Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:13])=[N:8][C:9]=2[O:11][CH3:12])[NH:4][N:3]=1.[OH-].[K+].Cl[CH:17]1[O:31][C@H:30]([CH2:32][O:33][C:34]([C:36]2[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35])[C@@H:19]([O:20][C:21]([C:23]2[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[CH2:18]1.C(OCC)(=O)C.CCCCCC>CO.C1(C)C=CC=CC=1>[CH3:38][C:39]1[CH:42]=[CH:37][C:36]([C:34]([O:33][CH2:32][C@@H:30]2[CH:19]([O:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH3:25])=[CH:29][CH:24]=3)=[O:22])[CH2:18][C@H:17]([N:4]3[C:5]4=[N:6][C:7]([NH2:13])=[N:8][C:9]([O:11][CH3:12])=[C:10]4[C:2]([I:1])=[N:3]3)[O:31]2)=[O:35])=[CH:41][CH:40]=1
Reactant: Cc1ccccc1C(=O)OC[C@H]1OC(Cl)C[C@@H]1OC(=O)c1ccccc1C
Reactant: COc1nc(N)nc2[nH]nc(I)c12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nc(N)nc2c1c(I)nn2[C@H]1CC(OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Reaction time: 0.02 h

Procedure:
To a suspension of (14) (6.68 g, 22.95 mmol) in 150 mL of methanol was added 8.05 mL of a 2.85 M methanolic potassium hydroxide. The mixture was stirred for one minute and then diluted with 100 mL of toluene and evaporated. The solid potassium salt of 1 was dried under vacuum. The potassium salt was suspended in 75 mL of anhydrous DMF and then diluted with 420 mL of anhydrous acetonitrile. 1-Chloro-1,2-dideoxy-3,5-di-O-toluoylribofuranose (8.95 g, 22.95 mmol) was immediately added and the reaction mixture was stirred at room temperature under argon for 1 h. and then filtered. The filtrate was evaporated and the residual foam was recrystallized twice from methanol: 6.59 g (45%) yield; TLC (1:1, ethyl acetate/hexane), Rf=0.52; 1H NMR (DMSO-d6) δ 7.93 and 7.37 (8H, m and d, J=7.9 Hz for the d, aromatic), 7.10 (2H, br s, 6-amino), 6.51 (1H, t, J=6.6 Hz, 1′-H), 5.69 (1H, m, 3′-H), 4.44 (3H, m, 4′- and 5′-Hs), 3.99 (3H, s, 4-methoxy), 3.19 and 2.63 (2H, 2×m, 2′-Hs), 2.40 and 2.38 (6H, 2×s, toluoyl methyl protons).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:19]([O-])([O-])=O.[K+].[K+].CN(C=O)C>[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1oc2cccc(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with iodomethane (0.5 mL), K2CO3 (200 mg) and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was mixed with brine and extracted with ethyl acetate, and the combined ethyl acetate layers were washed with brine. Removal of the solvent gave the crude product that was purified by column chromatographt to give 162 mg (76% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as amber colored oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH:13][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=4[CH:29]=3)[O:8][C:7]=2[CH:14]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 100 °C
Yield: 40.3 %

Procedure:
2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine (3.8 g, 20 mmole), 7-(3-chloropropoxy)coumarin (4.8 g, 20 mmole), diisopropylethylamine (2.6 g, 20 mmole) and sodium iodide (5.0 g, 33 mmole) were combined in 200 ml of DMF and heated at 100° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with 500 ml of dichloromethane. The mixture was washed with 300 ml portions of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel using first dichloromethane, then chloroform, and finally 2% methanol in chloroform as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue crystallized from 100 ml of isopropanol with the addition of 5.0 ml of 4N isopropanolic HCl to give 3.2 g of title compound as a white solid, monohydrochloride, m.p. 223°- 225° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:11](Br)[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:52][N:53](C=O)C>[C-]#N.[Zn+2].[C-]#N.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]>[CH2:1]([O:8][C:9]1[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:11]([C:52]#[N:53])[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C#N)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 100 °C

Procedure:
A solution of ethyl 8-(benzyloxy)-6-bromo-2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (1.40 g, 2.79 mmol; Example 1, Step 7), zinc cyanide (0.26 g, 2.23 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.51 g, 0.56 mmol), triphenylphosphine (0.15 g, 0.56 mmol) in DMF (4.5 mL) was purged with nitrogen for 5 minutes. The reaction mixture was heated at 100° C. overnight and concentrated under vacuum. The reaction mixture was partitioned between dichloromethane and brine. The organic extract was dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography on silica gel eluted with 0-10% methanol in chloroform gradient to provide titled product.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[C:37]([O:39][CH3:40])[C:36](B(O)O)=[CH:35][N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:36]4[C:37]([O:39][CH3:40])=[N:38][C:33]([O:32][CH3:31])=[N:34][CH:35]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AS) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a beige solid. tR: 2.69 min (HPLC 5); ESI-MS: tR=0.90 min, [M+H]+ 545/547 (LC-MS 1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[N:2]1.[F:14][CH:15]([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:14][CH:15]([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=3)[C:9]#[N:10])=[N:2]2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(OC(F)F)cc1
Reactant: N#Cc1cccc(-c2cc[nH]n2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccn(-c3ccc(OC(F)F)cc3)n2)c1
Temperature: 35 °C
Yield: 27.2 %

Procedure:
A solution of 3-(1H-pyrazol-3-yl)-benzonitrile (400 mg, 2.36 mmol) and 4-difluoromethoxybenzeneboronic acid (1.02 g, 5.44 mmol) in dimethylformamide (20 mL) is treated with copper (II) acetate (472 mg), pyridine (0.36 mL), and powdered, activated 4 Å molecular sieves (1 g). The resulting mixture is heated to 35° C. for 3 h, cooled and partially evaporated. The residue is partitioned between 1 M aq. HCl and ethyl acetate (200 mL each), and the extract is washed with brine (100 mL), dried over MgSO4, filtered and evaporated. The residue is separated by column chromatography (silica gel, 1:1 CH2Cl2-hexane) to afford 3-[1-(4-difluoromethoxy-phenyl)-1H-pyrazol-3-yl]-benzonitrile (200 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1.[H][H]>C(O)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[C:4]1[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:7][CH:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:5]=1
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Yield: 89 %

Procedure:
A solution of 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (1 eq) in Acetic Acid (0.1M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.10 eq) was added. The reaction mixture was stirred at room temperature overnight an atmosphere of hydrogen. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. Organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (89%). LC/MS (m/z): MH+=348.3, Rt=0.79 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](B(CC)CC)[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1COCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:23][CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: CCB(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of 0.70 g (1.90 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 14 ml N,N-dimethylformamide was added 73.0 mg [1,1′-bis(diphenyphosphino)ferrocene]-dichloropalladium(II) and after 15 min, 4.8 ml of a 1M triethylborane solution in THF and 0.79 g (5.70 mmol) potassium carbonate were added. After 4 h another 2.4 ml triethylborane solution was added and the reaction mixture stirred overnight at 65 deg C. The mixture was cooled to room temperature and the suspension was poured into water and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (Q0.032–0.063 mm) with tert-butyl methyl ether:n-hexane (1:4) as eluant to yield the product as a colorless oil (89.5%).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18][CH2:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>C(O)C.C1(C)C=CC=CC=1>[CH2:28]([O:27][P:23]([CH2:22][C:21]1[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=1[CH2:19][CH2:18][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:24][CH2:25][CH3:26])=[O:30])[CH3:29]
Reactant: CCOP(=O)(Cc1ccccc1CCBr)OCC
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 34 %

Procedure:
To 1.03 g (44.8 mmol) of sodium in 50 mL of dry ethanol was added 9.72 g (44.8 mmol) of solid diethyl acetamidomalonate portionwise. This solution was stirred at reflux under nitrogen for 2 h. After cooling to room temperature the solvent was removed under reduced pressure yielding a tan solid. This solid was dried under vacuum about 2 h. The sodium salt of diethyl acetamidomalonate was then suspended in 50 mL of dry toluene and 15.0 g (44.8 mmol) of diethyl 2-(2-bromoethyl)benzylphosphonate in 25 mL of toluene was added dropwise. This solution was stirred at reflux under nitrogen for 36 h. After cooling the solution to room temperature the solid precipitate was removed by filtration and washed with 20 mL of toluene. The combined toluene solutions were concentrated under reduced pressure to yield a viscous oil. This oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under pressure to give 7.2 g (34%) of the product as a clear viscous oil. IR(neat): 1745, 1676 (C=O) cm-1. 1H NMR(CDCl3) δ 1.0-6 (m, 12H); 1.8-3.2 (complex m, 9H); 3.7-4.6 (m, 8H); 6.8-7.4 (m, 5). Anal. Calcd. for C22H34NO8P0.5H2O: C, 54.99; H, 7.34; N, 2.92. Found: C, 54.75; H, 7.37; N, 2.97.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23](I)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].N1CCOCC1>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: CCCCCCI
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCn1c(=O)n(C)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 90 h
Yield: 54.4 %

Procedure:
To a solution of 8-chloro-1-methyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) in anhydrous DMF (3 ml) was added sodium carbonate (58 mg, 0.54 mmol), after 10 minutes stirring hexyl iodide (0.08 ml, 0.54 mmol) was added and the reaction mixture stirred at room temperature under nitrogen for 90 hours. Pd(PPh3)4 (73 mg, 0.063 mmol) was then added and the reaction vessel evacuated and flushed with nitrogen (x3), morpholine (0.37 ml, 4.3 mmol) was added and stirring at room temperature under nitrogen continued for 4 hours. The reaction mixture was diluted with EtOAc (25 ml) and washed with 2M HCl aq. (25 ml). The organic extract was dried (MgSO4) filtered and evaporated. Purification by aminopropyl SPE (5 g) loading the compound and washing with MeOH before eluting the product with 5% AcOH/MeOH afforded the title compound as a white solid (65 mg, 54%). NMR; δH (400 MHz, d6-DMSO) ) 0.85 (t, 3H, J=7 Hz), 1.23-1.33 (m, 6H), 1.58-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t, 2H, J=7.5 Hz), 14.46 (br. s, 1H); m/z 285.3 [MH+].
Reaction SMILES: C(O)(=O)C.[CH:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6].[NH3:20]>CO>[NH2:20]/[C:12](/[CH2:11][S:10][CH2:9][CH2:8][NH:7][CH:5]=[O:6])=[CH:13]\[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=O)CSCCNC=O
Reactant: N
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\N)CSCCNC=O
Temperature: 0 °C

Procedure:
Acetic acid is added to a solution of ethyl 4-(2-formylamino-ethylthio)-3-oxo-butanoate (12.5 g) in MeOH (ml 120), previously saturated with ammonia at 0° C. and cooled at 0° C., up to pH 4-45. The mixture is refluxed for 2 hours and the excess solvent is evaporated in vacuum, to give a syrup from which a solid material is separated by treatment with AcOEt. After filtration, the organic phase is washed with water (8×10 ml), and with a saturated aqueous solution of NaHCO3 (3×10 ml), dried (Na2SO4) and concentrated in vacuum to give 11,5 g of ethyl 3-amino-4-(2-formylaminoethylthio)crotonate as a yellow oil.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[C:25]1(=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCCC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=C1CCCC1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.054 g, 0.15 mmol) was reacted with cyclopentanone (0.95 g, 11.3 mmol) in N,N-dimethylacetamide (1 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([Cl:29])=[CH2:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19]CCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C1COCC1.[OH-].[Na+].CCOCC>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([Cl:29])=[CH2:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OCCCC)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Yield: 75 %

Procedure:
n-Butyl 6-[N-(5-bromo-2-(2-chloroprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylate (0.24 g, 0.5 mmol) was dissolved in methanol (2 ml), THF (2 ml) and treated with aqueous 1N sodium hydroxide solution (2 ml). The resultant solution was left at ambient temperature for 1.5 hours, evaporated to low bulk and the resultant precipitate dissolved in water and acidified with acetic acid to give a gummy precipitate. It was extracted with methylene chloride and the organic extracts dried and evaporated to give a gum. Trituration with ether yielded a solid which was filtered and sucked dry to give the title compound as a white solid (0.16 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O[C:18]1(O[Si](C)(C)C)[CH2:20][CH2:19]1)C.C(O)(=O)C>CO.C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH:18]3[CH2:20][CH2:19]3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Fc1cc(Br)cc(N2CCNCC2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Fc1cc(Br)cc(N2CCN(C3CC3)CC2)c1

Procedure:
To mixture of 1-(3-bromo-5-fluorophenyl)piperazine (2.91 g, 11 mmol) in MeOH (50 mL) was added (1-ethoxycyclopropoxy)trimethylsilane (13.5 mL, 67.2 mmol), acetic acid (6.5 mL, 112 mmol) and NaBCNH4 (1.0 M in THF) (51 mL, 50.4 mmol). The resulting mixture was heated to 70 C overnight and concentrated in vacuuo to give crude residue which was diluted with EtOAc and washed with 1 N NaOH followed by brine. The organic layer was separated, dried with anhydrous MgSO4, filtered and concentrated in vacuo to give desired 1-(3-bromo-5-fluorophenyl)-4-cyclopropylpiperazine in quantitative yield.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[F:17][C:18]([C:21]([OH:23])=[O:22])([F:20])[F:19].[NH:24](C(OC(C)(C)C)=O)[CH2:25][C:26]([NH:28][C@H:29]([C:37](ON1C(=O)CCC1=O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27].C(OCC)(=O)C>C([O-])(O)=O.[Na+].CC(C)=O>[NH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([NH:1][C@H:2]([C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27].[F:17][C:18]([C:21]([OH:23])=[O:22])([F:20])[F:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CCOC(=O)[C@@H](N)CCSC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
25 g of H-Met-OCH2CH2N(CH2CH3)2.TFA was dissolved in 300 ml of 5% NaHCO3. 22 g of Boc-Gly-Phe-OSu in 150 ml of acetone was added into the reaction mixture. The mixture was stirred for 5 h at RT. 500 ml of ethyl acetate was added into the mixture. The ethyl acetate solution was washed with water (3×100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 ml of dichloromethylene. 200 ml of trifluoroacetic acid was added into the mixture and the mixture was stirred for 30 min. The mixture was evaporated to dryness to yield 25 g of H-Gly-Phe-Met-OCH2CH2N(CH2CH3)2.TFA.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(-c2ccccc2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 184 mg (1.0 mmol) of 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) in 3 mL of dimethylformamide was treated with 55 mg of 60% sodium hydride (33 mg NaH, 1.4 mmol). The reaction mixture was stirred at room temperature for 30 minutes then treated with 169 mg (1.19 mmol) of 1-fluoro-4-nitrobenzene. The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled, poured into 50 mL of water and the resultant mixture was extracted with ethyl ether. The combined extracts were washed with water, dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed on silica, eluting with hexane/ethyl acetate (10:1) to give 271 mg (0.89 mmol, 88%) of the product. FAB-MS: calculated for C19H15NO2 305: found 306 (M+H). 1H NMR (200 MHz,CDCl3): 2.28 (s,3H), 6.82 (d,2H), 7.19 (d,3H), 7.2-7.5 (m,5H), 8.05 (d,2H).