Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2(O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:25])=[CH:11][C:10]=1[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C:9]1[C:10]([CH3:27])=[CH:11][C:12]([CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=3)[C:17]2=[O:25])=[CH:13][C:14]=1[CH3:15])([CH3:5])([CH3:7])[CH3:6]
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(N2C(=O)C(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)c3ccccc32)c1
Yield: 50.7 %

Procedure:
Combine 3-[4-(tert-Butyl-dimethylsilanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (15.34 g, 40 mmol), 3-methoxyphenylboronic acid (12.16 g, 80 mmol), copper (II) acetate (7.27 g, 40 mmol), triethyl amine (11.2 ml, 80 mmol) and 4A sieves (100 g) in dichloromethane (1 L) and heat at 32° C. for 1 day stirring mechanically. Add more 3-methoxyphenylboronic acid (6.0 g, 39 mmol), copper (II) acetate (7.27 g, 40 mmol), triethyl amine (5.6 ml, 40 mmol) and 4A sieves (50 g) and continue heating for 3 days. Filter the reaction through Celite washing liberally with dichloromethane. Add ethyl acetate to get more precipitate and refilter through Celite. Evaporate in vacuo to obtain an oil of about 30 g. Purify by preparative HPLC (gradient of 15% ethyl acetate/dichloromethane to 50% ethyl acetate/dichloromethane) to obtain 9.60 g of an orange foam. MS (ES): m/z=490 (M+1); 1H NMR (DMSO-d6); δ7.50 (t, 1H), 7.28-7.23 (m, 2H), 7.12-6.98 (m, 6H), 6.82 (d, 1H), 6.72 (s, 1H), 3.81 (s, 3H), 2.14 (s, 6H), 0.99 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[H-].[Na+].[CH3:17]I.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([N:7]([CH:8]1[CH2:9][CH2:10]1)[CH3:17])=[O:6]
Reactant: CI
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(C)C2CC2)cc1Br
Temperature: 25 °C

Procedure:
A stirred, cooled (ice bath) solution of 3-bromo-N-cyclopropyl-4-methyl-benzamide (Intermediate 95, 6 g, 23.25 mmol) in anhydrous tetrahydrofuran (100 mL) under argon was treated with small portions of sodium hydride (1.6 g, 40 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to warm to ambient temperature and after 1 h, methyl iodide (3.11 mL, 50 mmol) was added and the reaction mixture was refluxed for 5 h. It was cooled to ambient temperature, poured into cold water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a dirty brown solid that was used as such for the next step (6.3 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10](=S(C)(C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[ClH:21]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH:10]([Cl:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Cl
Reactant: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)=S(C)(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.5 grams (0.05 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-(dimethyloxosulfuranylidene)-3-oxopropanoate prepared in Example XLXII (Compound 205) in 25 milliliters of chloroform was stirred at room temperature for two hours while passing in a flow of anhydrous hydrogen chloride. After ceasing the gas feed the solution was stirred at ambient temperature for about 64 hours after which the solvent was removed under reduced pressure. Flash chromatography of the residue eluting with hexane-ethyl acetate (7:3), gave a white solid which was recrystallized from ethyl acetate-hexane to give 0.20 gram (0.001 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-chloro-3-oxopropanoate having a melting point of 104° C.-105° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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:20][C:15]1[CH:14]=[C:13]([C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[N:27])[CH:3]=3)[N:9]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(C#N)c2)n1
Temperature: 200 °C

Procedure:
100 mg (0.236 mmol) of the compound of Example 51A are provided in 1 ml of 1-methyl-2-pyrrolidone, 55.4 mg (0.472 mmol) of zinc cyanide and 27.3 mg (0.024 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is heated in a closed glass vessel at 200° C. under microwave irradiation for 30 min. The reaction mixture is subsequently filtered through kieselguhr and eluted with methanol, the filtrate is rendered weakly acidic with a 1N aqueous hydrogen chloride solution and concentrated, and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 33 mg (34% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.[N-:17]=[N+:18]=[N-:19]>C1COCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([N:17]=[N+:18]=[N-:19])=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(=O)c1cnccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of Pyrazine-2-carboxylic acid (295 mg, 2.1 mmol, 1 eq) and triethylamine (765 ul, 5.4 mmol, 2.6 eq) in THF (6 ml) at 0° C. was added dropwise diphenylphophoryl azide (1.4 ml, 2.8 mmol, 1.3 eq). The mixture was stirred under nitrogen at 0° C. for 30 minutes, then warmed to RT and stirring continued for a further 2 hours. The reaction mixture was concentrated under vacuum and purified by flash chromatography (90/10-60/40 Iso-hexane/EtOAc) to afford the title compound as white solid (265 mg, yield=78%). 1H NMR (400 MHz, CDCl3) δ 9.14 (d, 1H, J=1.2); 8.50 (dt, 1H, J=1.2, 0.4), 2.62 (s, 3H, broad).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:21][O:22]CC3C=CC=CC=3)=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(COCc3ccccc3)nc2n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(CO)nc2n(C)c1=O
Yield: 88.7 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-benzoxymethyl-3-methylxanthine (4.0 g, 9.33 mmol) in acetic acid (40 ml) was added 10% palladium on carbon (0.52 g). The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. After removing catalyst by filtration, evaporation of the solvent under reduced pressure provided (R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (2.8 g, 88% yield) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])(C(C)(C)C)(C)C.O>C(O)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(CCCCO[Si](C)(C)C(C)(C)C)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCOP(=O)(CCCCO)OCC
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
Diethyl 4-(tert-butyldimethylsilyloxy)butylphosphonate (1.7 g, 5.25 mmol) was dissolved in 80% acetic acid (5 ml) and the resulting solution was stirred at 70° C. for 20 min. The reaction mixture was then allowed to cool and water (2 ml) was added. The resulting mixture was washed with hexane (3×5 ml) and chloroform (5×5 ml). The combined chloroform phase was washed with sat. aq. NaHCO3 (2×10 ml), water (1×10 ml) and the solvents were evaporated under vacuum. The residue was chromatographed on silica gel (eluted with chloroform: ethanol 96:4) to give the title compound as a colorless oil (1 g, 91%). 1H NMR:δH ((CD3)2SO), 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.47 (4H, br.s, CH2CH2), 1.68 (2H, m, CH2P), 3.38 (2H, br.s, HOCH 2), 3.96 (4H, m, (OCH2CH3)2), 4.43 (1H, br.s, HOCH2, D2O exchangeable).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][NH:15][CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:3].C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:3][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:1]
Reactant: CC(C)C1C(=O)NCCN1C[C@H]1CNCCN1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3-(1-methylethyl)-4-((2R)-2-piperazinylmethyl)-2-piperazinone (0.161 g, 0.670 mmol, Example 184) and triethylamine (0.290 mL, 2.083 mmol) in dichloromethane (5.82 mL) was added a solution of 2-thiophenesulfonyl chloride (0.138 g, 0.756 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (1 mL) drop-wise at room temperature. The solution was stirred for 30 min and then the mixture was concentrated. The residue was re-dissolved in CH2Cl2 and washed with water followed by brine. The organic layer was dried (Na2SO4), filtered, and concentrated to give 3-(1-methylethyl)-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-2-piperazinone (242 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22](=O)[CH2:21][C:20]3([CH3:29])[CH3:28])[N:8]=2)[CH2:3][CH2:2]1.C(OCC)(=O)C.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Pt]>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:8]=[C:9]([N:19]3[C:20]([CH3:29])([CH3:28])[CH2:21][CH:22]([NH:40][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:23][C:24]3([CH3:26])[CH3:25])[N:10]=2)[CH2:18][CH2:17]1
Reactant: CCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCNC1CC(C)(C)N(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)C(C)(C)C1

Procedure:
12 g of 2,4-bis-morpholino-6-(4-oxo-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 21) are hydrogenated in 120 ml of methanol and 60 ml of ethyl acetate at 40° and a pressure of 80 bar with 5% platinum on charcoal as the catalyst in the presence of 6 g of butylamine and 0.25 g of p-toluenesulfonic acid until the reaction has ended. The reaction mixture is filtered and evaporated. After dissolving the residue in methylene chloride and washing with water, the organic phase is dried over Na2SO4 and evaporated. The residue is dissolved in toluene/acetone and purified chromatographically on an SiO2 column. The oily product crystallizes after a few days and melts at 82°-87°.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1.[Li]CCCC>>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:10]([OH:11])[C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)c1nc2ccccc2s1

Procedure:
31 (1.0 g, 5.02 mmol), benzothiazole (0.6 ml, 5.52 mmol), n-BuLi (1.6M) (3.45 ml 5.52 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:23])[CH3:22]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:22][C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[OH:14])=[O:23])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: CC(=O)c1ccccc1O
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1O

Procedure:
The procedure described in Example 8 was repeated using 1.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.74 g of 2'-hydroxyacetophenone. Yield 0.2 g (12%), m.p. 231°-234° C.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20](N(OC)C)=[O:21])=[N:12]1>C1COCC1>[C:20]([C:13]1[C:14](=[O:19])[C:15]([O:17][CH3:18])=[CH:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[F:4])[N:12]=1)(=[O:21])[CH3:1]
Reactant: COc1cn(-c2ccccc2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccccc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 85.1 %

Procedure:
MeMgBr (1 M solution in THF, 30 mL, 30 mmol) was added dropwise at −78° C. to a solution of 1-(2-fluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (3.20 g, 10.4 mmol) in THF (30 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution, saturated with NaCl, and extracted with AcOEt rive times. The combined extracts were dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (2.32 g, 85% yield) as pale yellow crystals: mp 154-156° C.; NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.91 (3H, s), 7.27-7.38 (2H, m), 7.45-7.53 (1H, m), 7.65 (1H, dt, J=1.5, 7.9 Hz), 7.77 (1H, d, J=2.3 Hz). Anal. Calcd for C13H11FN2O3: C, 59.54; H, 4.23; N, 10.68. Found: C, 59.62; H, 4.22; N, 10.79.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=2[N:9]([CH3:19])[C:8](=[O:20])[CH2:7]1)[CH3:2].[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([NH:18][C:30]([NH:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[CH:16]=[CH:17][C:10]=2[N:9]([CH3:19])[C:8](=[O:20])[CH2:7]1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)CN1CC(=O)N(C)c2ccc(N)cc2C1=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CC(=O)N(C)c2ccc(NC(=O)NCc3ccccc3)cc2C1=O
Yield: 98.2 %

Procedure:
To a solution of (7-amino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (0.65 g, 2.23 mmol) in DMF (5 ml) was added benzylisocyanate (0.5 g, 3.75 mmol) and DMAP (5 mg). After 2 h at 60° C. the reaction mixture was poured into AcOEt (70 ml), washed with aqueous KHSO4 (0.1 N) and water. After drying over Na2SO4 and evaporation of the solvents the residue was purified by chromatography (dichloromethane/MeOH 19:1) to give [7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid ethyl ester (930 mg, 2.19 mmol): mp. 151° C.; MS (EI): 424 (M)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])[CH:36]=[CH:35][N:34]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccnc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a off-white foam (10%).
Reaction SMILES: [NH2:1][C@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11](OCC)=[O:12])[C:6]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:5]=2[S:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH3:27]>CO>[NH2:1][C@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:27])=[O:12])[C:6]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:5]=2[S:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CN1C(=O)[C@H](N)[C@H](c2ccccc2)Sc2cc(Cl)ccc21
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)[C@H](N)[C@H](c2ccccc2)Sc2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
In 220 ml of methanol is dissolved 6.9 g of ethyl cis-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, into which ammonia gas is blown to the level of saturation under ice-cooling. The reaction temperature is slowly elevated to room temperature, and the mixture is allowed to stand still overnight. Then, the reaction mixture is concentrated under reduced pressure. The separated crystals are collected by filtration to give 6.2 g of cis-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:34])[C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH3:34])[C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CN(C(=O)CCc1ccccc1)c1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: CN(C(=O)CCc1ccccc1)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 56 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3dione in acetic acid was added N-[4(hydrazinocarbonyl)phenyl]-N-methyl-3-phenylpropanamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH and water and drying under vacuo at 60° C. overnight gave the title compound (226 mg, 56%) as an orange solid in 96.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[C:20]([F:25])[CH:19]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Compound 83 (250 mg, 1.08 mmol), 4-amino-2-fluoro-phenol (276 mg, 2.17 mmol), and cesium carbonate (1.41 g, 4.34 mmol) were suspended in DMF (5 mL), and stirred for 30 minutes at 120° C. in microwave. The reaction mixture was diluted with H2O. The resulting precipitate was filtered. The precipitate was tritturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 182 (312 mg, 90% yield) as a solid. LC-MS (M+H=322, obsd.=322).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:9]2[C:10](=[O:19])[C:11]2[N:12]([C:14]([CH:17]=O)=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:9]2[C:10](=[O:19])[C:11]2[N:12]([C:14]([CH2:17][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:15][CH:16]=2)[CH2:13]3)=[CH:6][CH:7]=1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(C=O)n3CC12c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(CN4CCOCC4)n3CC12c1ccc(Cl)cc1
Yield: 89 %

Procedure:
10a-(4-chlorophenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-8-carbaldehyde (25 mg, 0.059 mmol) and morpholine (10.2 μL) were combined and stirred at room temperature in 1,2-dichloroethane for 10 min. To the mixture was added sodium triacetoxyborohydride (24.7 mg). After 18 h at room temperature the reaction was quenched by the addition of a saturated aqueous solution of NaHCO3 (1 mL) and CH2Cl2 (5 mL). The organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give a yellow solid. The solid was purified by flash column chromatography (Biotage SP4, 4 g cartridge, 0-5% MeOH gradient in CH2Cl2) to give 10a-(4-chlorophenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-8-(morpholin-4-ylmethyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (25) as a white solid (26 mg, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.I[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: OCc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=c1ccc(Cl)cn1-c1ccc(CO)cc1

Procedure:
5-Chloro-2-pyridinol (0.61 g, 4.7 mmol), 4-iodobenzyl-alcohol (1.00 g, 4.27 mmol), Copper (0.27 g, 4.27 mmol) and K2CO3 (0.65 g, 4.70 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc as eluent) to afford the title compound as a white solid.