Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.OO.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>O1CCCC1>[NH2:9][C:4]1[N:3]([O:15][C:12](=[O:14])[CH3:13])[C:2](=[NH:1])[N:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: C1CCOC1
Product: CC(=O)On1c(N)cc(Cl)nc1=N
Temperature: 40 °C
Yield: 11 %

Procedure:
5 g (0.035 mole) of 2,6-diamino-4-chloropyrimidine are dissolved in 50 ml of anhydrous tetrahydrofuran. 7 ml of a 70% aqueous hydrogen peroxide solution and 16 ml of acetic anhydride are added dropwise while stirring at a temperature of 40° C. in half an hour. The mixture is stirred at 60° C. for further two hours. After evaporating the tetrahydrofuran 50 ml of water are added to the residue, then it is kept in a refrigerator for a night. Thus 4.00 g (57%) of the aimed compound separate. Further 0.77 g (11%) of this compound is obtained by filtering the product achieved by the second separation.
Reaction SMILES: C(OC([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([C:38](=C=O)[O:39]OCC)[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=O)C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[CH2:13]([O:28][C:29]([O:39][CH2:38][C@H:36]1[O:37][C@@H:29]([O:28][C:13]2[C:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=3)=[C:15]([CH3:16])[NH:11][N:12]=2)[C@H:30]([OH:31])[C@@H:32]([OH:33])[C@@H:34]1[OH:35])=[O:37])[CH3:14]
Reactant: CCOOC(=C=O)[C@H]1O[C@@H](Oc2nn(C(=O)OCc3ccccc3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 150 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(6-O-ethoxy-carbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)-methyl]-5-methylpyrazole (0.17 g) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder, and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The resulting insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.10 g).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3cccnc3)ccc2O)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cc(-c3cccnc3)ccc2O)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A trifluoroacetic acid (4.0 mL) solution of the obtained tert-butyl 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and toluene was added to the residue. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration. Dioxane (2.0 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.49 mL) were added to the obtained solid substance, followed by stirring at room temperature for 45 minutes. A 10% aqueous solution of citric acid was added to the reaction mixture, and the solid substance was collected by filtration. Ethanol and water were added to the obtained solid substance, and the solid substance was collected by filtration to obtain 0.053 g of 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Br)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:36]2[CH:35]=[CH:34][C:33]([F:32])=[C:38]([F:39])[CH:37]=2)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)N1CCn2c(Cc3ccccc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
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: CCO
Solvent: Cc1ccccc1
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccc(F)c(F)c3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 90 °C
Yield: 99.8 %

Procedure:
9-Benzyloxy-6-[(2-bromophenyl)methyl]-2-isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione (169) (150 mg, 0.311 mmol) and 3,4-difluorphenylboronic acid (56.5 mg, 0.358 mmol) were suspended in a mixture of toluene/ethanol (10 ml/1 ml), treated at room temperature under argon with tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 12.4 μmol) and 2M sodium carbonate solution (342 μl, 684 μmol) and the reaction mixture was then heated at 90° C. for 7 h. The reaction was quenched with water and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 25 g silica gel with methanol/dichloromethane (gradient: 0 to 10% methanol). All fractions containing product were combined and concentrated to afford 9-benzyloxy-6-[[2-(3,4-difluorophenyl)phenyl]methyl]-2-isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione (160 mg) as a white solid.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.O.[CH:14](=[C:21]1[C:37](=[O:38])[C:36]2([CH3:39])[CH:23]([CH:24]3[CH:33]([CH2:34][CH2:35]2)[C:32]2[CH:31]=[CH:30][C:29]([OH:40])=[CH:28][C:27]=2[CH2:26][CH2:25]3)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C.CC(N(C)C)=O>[CH:14](=[C:21]1[C:37](=[O:38])[C:36]2([CH3:39])[CH:23]([CH:24]3[CH:33]([CH2:34][CH2:35]2)[C:32]2[CH:31]=[CH:30][C:29]([O:40][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:28][C:27]=2[CH2:26][CH2:25]3)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccc1)C2=O
Reactant: NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC12CCC3c4ccc(OS(N)(=O)=O)cc4CCC3C1CC(=Cc1ccccc1)C2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 ml of a 0.7 M sulphamoyl chloride solution in toluene (3.5 mmol) were concentrated under reduced pressure (30° C. water bath temperature). The residue was cooled to 0° C. (ice bath) and DMA (10 ml) and 16-Benzylidene-3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-one (717 mg, 2.0 mmol, CAB01122) were added. The resulting clear solution was stirred for 1 h at 0° C., then allowed to warm up to room temperature and stirred overnight. Ethyl acetate (50 ml) was added and the solution was washed with water (2×30 ml) and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The resulting off-white solid was dissolved in a small amount of ethyl acetate and precipitated by addition of hexane. Yield: 683 mg (78%) off-white solid. 1H-NMR (CDCl3, 400 MHz), δ: 0.96 (s, 3H), 1.20-2.60 (m, 11H), 2.80-3.02 (m, 3H), 5.38 (s, 2H, —NH2), 7.06 (d, J=2.3 Hz, 1H), 7.11 (dd, J=8.0, 2.3 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.34-7.47 (m, 2H), 7.52-7.65 (m, 2H). LRMS (FAB+): 438.2 (100, [M]+).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[H-].[Na+].[O:9]([C:16]1[CH:35]=[CH:34][C:19]([O:20][CH2:21][CH2:22]C2C=C(S([O-])(=O)=O)C=CC=2C)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[O:9]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][O:1][N:2]2[CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:34][CH:35]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CCOc1ccc(Oc2ccccc2)cc1
Reactant: On1cccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(OCCOn3cccn3)cc2)cc1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
While cooling and at 0° C., a solution of 1.0 g of N-hydroxypyrazole in 10 ml of dimethylformamide is dripped into a suspension of 0.3 g of sodium hydride in 10 ml of dimethylformamide. The mixture is stirred for a further hour, after which a solution of 4.7 g of 2-(4-phenoxyphenoxy)-ethyl-p-toluenesulfonate in 50 liters of dimethylformamide is added. The reaction batch is stirred for 12 hours at room temperature and then poured into 250 ml of ice water. The mixture is extracted three times with methyl tert-butyl ether, and the combined extracts are washed with 1N sodium hydroxide solution and then with water. The organic phase is dried with sodium sulfate, the solvent is stripped off under reduced pressure and the residue is chromatographed over silica gel using toluene as developer; there is obtained 2.7 g of N-[2-(4-phenoxyphenoxy)-ethoxy]-pyrazole of melting point 83°-85° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH:19]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[O:20]C(=O)C(F)(F)F.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH:19]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[OH:20]
Reactant: COc1cccc(CC(OC(=O)C(F)(F)F)C2CCNCC2)c1OC
Agent: NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cccc(CC(O)C2CCNCC2)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[2-(2,3-dimethoxyphenyl)-1-(trifluoro acetyloxy)ethyl]piperidine trifluoroacetamide compound (2.3 g, 6.0 mmol), K2CO3 (powdered, 1.0 g 6.6 mmol) and anhydrous methanol (15 ml) was stirred at ambient temperature for 3 h. The reaction was filtered and the filtrate concentrated to 2.3 g of a thick, yellow oil. The oil was triturated with Et2O (a white solid resulted). The solid was filtered, and the filtrate concentrated to afford a thick yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:33])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[NH:39][C:40](N1C=CN=C1)=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C>[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[NH:39][C:40]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:33])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12]1)=[O:41]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCN(C(=O)Nc2ncc[nH]2)CC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
The amine from above (131 mg, 0.28 mmol), and imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (168 mg, 0.56 mmol) were combined in DMF (4.0 mL) and treated with DIPEA (0.29 mL, 1.7 mmol). The solution was stirred at 75° C. for 2 hours and then concentrated under reduced pressure. This afforded, after column chromatography with silica gel (25:1:0.1 CH2Cl2:MeOH:NH4OH), COMPOUND 307 (72 mg, 45%). 1H NMR (CDCl3): δ 1.30 (q, 2H, J=11.1 Hz), 1.59 (s, 6H), 1.66 (d, 2H, J=12.3 Hz), 2.26 (s, 3H), 2.61 (br t, 3H, J=11.7 Hz), 3.35 (s, 2H), 3.65 (s, 2H), 4.14 (d, 2H, J=13.2 Hz), 6.68 (s, 2H), 6.86 (m, 4H), 7.19 (br, 2H), 7.37 (s, 1H), 7.82 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 8.48 (br d, 1H). 13C NMR (CDCl3) δ 18.40, 18.81, 28.08 (2C), 31.12 (2C), 42.14, 44.20 (2C), 54.06, 54.67, 58.01, 115.13 (d, 2C, J=84 Hz), 121.44, 127.07 (d, 2C, J=30 Hz), 130.07, 133.81, 134.84, 137.31, 142.96, 144.59 (2C), 145.07, 145.36, 146.61 (2C), 155.31, 155.96, 157.96, 161.91 (d, 1C, 975 Hz). ES-MS m/z 577 (M+H). Anal. Calcd. for C31H35N7OClF.0.2CH2Cl2O.0.2H2O: C, 62.46; H, 6.02; N, 16.32; Cl, 8.85; F, 3.16. Found: C, 62.60; H, 6.02; N, 16.09; Cl, 8.79; F, 2.94.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:11]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([NH:30]C(=O)OC(C)(C)C)=[CH:26][CH:25]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[N:11]=[C:10]([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Tert-butyl (4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[(phenylsulfonyl)methyl]pyrimidin-2-yl}phenyl)carbamate (3.1 g, 5.91 mmol) was dissolved in DCM (20 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). Organic phase collected, dried over magnesium sulphate, filtered and concentrated in vacuo to give the desired material as a beige solid (2.5 g).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].C(O)C.Br[CH2:22][C:23]1[C:36]2[C:37]3=[C:38]4[C:33](=[CH:34][CH:35]=2)[CH:32]=[CH:31][CH:30]=[C:29]4[CH:28]=[CH:27][C:26]3=[CH:25][CH:24]=1>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:22][C:23]1[C:36]2[C:37]3=[C:38]4[C:33](=[CH:34][CH:35]=2)[CH:32]=[CH:31][CH:30]=[C:29]4[CH:28]=[CH:27][C:26]3=[CH:25][CH:24]=1)([NH:4][C:1](=[O:3])[CH3:2])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: BrCc1ccc2ccc3cccc4ccc1c2c34
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2ccc3cccc4ccc1c2c34)(NC(C)=O)C(=O)OCC
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
A 9.78 g (45.04 mmol) sample of diethyl acetamidomalonate, and 1.08 g sodium hydride (45.04 mmol) were suspended in 100 mL of anhydrous THF, under nitrogen, and at 0°C. After stirring for 5 min., 2.5 mL of anhydrous ethanol were added slowly, and the solution returned to room temperature. A solution of 1-(bromomethyl)pyrene (12.03 g, 40.9 mmol, dissolved in 100 mL dry THF) was slowly added to the reaction mixture, and the solution brought to reflux for 18 h. The bulk of the THF was removed under reduced pressure, and the remaining yellow slurry was dissolved in 400 mL 1:1 CH2Cl2:H2O. The organic fraction was washed 3× with 100 mL H2O, and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to produce Diethyl-2-(1-pyrenylmethyl)-2-acetamidomalonate (14.70 g, 83.1%) as a light yellow powder. TLC (SiO2, 1:1 Hexane:EtOAc) Rƒ=0.57. Mp=135-140° C. 1H NMR (CDCl3), δ1.37 (t, 6H), 1.95 (s, 3H), 3.76 (s, 2H), 4.30 (q, 6H), 6.42 (s, NH), 8.00-825 (m, 9H from pyrene).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[Mg]Br>C1COCC1>[OH:2][CH:1]([C:19]1[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(O)c2cnccc2-c2cccc(C#N)c2)c(C)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 2,4,6-trimethylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2,4,6-trimethyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:15]([O:23][CH3:24])=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>C1COCC1>[CH:20]([C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=1)[O:23][CH3:24])([CH3:22])[CH3:21]
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=C(C(C)C)C(C)C)c1cccc(O)c1

Procedure:
To a solution of 0.97 g (2.78 mmol) of alkene 1a in 30 ml of dry THF was added 0.81 g (1.1 eq.) of tetra-n-butylammonium fluoride. After stirring for one hour TLC (silica, 20% ethyl acetate/hexane) showed complete conversion of starting material to a new compound. The THF was evaporated and the residue dissolved in ethyl acetate. The ethyl acetate solution was extracted four times with water and dried. Silica gel (2 g) was added and the solvent evaporated. The material was purified by column chromatography on silica gel, eluting with 10-20% ethyl acetate/hexane yielding 0.568 g (87%) of 1b: 1H NMR (CDCl3) δ 7.5-6.5 (m, 4H), 4.91 (s, 1H), 3.20 (s, 3H), 2.47 (sept, 1H), 2.33 (sept, 1H), 1.25 (d, 6H), 0.92 (d, 6H); 13C NMR (CDCl3) δ 129.25, 124.98, 122.60, 116.54, 114.98, 114.56, 56.38, 30.52, 26.80, 22.11, 21.08; Mass spectrum (m/z): 234, 219, 191; exact mass, cald'd. 234.1620, found 234.1620.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+]>C1COCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1
Yield: 94.4 %

Procedure:
Bromobenzene (79 mg, 0.50 mmol) reacted with 4-methoxyphenylboronic acid (99 mg, 0.65 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in THF solvent at room temperature to give the title compound (87 mg, 95%) as a white solid. The reaction of 4-chloroanisole (71 mg, 0.50 mmol) with phenylboronic acid (92 mg, 0.75 mmol) gave the title compound (74 mg, 80%) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF in THF solvent at 40° C. 1H-NMR (400 MHz, CDCl3): δ 7.61 (m, 4H), 7.48 (t, 2H, J=7.6 Hz), 7.37 (app.t, 1H, J=7.2 Hz), 7.04 (d, 2H, J=8.8 Hz), 3.90 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 159.09, 140.76, 133.69, 128.66, 128.08, 126.67, 126.60, 114.14, 55.26. GC/MS(EI): m/z 184 (M+). Anal. Calcd for C13H12O: C, 84.75; H, 6.56. Found: C, 84.86; H, 6.76.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:19]([C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCNCC2
Yield: 43.8 %

Procedure:
A mixture of 3-(tert-butyloxycarbonyl)-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (765 mg, 2.81 mmol) and trifluoroacetic acid (2 ml), in dichloromethane (20 ml) was stirred at 40° C. for 1 h. The reaction mixture was evaporated to dryness in vacuo and partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was basified using potassium carbonate and re-extracted with ethyl acetate (2×30 ml). The combined basic organic extracts were dried over sodium sulfate and evaporated in vacuo to give the title compound as a colourless oil (212 mg, 44%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:14]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:14]=1
Reactant: COC(=O)CCCCc1noc(-c2ccccc2OC)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCc1noc(-c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Add boron tribromide (4.9 mL, 51.7 mmol) dropwise to a stirred solution of methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.0 g, 10.3 mmol) in methylene chloride (70 mL) at 0° C. under nitrogen. Allow to warm to room temperature and stir for 5 hours. Cool the mixture to 0° C., add methanol (20 mL) dropwise and allow to warm to room temperature. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:9), to provide methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate, which is used without further purification. Add a solution of sodium hydroxide (800 mg, 20 mmol) in water (15 mL) to a solution of methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (2.6 g, 9.4 mmol) in methanol (30 mL) at room temperature and stir the mixture for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (2×150 mL). Wash the combined organic extracts with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by vacuum filtration to afford the title compound (2.4 g, 89% over two steps). APCI MS m/z 261 [C13H14N2O4—H]−.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[NH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:36][Si:37]([CH2:40][CH2:41][O:42][CH2:43]Cl)([CH3:39])[CH3:38]>C1COCC1.CCOC(C)=O>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[N:11]([CH2:43][O:42][CH2:41][CH2:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C

Procedure:
To a solution of 5-biphenyl-4-yl-6-chloro-2-(methylsulfonyl)-1H-benzimidazole (5.37 g, 14.0 mmol) in THF (70 mL) was added DIPEA (3.67 mL, 21.0 mmol) followed by SEMCl (3.7 mL, 21.0 mmol). The reaction was maintained for 5 h at ambient temperature. Then the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, followed by brine. The organic phase was dried over Na2SO4, filtered, and concentrated. Chromatography of the resulting residue over silica eluting with 5-25% EtOAc/hexanes afforded the desired product as a white solid. LC-MS: calculated for C14H20ClN2O3SSi 485.97, observed m/e 428.83 (M+H)+ (Rt 2.30 min).