilled at 90° C. at a pressure of 0.5 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.C([O-])=O.[NH4+]>[Pt].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(Cl)ccc1N
Temperature: 25 °C

Procedure:
A mixture of 5-chloro-2-nitroanisole (1.0 g, Sigma-Aldrich), ammonium formate (3.36 g, Alfa-Aesar) and 10% platinum on carbon (100 mg) in MeOH (10 mL) was heated to reflux for 45 minutes then cooled to room temperature and filtered through celite, washing with MeOH. The filtrates were concentrated and the residue was dissolved in EtOAc and water. The organics were dried (MgSO4) and concentrated to a brown oil. The material was absorbed onto silica and columned eluting ethyl acetate/heptane mixtures to give the product as a brown oil. Yield: 0.7 g. 1H NMR (400 MHz, CDCl3): δ 6.72-6.78 (2H, m, ArH), 6.58-6.62 (1H, m, ArH), 3.83 (3H, s, OMe).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)(O)O.[Na].C([SiH](CC)CC)C.S(=O)(=O)(O)O.[OH-].[Na+]>FC(F)(F)C(O)=O.C(N(CC)CC)C.C(#N)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: O=C(O)O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a 10 ml acetonitrile solution of 426 mg of 4,4′-difluorobenzophenone and 841 mg of piperazine, 395 mg of triethylamine was added and stirred at 100° C. for 12 hours. After cooling to room temperature, saturated aqueous sodium hydrogenbicarbonate solution was added, followed by extracting with chloroform. The extract was dried, filtered and concentrated under reduced pressure. The residue obtained was dissolved in 5 ml of trifluoroacetic acid and treated with 520 mg of triethylsilane and 60 mg of concentrated sulfuric acid, and stirred at room temperature for 1 hour. The reaction, mixture was adjusted to pH=9 to 11 with 10% aqueous sodium hydroxide solution, followed by extracting with ethyl acetate. The extract was dried, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (chloroform:methanol:water (2% acetic acid)=65:35:5) to give the above-referenced compound, 1-[4-(4-fluorophenyl)methylphenyl]piperazine in an amount of 305 mg (yield 58%).
Reaction SMILES: CO.CN(C)C[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1.[CH3:17][NH:18][CH3:19].C1C(=O)CC2C(=CC=CC=2)C1>O1CCCC1>[CH3:17][N:18]([CH3:19])[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: CN(C)CC1CCc2ccccc2C1
Reactant: CNC
Agent: O=C1CCc2ccccc2C1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C1CCc2ccccc2C1
Temperature: 25 °C

Procedure:
46 ml of a methanol solution of 0.3 M sodium cyanoborohydride-1/2 zinc chloride and 6.9 mL of a tetrahydrofuran solution of 2 M dimethylamine were added to a tetrahydrofuran (10 mL) solution of 2.02 g of β-tetralone, and stirred for a day at room temperature. The reaction liquid was concentrated, and 1 N hydrochloric acid was added thereto. The acidic solution was washed with ethyl acetate, then made alkaline with aqueous 5 M sodium hydroxide solution, and extracted with ethyl acetate. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away to obtain 857 mg of the entitled compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[CH:12][C:13](=[O:17])[N:14]([CH3:16])[CH:15]=2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=O.C(=O)(O)[O-].[Na+].NC1N=CN=C2C=1N=C(C1C=CC=C(F)C=1)N2C1C=CC(=O)N(C)C=1>C(OCC)(=O)C.CN1C(=O)CCC1>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=1)[N:9]2[C:10]1[CH:11]=[CH:12][C:13](=[O:17])[N:14]([CH3:16])[CH:15]=1
Reactant: Cn1cc(Nc2ncnc(Cl)c2N)ccc1=O
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cn1cc(-n2c(-c3cccc(F)c3)nc3c(N)ncnc32)ccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cn1cc(-n2c(-c3cccc(F)c3)nc3c(Cl)ncnc32)ccc1=O
Temperature: 40 °C
Yield: 66.7 %

Procedure:
5-(5-Amino-6-chloropyrimidin-4-yl)amino-1-methyl-1,2-dihydro-2-pyridinone (1 g) and NMP (10 mL) were introduced into a flask and stirred at 40° C. 3-Fluorobenzoyl chloride (0.53 mL, 1.1 eq.) was added dropwise to this suspension, and after additional NMP (3.2 mL) was added thereto and stirred for about 1.5 hours, the reaction solution was elevated to 110° C. and stirred for 3 hours. Ethyl acetate (33 mL) and 10% aqueous sodiumbicarbonate solution (16.5 mL) were added to the reaction solution, and the organic layer was washed with brine (16.5 mL) and concentrated. The concentrate was dissolved by adding DME (16.5 mL) and stirring it at 55° C., and then crystallized by adding water (33 mL). The crystals were collected by filtration and dried at 50° C. for 4 hours, to give 0.94 g of 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone (two-steps, yield 66.7%) (6) 5-[6-Amino-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][SH:5].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[C:59]([O:63][C:64]([N:66]1[CH2:70][CH2:69][C@@H:68]([C:71]2[CH:76]=[CH:75][C:74](Br)=[CH:73][CH:72]=2)[CH2:67]1)=[O:65])([CH3:62])([CH3:61])[CH3:60].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:59]([O:63][C:64]([N:66]1[CH2:70][CH2:69][C@@H:68]([C:71]2[CH:76]=[CH:75][C:74]([S:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[CH:73][CH:72]=2)[CH2:67]1)=[O:65])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(Br)cc2)C1
Reactant: C[Si](C)(C)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(SCC[Si](C)(C)C)cc2)C1
Temperature: 97.5 °C
Yield: 100.3 %

Procedure:
2-(Trimethylsilyl)ethane thiol (0.33 mL, 2.1 mmol), Pd2(dba)3 (183.9 mg), Xantphos (231.4 mg) and DIPEA (0.296 mL) were added to a solution of (S)-3-(4-bromo-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (528 mg, 1.618 mmol) in 1,4-dioxane (7 mL) under nitrogen atmosphere. The reaction mixture was heated at 95-100° C. for 20 hours. After cooling to room temperature, a solution of 10% KHSO4/Na2SO4 was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 94/6) to give 616 mg (quantitative yield) of (S)-3-[4-(2-trimethylsilanyl-ethylsulfanyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C@H:16]([NH2:20])[C:17]([OH:19])=[O:18])[CH2:2][C:3]([NH:5][C@H:6]([C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:7][SH:8])=[O:4].[N:21]([O-])=[O:22].[Na+].CC(C)=O>O.Cl>[N:21]([S:8][CH2:7][C@@H:6]([C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[NH:5][C:3](=[O:4])[CH2:2][CH2:1][C@@H:16]([C:17]([OH:19])=[O:18])[NH2:20])=[O:22]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H](CCC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)C(=O)O
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 76 %

Procedure:
1.53 g (5 mmol) L-glutathione (GSH) was dissolved in a mixture of 5.5 ml water and 2.5 ml (2 N) aqueous HCl solution cooled in ice bath, then 0.345 g (mmol) sodium nitrite was added. The mixture was stirred for 40 min at 5° C., then 10 ml acetone was added and the solution was stirred for further 10 min. The precipitated brown deposit was filtered and subsequently washed with ice-cold water (5×1 ml), acetone (3×10 ml) and ether (3×10 ml). Thus 1.29 g (3.8 mmol) of S-nitrosoglutathione was obtained (76% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.Cl>>[ClH:1].[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([NH:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[N:7][CH:6]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cc1cccc(N)c1
Agent: Cl
Product: Cc1cccc(Nc2ncnc3[nH]ccc23)c1

Procedure:
Following the procedure described in Example 1, the title compound was prepared from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and m-toluidine (34%). HRMS: Calcd. 225.1140, Found 225.1131; anal. RP18-HPLC RT: 3.45 min; HCl salt MP: 219° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]3[CH:12]=[CH:13][N:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5](COCC[Si](C)(C)C)[C:4]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1)[CH3:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl.O>[CH2:1]([C:3]1[C:11]2[N:10]3[CH:12]=[CH:13][N:14]=[C:9]3[CH:8]=[N:7][C:6]=2[NH:5][C:4]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1c(-c2ccc(C(C)=O)cc2)n(COCC[Si](C)(C)C)c2ncc3nccn3c12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(-c2ccc(C(C)=O)cc2)[nH]c2ncc3nccn3c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
1-(4-(1-Ethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone (0.12 g, 0.28 mmol) in DCM (2 mL) was treated with TFA (1.50 mL, 19.5 mmol) then stirred at rt for about 45 min. The solvents were evaporated under reduced pressure then the material was dissolved in 1,4-dioxane (2 mL) and treated with ˜28 wt % aqueous NH4OH (1.2 mL, 31 mmol). The mixture was stirred for about 15 min then diluted with water (10 mL). The volatiles were removed by evaporation under reduced pressure (bath temp 40° C., 85 mm Hg) then the mixture was further diluted with water (20 mL). The solids were collected by filtration then the material was dried to constant weight under vacuum at about 60° C. to give 1-(4-(1-ethyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone (0.062 g, 74%): LC/MS (Table 2, Method a) Rt=1.92 min; MS m/z 305 (M+H)+.