Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH:13]3[CH2:19][CH2:18][C:17]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:14]3=[O:30])[CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:37][C:38]1[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.CCOC(C)=O.O>[F:24][C:20]1[C:17]2[CH2:18][CH2:19][CH:13]([N:11]3[CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:37][C:38]5[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=5)=[CH:3][CH:4]=4)[N:9]=[N:10]3)[C:14](=[O:30])[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:16]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1C(n2cc(-c3ccc(Br)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: Cc1ncccc1O
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ncccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1

Procedure:
3-[4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl]-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (150 mg, 0.310 mmol), cesium carbonate (202 mg, 0.621 mmol), 3-hydroxy-2-methylpyridine (67.7 mg, 0.621 mmol), cuprous chloride (915.36 mg, 0.155 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (14.30 mg, 0.078 mmol) in NMP (1.55 mL) in a sealed microwave vial was heated to 120° C. overnight in an oil bath. The reaction vessel was allowed to cool before water was added to dilute the mixture; EtOAc was then added to extract the product. The organic phase was separated and washed with water (2×) and brine (1×) before being dried with Na2SO4 and evaporated to afford an oil. This material was chromatographed on silica (0-80% EtOAc in hexanes to yield 68.4 mg as a solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>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(Cl)Cl.CN(C=O)C>[N+:16]([C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:22]=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 115 °C

Procedure:
To ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (10.0 g, 44.3 mmol), (3-nitrophenyl)boronic acid (11.8 g, 70.9 mmol), PdCl2(dppf)-CH2Cl2 (3.62 g, 4.43 mmol) and aqueous sodium carbonate (2 M solution, 55.4 mL, 111 mmol) in a flask was added DMF (148 mL). The mixture was degassed for 10 minutes then heated at 115° C. for 1.5 hours. The reaction was cooled to ambient temperature, then water was added and the mixture was extracted with DCM (×3) and EtOAc (×1). The combined organics were concentrated, diluted with EtOAc (300 mL) and washed with sorbitol/Na2CO3 solution to remove excess boronic acid. The aqueous layer was extracted with EtOAc (×4). The combined organics were concentrated after which EtOAc and hexanes were added with stirring. The resulting precipitate was filtered to give solid product that was further triturated with DCM and hexanes to give ethyl 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. The combined organic fractions were concentrated under reduced pressure to give a residue containing product and DMF. Addition of MeOH and water led to formation of a precipitate which was filtered to afford additional ethyl 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C15H13N4O4 [M+H]+: 313, found 313. 1H NMR (600 MHz, DMSO-D6) δ 13.17 (s, 1H), 8.99 (s, 1H), 8.43 (s, 1H), 8.39-8.36 (m, 2H), 8.12 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 3.93 (q, J=7.2 Hz, 2H), 0.95 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][C@@H:13]([OH:22])[C@@:12]2([OH:23])[C:11]2[C:24]([O:31][CH2:32][CH3:33])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[CH:27][C:10]=2[O:9]3)=[CH:4][CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:29]([O:28][C:26]1[CH:25]=[C:24]([O:31][CH2:32][CH3:33])[C:11]2[C@:12]3([OH:23])[C@H:13]([OH:22])[CH2:14][C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@:8]3([C:5]3[CH:4]=[CH:3][C:2]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:27]=1)[CH3:30]
Reactant: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(Br)cc3)[C@H](c3ccccc3)C[C@@H](O)[C@@]21O
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(N4CCCC4)cc3)[C@H](c3ccccc3)C[C@@H](O)[C@@]21O

Procedure:
51.1 mg (0.10 mmol) of (1R*,3S*,3aR*,8bS*)-3a-(4-bromophenyl)-6,8-diethoxy-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1,8b-(1H)-diol (Example 8A), 4.7 mg (0.07 mmol) of pyrrolidine, 7.1 mg (0.07 mmol) of sodium tert-butoxide, 1.2 mg (0.001 mmol) of tris(dibenzylideneacetone)dipalladium(0) and 1.7 mg (0.003 mmol) of rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl are heated in 0.6 ml of toluene at 80° C. under argon overnight. The mixture is then concentrated, taken up in DMSO and filtered, and the filtrate is purified by preparative HPLC. 14.5 mg (43% of theory) of the product are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)=[C:21]([CH3:28])[CH:20]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Cc1cc(Cl)ncc1B(O)O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 120 °C
Yield: 84.4 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (300 mg, 1.0 mmol), 6-chloro-4-methylpyridin-3-ylboronic acid (350 mg, 2.1 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (56 mg, 0.08 mmol), and saturated aqueous sodium carbonate (0.5 mL) in acetonitrile (5 mL) was heated under microwave irradiation (Biotage, 200 watts) at 120° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-75% ethyl acetate in heptane) to afford the title compound as an off-white solid (285 mg, 80%), which was used in the next step without further purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].CN([CH:15]=[N:16][C:17](=[O:19])[CH3:18])C>C1COCC1.CC(O)=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10]/[N:11]=[CH:15]/[NH:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)N=CN(C)C
Reactant: NNc1cc(F)ccc1Br
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)N/C=N/Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
Alternatively, to a mixture of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (5.9 g, 28.8 mmol) and N-((dimethylamino)methylene)acetamide (3.30 g, 28.8 mmol) in THF (30 mL) was added 5 drops of HOAc, and the mixture stirred at room temperature under nitrogen for 15 min. The mixture was concentrated in vacuo, and the residue suspended in a mixture of ether (50 mL) and hexanes (50 mL) and the resulting precipitate collected and air-dried to provide 5.7 g of the title compound as an off-white powder. A second crop gave an additional 0.3 g.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH:12]([Br:16])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[C:22]([CH3:25])([CH3:24])[CH3:23].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C1CCCCC1>[Br:16][CH:12]([CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17])[C:13]([O:15][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:14]
Reactant: O=C(CCC(Br)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)C(Br)CCC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
5-(Benzyloxy)-2-bromo-5-oxopentanoic acid, 10.0 g (0.033 mole), was dissolved in chloroform, 20 mL. To this was added a solution of t-butyl trichloroacetimidate, 15.9 g (0.073 mole), dissolved in cyclohexane, 50 mL, drop-wise over 30 minutes. The mixture was allowed to stir an additional 5 minutes and boron trifluoride etherate, 100 μL, was added. The reaction mixture was allowed to stir overnight. Sodium bicarbonate, 5 g, was added. After stirring 10 minutes, hexanes, 50 mL, was added and the mixture filtered to remove the solids present. The filtrate was evaporated and the residue purified by flash chromatography, ethyl acetate-hexanes, to give a clear-colorless oil. The yield was 8.2 g, 69% based on starting 5-(Benzyloxy)-2-bromo-5-oxopentanoic acid. NMR is consistent with structure.
Reaction SMILES: C[Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[N:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][C:19]3=[O:21])[CH2:14][C:13](=[O:22])[CH2:12]2)=[CH:7][CH:6]=1.[Cl-].[NH4+].[C:25](OCC)(=O)C>C1COCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:12][C@@:13]([OH:22])([CH3:25])[CH2:14][C@@H:15]3[N:20]2[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:9][CH:10]=1
Reactant: O=C1C[C@H]2CCCC(=O)N2[C@H](c2ccc(F)cc2)C1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@]1(O)C[C@H]2CCCC(=O)N2[C@H](c2ccc(F)cc2)C1
Reaction time: 0.83 h

Procedure:
Methylmagnesium bromide (0.96 M solution in THF, 5.98 mL) was added to a solution of (4S*,9aR*)-4-(4-fluorophenyl)hexahydroquinolizine-2,6-dione (1.0 g) in THF (15 mL) under ice-cooling, and the reaction solution was stirred for 50 minutes. Because the starting material did not disappear, methylmagnesium bromide (0.96 M solution in THF, 5.98 mL) was further added to the reaction solution, which was then stirred for 30 minutes. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain a mixture of the starting material with the title compound. Methylmagnesium bromide (0.96 M solution in THF, 5.98 mL) was added to a solution of the resulting mixture in THF (15 mL) again under ice-cooling, and the reaction solution was stirred for one hour. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain a mixture of the starting material with the title compound. Methylmagnesium bromide (0.96 M solution in THF, 5.98 mL) was added to a solution of the mixture obtained again in THF (15 mL) again under ice-cooling, and the reaction solution was stirred for 1.5 hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 760 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:17](I)[CH3:18]>C(O)C>[CH2:17]([S:15][C:9]1[N:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[C:12](=[O:13])[CH2:11][N:10]=1)[CH3:18]
Reactant: CCI
Reactant: Cc1ccc(F)cc1NC(=S)NCC(N)=O
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1cc(F)ccc1C
Yield: 66.9 %

Procedure:
A mixture of 2-[3-(5-fluoro-2-methylphenyl)-thioureido]-acetamide (6.0 g), ethyl iodide (15.6 g), and ethanol (120 mL) was heated at reflux for 4 hours. The solvent was evaporated. The residue was treated with ethyl acetate (400 mL) and filtered. The filtrate was washed with water (300 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol. The solution was saturated with hydrogen chloride. The solvent was evaporated and the residue was crystallized from ethyl acetate and dried under vacuum to give the mono-hydrochloride of the title compound as a white solid (4.2 g), m.p. 181°-183° C. Anal. Calcd. for. C12H13F N2O S . HCl: C, 49.91; H, 4.89; N, 9.70. Found: C, 49.83; H, 4.82; N, 9.71. Mass spectrum (+FAB,[M+H]+) m/z 253. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.50-8.45 (broad s, 2 H), 7.45 (m, 1 H), 7.27-7.34 (m, 2 H), 4.48 (q, 2 H), 3.21 (m, 2 H), 2.10 (s, 3 H), and 1.29 ppm (t, 3 H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cccc(Br)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Reaction time: 17 h
Yield: 60.2 %

Procedure:
A solution of (6-bromo-pyridin-2-yl)-methanol (3.37 g, 17.9 mmol) (H. Tsukube et al., J. Org. Chem., 1993, 58, 4389), triphenylphosphine (5.17 g, 19.7 mmol) and phtalimide (2.90 g, 19.7 mmol) in THF was cooled in an ice bath. A solution of diethylazodicarboxylate (3.43 g, 19.7 mmol) in THF (15 ml) was added slowly and the mixture was left to reach rt. Stirring was continued for 17 hr, then the solvent was distilled off and the residue chromatographed (SiO2 with hexane/AcOEt=4/1) to provide 3.42 g (66%) of the title compound as a colorless viscous oil. MS: m/e=316 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:14]([C:20]5[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1.Cl.Cl.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]2[N:46]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[NH:44][N:43]=2)[CH2:38][CH2:37]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:14]([C:20]5[CH:27]=[CH:26][C:23]([CH2:24][N:36]6[CH2:41][CH2:40][CH:39]([C:42]7[NH:46][C:45]([C:47]8[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=8)=[N:44][N:43]=7)[CH2:38][CH2:37]6)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C=O)cc5)nc4ccn23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(CN6CCC(c7nnc(-c8ccccn8)[nH]7)CC6)cc5)nc4ccn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 13-2 (0.5 g, 1.2 mMol) and 8-5 (0.34 g, 1.3 mMol) in NMP (10 mL) was added triethylamine (0.33 mL, 2.3 mMol) followed by acetic acid (0.13 mL, 2.3 mMol). After stirring overnight at room temperature, sodium triacetoxyborohydride (0.3 g, 1.3 mMol) was added in portions. After stirring for 6 hours, the solution was filtered through a syringe filter and purified on a C18 reverse phase HPLC to give 13-3 as a solid. Mass (M+1) calculated: 644.2993 observed: 644.2988
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=O)[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][CH:2]1[CH2:7][NH:6][CH:5]([CH2:8][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4][CH2:3]1
Reactant: CC1CCC(C(=O)N2CCCC2)NC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCC(CN2CCCC2)NC1

Procedure:
By reducing g 4.5 (0.023 moles) of 5-methyl-2-(pyrrolidin-1-yl)carbonyl piperidine with LiAlH4 in THF the corresponsing diamine was obtained. The diastereoisomeric composition was checked by GLC performed on a 10 m Ph-Me silicone 50% capillary column, from 80° to 180° (rate 5° /min). Diast. A Rt 8.86 (57.93%), Diast. B. Rt 9.11 (42.07%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]=[C:16]=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[CH3:19][O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23].O>O1CCCC1>[CH2:8]([NH:15][C:16](=[O:17])[NH:23][CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([O:20][CH3:19])=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)NC(=O)NCc1ccccc1
Reaction time: 12 h
Yield: 95 %

Procedure:
Triethylamine (1.86 mmol, 0.26 ml) and benzyl isocyanate (1.86 mmol, 0.23 mL) were added at 0° C. to a solution of phenylalanine methylester hydrochloride (0.93 mmol, 0.2 g) in tetrahydrofuran, and the mixture was stirred over a period of 12 h. The reaction was poured into water (30 mL) and extracted with ethyl acetate (5×30 mL). The organic layers were washed with saturated sodium chloride solution (3×30 mL), dried with anhydrous sodium sulfate and concentrated. The residue was purified by chromatographic column on silica gel eluting with ethyl acetate/n-hexane 1/2 to afford the pure compound as a colorless oil, 95% yield; 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 2.91-2.92 (dd, 1H, PhCHHCHCOO), 2.96-2.97 (dd, 1H, PhCHHCHCOO), 3.56 (s, 3H, COOCH3), 4.70-4.71 (m, 1H, PhCHHCHCOO), 4.17-4.19 (dd, 1H, PhCHHNHCONH), 4.22-4.24 (dd, 1H, PhCHHNHCONH), 5.46 (bs, 2H, NHCONH), 7.03-7.04 (2H, aromatic protons), 7.17-7.25 (m, 8H, aromatic protons); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 36.3, 44.4, 51.9, 57.3, 125.9, 126.7, 126.9 (2C), 127.7 (2C), 128.5 (2C), 128.6 (2C), 136.6, 137.9, 157.9, 171.5; MS (ESI) m/z: 312.14 [M]+.
Reaction SMILES: C(C(CCCC)C([O-])=O)C.[Na+].[CH2:12]([O:19][N:20]1[C@H:25]2[CH2:26][N:22]([C@H:23]([C:27]([O:29]CC=C)=[O:28])[CH2:24]2)[C:21]1=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)=O>O1CCCC1>[CH2:12]([O:19][N:20]1[C@H:25]2[CH2:26][N:22]([C@H:23]([C:27]([OH:29])=[O:28])[CH2:24]2)[C:21]1=[O:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CCOC(=O)[C@@H]1C[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium 2-ethylhexanoate (0.5 M in ethyl acetate, 2.5 mL, 1.25 mmol) was added to a solution of allyl (4R,6S)-3-(benzyloxy)-2-oxo-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate (459 mg, 1.52 mmol), 1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloride dichloromethane complex (116 mg, 0.14 mmol) in tetrahydrofuran (7.6 mL). The reaction mixture was stirred at room temperature for 2 hours (precipitate formed). Acetone (37 mL) was added. The resulting mixture was stirred at room temperature for 2 hours and the mixture was centrifuged. The solid was collected and washed with acetone and ether and dried under vacuum to afford the title compound as a tan solid. LC-MS (positive ionization) m/e 363 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[N+:24]([O-])=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[NH2:24])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a stirred suspension of the compound obtained in Step A (8.0 g) in ethanol (66 ml) and water (80 ml) at 60° C. was added sodium dithionite (11 g). The resulting mixture was stirred at 60° C. for 1 hour then ethanol was removed in vacuo. The suspension was extracted three times with ethyl acetate, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was filtered on silica gel (eluent ethyl acetate) to afford 1-[(E)-3-(4-chloro-phenyl)-allyl]-4-(5-fluoro-2-amino-phenyl)-piperazine (4.1 g). 1H NMR (400 MHz, CDCl3) 2.6 (m, 4H), 2.9 (m, 4H), 3.2 (d, J=9 Hz, 2H), 3.7 (m, 2H), 6.2 (dt, J=18, 9 Hz, 1H), 6.5 (d, J=18 Hz, 1H), 6.6 (m, 2H), 6.7 (d, J=10 Hz, 1H), 7.2-7.3 (m, 4H); MS (ES+) 151/153, 346/348 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[OH:17].[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:17][CH2:20][CH:19]=[CH2:18])[CH:4]=[CH:5][C:6]=1[C:9]([C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: Cn1nccc1C(=O)c1ccc(O)c(Cl)c1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)c2ccnn2C)c(Cl)c1Cl
Yield: 87.2 %

Procedure:
A suspension of 8.35 g of 2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenol, 5.59 g of allyl bromide and 10.64 g of potassium carbonate in acetone is refluxed for 3 hours. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. The residue is dissolved in toluene, and the solution is treated with activated charcoal and then evaporated to give 8.36 g of (2,3-dichloro-4-allyloxyphenyl)(1-methyl-5-pyrazolyl)methanone.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:7]=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=2)[CH3:5])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:5])[CH:7]=1
Reactant: CC(c1cccc(CO)c1)C1CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(c1cccc(CCl)c1)C1CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(1-cyclopropylethyl)phenyl]methanol (0.128 g, 0.73 mmol) in carbon tetrachloride (20 mL) was added polystyrene bound triphenyl phosphine (2.15 mmol/g, 0.68 g, 1.5 mmol). After stirring at 100° C. overnight the resin was filtered of and the solvent was removed under vacuum to afford the desired product.