Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CC[NH:6][CH2:7][C:8]([O-:10])=[O:9])(O)=O.[Na+].[Na+].[C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]([O-:22])=[O:21])([OH:15])=[O:14].[C:23](Cl)(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[OH-].[Na+].Cl>CC(C)=O>[NH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:13]([CH2:16][CH2:17][N:18]([C:23](=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:19][C:20]([OH:22])=[O:21])([OH:15])=[O:14]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C([O-])CNCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N(CCC(=O)O)CC(=O)O
Product: NCC(=O)O
Temperature: 17.5 °C

Procedure:
150 ml of acetone was added to the aqueous solution of disodium N-carboxyethylglycinate obtained in Example 7 while continuously stirring. Then, 228.29 g (1.0435 mol) of dodecanoyl chloride was dropwise added to this solution over a period of 1.5 hours while stirring. During this period, the reaction system was maintained at a pH of from 9 to 11 by dropwise adding a 40% aqueous solution of NaOH while the temperature was maintained at 10 to 25° C. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 2 hours. Thereafter, the pH of the reaction mixture was adjusted to 1.2 with concentrated hydrochloric acid. A formed white precipitate was separated by filtration, washed with water and dried to thereby give 324.71 g (yield from glycine: 92.5%) of a white powder of N-carboxyethyl-N-dodecanoylglycine. The infrared absorption spectrum, 1H-NMR spectrum, mass spectrum, and results of elemental analysis thereof were the same as those obtained in Example 6.
Reaction SMILES: C([O:5]O)(C)(C)C.[CH2:7]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][OH:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.C(CC(C)(C)C)(C)C>[CH2:7]([O:14][CH2:15][C@H:16]1[O:5][C@H:17]1[CH2:18][OH:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC/C=C\COCc1ccccc1
Reactant: CC(C)(C)OO
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: OC[C@@H]1O[C@@H]1COCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 5.0 g of powdered 4A molecular sieves in 400 ml of dry CH2Cl2 was added 2.09 g (8.42 mmole) of Ti(Oi-Pr)4 and 2.76 g (11.8 mmole) of L(+)diisopropyl tartrate at O'C under argon. The mixture was allowed to stir for 10 min, cooled to -20° C., and 22.5 ml of 3.8M tert-butyl hydroperoxide in isooctane is added slowly at -20° C. The catalyst was allowed to "age" for 30 min. A solution of 7.50 g (42.1 mmole) of Z-4-(benzyloxy)-2-buten-1-ol in 15 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min and then added to the mixture at -20° C. over 10 min. The mixture was allowed to stand in a refrigerator at 2° C. for 8 days. The reaction mixture was removed from the refrigerator and 40 ml of H2O was added with stirring. After stirring for 30 min, 15 ml of 30% NaOH in saturated brine was added and the mixture was allowed to stir 60 min longer. The organic layer was separated and the aqueous layer washed twice with 50 ml of CH2Cl2. The organic layers were combined, dried over MgSO4, filtered and evaporated to afford a milky, pale yellow oil. Distillation yielded 4.80 g of a clear viscous oil, bp 132°-5° C. (0.2 mm Hg). 1H NMR, δ7.4-7.2 (m, 5), 4.58 (dd, 2, J=12, 20 Hz), 3.7 (m, 4), 3.27 (ddd, 2, J=5, 10, 15 Hz), 1.98 (t, 1, J=6 Hz). Mass Spectra; EI; M+, Calc. 194.0942, Found 194.0929.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH3:20])=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=1>>[ClH:27].[CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH3:20])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([S:35]([NH2:38])(=[O:36])=[O:37])[CH:34]=4)[N:22]=3)=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Cl)n1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccccc3)n4C)n2)cc1S(N)(=O)=O
Product: Cl
Yield: 80.7 %

Procedure:
The title compound was prepared following the procedure of Example 1 with N2-benzyl-N5-(2-chloropyrimidin-4-yl)-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (95 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (47 mg, 0.25 mmol) to give the desired product as a pink solid (114 mg, 81%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.31 (br s, 2H), 9.61 (br s, 1H), 8.46 (s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.63 (m, 2H), 7.51 (d, J=7.5 Hz, 2H), 7.23-7.39 (m, 7H), 5.77 (d, J=6.3 Hz, 1H), 4.77 (d, H=6.0 Hz, 2H), 3.74 (s, 3H), 3.50 (s, 3H), 2.52 (s, 3H). MS (ESI) m/z=529 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH3:13]N(C)C=O.C(=O)(OC)OC.N1C2C(=CC=CC=2)C=C1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: CN(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: COC(=O)OC
Product: Cn1cc(CC#N)c2ccccc21
Temperature: 126 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A 1 L, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with indole-3-acetonitrile (58.0 g, 90% pure=0.334 mol), tetrabutylammonium bromide (11.6 g, 36 mmol), N,N-dimethylformamide (348 mL) and dimethyl carbonate (92.8 mL, 1.10 mol) and the resulting mixture was heated to 126±1° C. The progress of the reaction was monitored by HPLC and after 3 h at this temperature, the presence of remaining starting indole could not be detected. After the reaction mixture was then cooled to zero to −5° C., water (696 mL) was added which resulted in the formation of a precipitate. The mixture was stirred at −5° C. for 1 hour, then the solid was collected by filtration, washed with water (150 mL) and dried under high vacuum at 45° C. for 24 h to give 1-methylindole-3-acetonitrile (52.0 g, 91.5%) as a brown solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)C.C1(NC2C=CC=CC=2)CCCCC1>>[CH:14]1([N:7]([CH2:6][CH2:4][OH:3])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CN(c1ccccc1)C1CCCCC1
Agent: c1ccc(NC2CCCCC2)cc1
Product: OCCN(c1ccccc1)C1CCCCC1
Yield: 18.9 %

Procedure:
N-ethoxycarbonylmethyl-N-cyclohexyl aniline 1.89 g was obtained from N-cyclohexyl aniline 1.30 g in the same manner as in the above example. This product 860 mg was reduced to give the title compound (300 mg, 42%).
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.[C:22]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37]O)[CH2:32][CH2:31]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:22]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][O:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH2:32][CH2:31]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1ccccc1)N1CCC(CCO)CC1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)c3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of p-toluene sulfonic anhydride (6.0 g, 18 mmol) in dichloromethane (50 mL) was added dropwise over 1 hour to a room temperature solution of 1-benzoyl-4-hydroxyethylpiperidine (4.3 g, 18 mmol) and dry triethylamine (2.8 mL, 2 mmol) in dichloromethane. After 2 hours, the mixture was diluted with ethyl acetate (500 mL) and extracted successively with H2O (2×100 mL), cold 0.1 M aqueous HCl (100 mL), saturated aqueous NaHCO3 (100 mL), and brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate, and concentrated to yield a crystalline solid (6.2 g, 89%) which melted at 81°-83° C. Analysis: Calculated for C21H25NO4S: C,65.09; H,6.50; N,3.61; S,8.27; found: C,65.31; H,6.74; N,3.41; S,8.30.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17])(=O)=O)=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C@@H:27]([CH2:34][OH:35])[O:26]2)=[CH:21][C:20]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C@@H:27]([CH2:34][OH:35])[O:26]2)=[CH:21][C:20]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17])=[CH:41][CH:42]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCCF)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.4 %

Procedure:
2-(2-fluoroethoxy)ethyl 4-methylbenzenesulfonate (52 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (0.12 g, 0.36 mmol) was added to the flask, and the resulting mixture was stirred at room temperature for 48 hr. The reaction mixture was diluted with diethyl ether (50 mL) and the organic layer was washed with aqueous solutions of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 mL), followed by drying over sodium sulfate. The organic layer was concentrated in vacuo, followed by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.5 mg, 5.0%). 1H NMR (CDCl3, 300 MHz): δ 7.30 (d, 1H, J=11.6 Hz), 7.17-7.12 (br m, 2H), 7.04 (d, 2H, J=11.6 Hz), 6.78 (d, 2H, J=11.6 Hz), 4.52 (dt, 2H, J1=5.6 Hz, J2=63.6 Hz), 4.33 (br s, 1H), 4.13 (br s, 1H), 4.04-3.96 (m, 4H), 3.81-3.67 (m, 5H), 3.63-3.49 (m, 2H), 3.38-3.21 (m, 3H), 2.78 (br s, 1H), 1.77 (br s, 2H); LC/MS: theoretical mass=470.15; observed M+1=471.6, M+Na=493.4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C>[C:12]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccccc2)c1

Procedure:
1.00 g (4.65 mmol) of methyl 3-bromobenzoate, 0.60 g (4.88 mmol) of phenylboronic acid, 161 mg (3 molar %) of tetrakistriphenylphosphine palladium and 2.0 g (18.6 mmol) of sodium carbonate were heated under reflux in 24 ml of a solvent mixture of toluene, ethanol and water (2/1/1) for 2 hours. The mixture was filtered through Celite, then after-treated by an ordinary method and purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: ClC1C(C)=C(S(Cl)(=O)=O)C=CC=1.N1C=CC=C[CH:14]=1.COC([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2)=O.[C:33]([O-:36])(O)=[O:34].[Na+]>ClCCl>[CH3:14][O:36][C:33]([C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH2:32])[CH:29]=2)[NH:24][CH:23]=1)=[O:34]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: c1ccncc1
Agent: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c[nH]c2ccc(N)cc12
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (124 mg, 0.552 mmol) in dichloromethane (4 mL) was added pyridine (100 μL, 1.3 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-1H-indole-carboxylic acid methyl ester (100 mg, 0.526 mmol) was added. The resulting mixture was stirred for 1.5 h at room temperature, then saturated NaHCO3 solution (15 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (129 mg, 65%), single spot at Rf 0.84 (ethyl acetate). mp 216.8-219.3° C., [22], HPLC purity 99+% (tR 2.07 min in 10% water-acetonitrile). 1H NMR (d6-DMSO): δ 11.91 (1H, s), 10.32 (1H, s), 8.03 (1H, d, J=3.0 Hz), 7.82 (1H, d, J=7.9 Hz), 7.70-7.67 (2H, m), 7.37-7.31 (2H, m), 6.95 (1H, dd, J=8.6, 2.0 Hz), 3.77 (3H, s), 2.65 (3H, s). LCMS: 377.09. FAB-MS (MH+, C17H15ClN2O4S): calcd 378.0441, found 378.0439.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28](Cl)[C:29](OCC)=[O:30])=[CH:23][CH:22]=1)([CH2:17][CH3:18])[CH2:9][CH2:8]2)(=O)C.[NH2:36][C:37](N)=[S:38].S1(CCCC1)(=O)=[O:41].Cl>O.COCCO>[CH2:17]([C:10]1([CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH:28]3[S:38][C:37](=[O:41])[NH:36][C:29]3=[O:30])=[CH:25][CH:26]=2)[CH2:9][CH2:8][C:7]2[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=2[CH3:35])[O:11]1)[CH3:18]
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(CC)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: Cl
Solvent: COCCO
Solvent: O
Product: CCC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
2.4 g of ethyl 3-[4-(6-acetoxy-2-ethyl-5,7,8-trimethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate, 494 mg of thiourea and 3 ml of sulfolane were heated under a nitrogen stream for 4.5 hours at 100°-110° C. At the end of this time, 3 ml of ethylene glycol monomethyl ether, 3 ml of water and 1 ml of concentrated hydrochloric acid were added and the resulting mixture was heated for a further 3.5 hours at 96°-98° C. The reaction mixture was then processed as described in Example 1(a) and the resulting crude product, in the form of an oil, was purified by column chromatography, eluted with a 10:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[F:12].CCN(C(C)C)C(C)C.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:5]3[CH:4]=[C:3]([F:12])[C:2]([F:1])=[CH:7][C:6]=3[N+:8]([O-:10])=[O:9])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(F)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 17.8 %

Procedure:
To a solution of 1,2,4-trifluoro-5-nitrobenzene (3.0 g, 18 mmol) and DIEA (4.2 ml, 24 mmol) in dry THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16 mmol) in THF (5 ml) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 20 hrs. It was then heated to 40° C. for 40 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=5:2). Recrystallization from EtOAc (10 ml) and hexanes (˜100 ml) gave the title compound as red crystals (0.8 g, 18%). NMR (400 MHz) 12.36 (s, 1H), 9.79 (s, 1H), 8.27 (m, 2H), 5.93 (s, 1H), 1.90 (m, 1H), 0.93 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 280; Found: [M+H]+ 281.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:13]1[CH:14]=[C:15]([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[CH3:25])[N:16]=[N:17][CH:18]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[N:16]=[N:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc(Cl)c(Cl)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=319.2 (M+), was prepared from 3,4-dichlorophenylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].C(O)CC#C.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[CH2:17]([N:16]([C@H:27]1[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1)[CH2:18][C:19]#[CH:20]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: C#CCCO
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Product: C#CCCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-butyn-1-ol and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([C:23](O)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([N:14]1[CH2:13][CH2:12][C@H:11]2[C@H:16]([N:9]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=3)[CH2:10]2)[CH2:15]1)=[O:24]
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(C)nc(N2C[C@H]3CCN(C(=O)c4ccccc4-c4ccccc4)C[C@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1S,6R)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and biphenyl-2-carboxylic acid for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C25H26N4O, 398.5; m/z found 399.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.56-7.25 (m, 7H), 7.24-6.72 (m, 2H), 6.44-6.17 (m, 1H), 4.57-3.20 (m, 6H), 3.01-2.40 (m, 2.5H), 2.37-2.00 (m, 6H), 1.38-1.31 (m, 1.5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.[OH-].[Na+]>CO.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:19]\[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (0.1 g, 0.404 mmol) in MeOH/H2O (1:1) was added nicotinaldehyde 241 (0.052 g, 0.484 mmol) and NaOH (0.032 g, 0.808 mmol). The reaction was stirred at RT for 6 h, diluted with chloroform and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound 242 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid (E)-6-methoxy-5-morpholino-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-inden-1-one 242.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([S:14][C:15]1[S:16][C@@H:17]2[C@H:34]([C:35]([OH:38])([CH3:37])[CH3:36])[C:33](=[O:39])[N:18]2[C:19]=1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])[CH3:13]>C(Cl)Cl>[CH2:12]([S:14]([C:15]1[S:16][C@@H:17]2[C@H:34]([C:35]([OH:38])([CH3:36])[CH3:37])[C:33](=[O:39])[N:18]2[C:19]=1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)=[O:21])=[O:6])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Solvent: ClCCl
Product: CCS(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 85% m-chloroperoxybenzoic acid (112 mg, 0.55 mmol) in CH2Cl2 (2.5 ml) is added dropwise over 5 mins. to an ice-cold, stirring solution of p-nitrobenzyl (5R,6R)-2-ethylthio-6-(2-hydroxy-2-propyl)-pen-2-em-3-carboxylate (212 mg, 0.5 mmol) in CH2Cl2 (5 ml). The mixture is stirred for 1 hour at 0°, then treated with excess Amberlyst-21 resin and stirred 5 minutes longer. The mixture is filtered and the filtrate is evaporated under vacuum to provide the crude product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
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: C1COCCO1
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCNC5=O)n[nH]c3n2)c1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (18.0 mg, 0.0400 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (16.4 mg, 0.0600 mmol), tetrakis(triphenylphosphine)palladium(0) (2.77 mg, 0.00240 mmol), and sodium carbonate (12.7 mg, 0.120 mmol) in 1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 120° C. for 3 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=470.0/471.9. 1H NMR (300 MHz, DMSO-d6) δ: 9.90 (s, 1H), 8.16-7.97 (m, 3H), 7.07 (s, 1H), 4.00 (s, 6H), 3.49-3.40 (m, 2H), 3.07 (t, J=6.5 Hz, 3H).