Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)CCC.[F-].[NH4+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:12]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Nc1c(I)cc(Br)c2c1C(=O)NC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1c(-c2cccs2)cc(Br)c2c1C(=O)NC2=O
Yield: 87.3 %

Procedure:
3-Amino-4-iodo-6-bromophthalimide (100 mg, 0.273 mmol) was dissolved in THF (5 mL), and the solution was added with 2-(tributylstannyl)thiophene (0.173 mL, 0.546 mmol) and bis(triphenylphosphine)dichloropalladium (15 mg, 0.022 mmol), followed by stirring under reflux for 12.5 hours under argon atmosphere. The reaction mixture was added with 10% aqueous ammonium fluoride solution, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using hexane, then purified by preparative thin-layer chromatography (chloroform/acetonitrile=30/1) to obtain 3-amino-4-(thiophen-2-yl)-6-bromophthalimide (77 mg, yield 87%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:34]([O:33][C:31]([CH2:30][O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])=[O:32])[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)COCCC1OC1(C)C1C(OC)C(OC(=O)N2CCOCC2)CCC12CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (76.2 mg) in a mixture of toluene (2 ml) and N,N-dimethylformamide (1 ml) was added sodium hydride (20.5 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and ethyl bromoacetate (68.5 mg) was added. After stirred for 3 hours at ambient temperature, the reaction mixture was quenched with aqueous saturated ammonium chloride solution (2 ml). The organic layer was washed with brine, dried, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (diethyl ether) to give 4-[3-(2-ethoxycarbonylmethoxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (66.9 mg).
Reaction SMILES: [Br:1][C:2]1([Br:15])[C:13](=[O:14])[N:4]2[C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[Br:15][C:2]1([Br:1])[C:13](=[O:14])[N:4]2[CH:5]([C:10]([O:12][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12
Reactant: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)C1C(=O)OCc1ccccc1
Yield: 85 %

Procedure:
To a stirred solution of 1646 g. of 6,6-dibromo-2,2-dimethyl-(5R)penam-3α-carboxylic acid in 10.1 liters of N,N-dimethylacetamide was added 709 ml. of triethylamine during 10 minutes at ca. 0° C. The temperature was adjusted to 10° C., and 602 ml. of benzyl bromide was added during 4 minutes. To the reaction mixture was then added 941 g. of 4A molecular sieves, and then the reaction mixture was stirred overnight without external cooling. At this point, the reaction mixture was filtered and the filtrate was added to a mixture of 44 liters of ice-water and 14 liters of ethyl acetate. The pH of the aqueous phase was adjusted to 2.0 using 6 N hydrochloric acid, and the layers were separated. The aqueous layer was extracted with further ethyl acetate and the combined ethyl acetate solutions were washed sequentially with 14 liters of saturated, aqueous sodium bicarbonate and 14 liters of saturated, aqueous sodium chloride. The ethyl acetate solution was dried (Na2SO4), and then it was evaporated in vacuo at 25° C. The residue was dissolved in 5.5 liters of isopropyl alcohol at 60° C., and then the isopropyl alcohol solution was cooled slowly with stirring. The solid which precipitated was recovered by filtration, washed with cold isopropyl alcohol and then air dried. This afforded 1777 g. (85% yield) of the title product. The NMR spectrum (CDCl3) showed absorptions at 1.40 (s, 3H), 1.55 (s, 3H), 4.55 (s, 1H), 5.20 (s, 2H), 5.75 (s, 1H) and 7.35 (s, 5H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19]([O:21]CC)=O)=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[NH2:25][NH2:26]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19]([NH:25][NH2:26])=[O:21])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(-c2nc(C)c(C(=O)NN)s2)cc(OC)c1OC
Yield: 59 %

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenyl)-4-methylthiazole-5-carboxylate prepared in Example 4 (6.2 g corresponding to its 0.02 mol), 6.1 g (0.1 mol) of hydrazine hydrate of purity of 82% and 150 ml of ethanol were heated for 6 hours at a temperature of 90° C. The crystals, which separated out after cooling the reaction mixture, were recrystallized from 95% aqueous ethanolic solution to obtain the object consisting of faintly yellow scale-like crystals, amounting to 3.8 g and melting at 179.5° to 181° C. at a yield of 59%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: OC1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 4-hydroxypiperidine. A yellow solid 98 was obtained (0.0299 g, 66%). 1H-NMR (CDCl3, 400 MHz) δ 1.76-1.84 (m, 2H), 2.02-2.10 (m, 2H), 3.69-3.76 (m, 2H), 3.83 (s, 3H), 4.01-4.07 (m, 2H), 4.12-4.17 (m, 1H), 6.95 (d, J=6.6 Hz, 1H), 6.99 (s, 1H), 7.01-7.07 (m, 3H), 7.46-7.52 (m, 3H), 7.85 (s, 1H), 8.23 (d, J=6.6 Hz, 1H), MS (APCI) m/z 461 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][NH:16][CH:17]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]1>>[CH3:15][N:16]([CH:17]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]1)[S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC1CCN(C)C1
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C)C2CCN(C)C2)cc1

Procedure:
4-Acetylaminobenzenesulfonyl chloride and methyl-(1-methylpyrrolidin-3-yl)amine are reacted according to the method described in Example 10, intermediate 2. The title compound obtained in the form of a slightly yellowish solid can be reacted further without further purification. (MS-ES+: 312.1; LCMS Rt=0.698 min)
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].Cl.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][NH2:19])=[CH:22][CH:23]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: NCc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Agent: Cl
Product: NCc1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-aminomethyl-phenylboronic acid hydrochloride gives “A77”; method 1: HPLC/MS: 1.07 min, [M+H]=320;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C(OC(=O)C)(=O)C>C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:10]/[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1nc2ccccc2s1
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: Oc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 120 °C
Yield: 39.7 %

Procedure:
A mixture of 25 g of 3-hydroxybenzaldehyde, 36.6 g of 2-methylbenzothiazole, 38.8 ml of acetic anhydride and 7.7 ml of formic acid was heated at 120° C. for 25 hours. The low boiling materials were evaporated together with toluene under reduced pressure, and the residue was added to 150 ml of methanol and refluxed with addition of 3 g of potassium carbonate for 1 hour. After cooled to room temperature, the mixture was filtered and filtrate was concentrated. The crude product formed was washed with methanol and ethyl ether and dried under reduced pressure to obtain 20.6 g (yield 40%) of the title compound.
Reaction SMILES: [CH2:1](N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].C[C@:14]1([C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][C@@H:16]([OH:20])[CH2:15]1>C(OCC)(=O)C>[CH3:11][S:8]([O:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][C@H:14]([C:21]([O:23][CH3:1])=[O:22])[CH2:15]1)(=[O:10])=[O:9]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]1(C(=O)O)CCC[C@@H](O)C1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
With cooling with ice, triethylamine (1.51 mL, 10.84 mol) and mesyl chloride (0.643 mL, 8.13 mmol) were added in that order to an ethyl acetate (10 mL) solution of a compound, methyl (1S*,3R*)-3-hydroxycyclohexanecarboxylic acid (857 mg, 5.42 mmol) known in a reference (Tetrahedron, 2003, Vol. 59, pp. 7465-7471), and then stirred at room temperature for 1 hour. The reaction solution was kept under cooling with ice for while, and then the reaction liquid was filtered. The resulting filtrate was concentrated under reduced pressure to give the intended product (1.18 g, 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:10][CH:9]=1>ClCCl.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:17])=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)CCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(CCc1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of morpholine (11 g, 126.44 mmol, 2.01 equiv) in dichloromethane (60 mL) 0˜5° C. was added a solution of 3-(4-bromophenyl)propanoyl chloride (15.5 g, 63.01 mmol, 1.00 equiv) in dichloromethane (30 mL) dropwise with stirring. The resulting solution was stirred at 0˜5° C. for 1 h. The reaction mixture was warmed to room temperature. The resulting solution was diluted with 40 mL of water. The mixture was extracted with dichloromethane 2×100 mL. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 17.4 g (93%) of 3-(4-bromophenyl)-1-morpholinopropan-1-one as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H][H]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]([CH3:31])[S:27]([CH3:30])(=[O:28])=[O:29])[CH:15]=[CH:14][N:13]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CN(c1ccccc1C#Cc1ccnc(Nc2ccc(S(C)(=O)=O)cc2)n1)S(C)(=O)=O
Reactant: [H][H]
Solvent: CO
Product: CN(c1ccccc1CCc1ccnc(Nc2ccc(S(C)(=O)=O)cc2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
100 mg of N-(2-{2-[2-(4-methanesulfonylphenylamino)pyrimidin-4-yl]ethynyl}-phenyl)-N-methylmethanesulfonamide are dissolved in 1 ml of methanol, and 100 mg of activated carbon (with 10% of Pd) are added. A hydrogen atmosphere is generated, and the suspension is stirred at room temperature for 3 h. The catalyst is subsequently filtered off, and the solvent is removed. The residue is chromatographed on silica gel, giving 50 mg of the title compound as colourless solid;
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23](=[O:30])[NH:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28]Cl)([CH3:21])([CH3:20])[CH3:19].[CH3:31]C#N>>[CH3:18][CH2:19][N:12]([CH:11]([CH3:10])[CH3:16])[CH:13]([CH3:14])[CH3:31].[C:18]([O:22][C:23](=[O:30])[NH:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][N:9]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC/C=C\CCl
Reactant: Cc1cccnc1CNCc1ncccc1C
Reactant: CC#N
Product: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(C/C=C\CNC(=O)OC(C)(C)C)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine, (4-chloro-cis-but-2-enyl)-carbamic acid tert-butyl ester (Casara, P et al, J. Am. Chem. Soc. 1989, 111, 9111-9113), KI in anhydrous CH3CN and DIPEA gave {4-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-cis-but-2-enyl}-carbamic acid tert-butyl ester. 1H NMR (CDCl3) δ 1.46 (s, 9H), 2.13 (s, 6H), 3.18 (d, 2H, J=6.0 Hz), 3.63 (t, 2H, J=6.0 Hz), 3.74 (s, 4H), 5.69 (br, 2H), 5.80 (br, 1H, (NH)), 7.08 (m, 2H), 7.39 (d, 2H, J=6.0 Hz), 8.38 (d, 2H, J=3.6 Hz). Conversion to the HBr salt using General Procedure D gave COMPOUND 234 (56 mg) as a light beige solid. 1H NMR (D2O) δ 2.49 (s, 6H), 3.45 (d, 2H, J=6.9 Hz), 3.59 (d, 2H, J=6.9 Hz), 4.31 (s, 4H), 5.69 (m, 1H), 5.94 (m, 1H), 7.85 (t, 2H, J=6.9 Hz), 8.36 (d, 2H, J=7.8 Hz), 8.59 (d, 2H, J=5.4 Hz). 13C NMR (D2O) δ 17.37 (2C), 36.60, 51.89, 54.10 (2C), 125.93, 126.18 (2C), 130.97, 137.94 (2C), 138.86 (2C), 148.65 (2C), 150.66 (2C). ES-MS m/z 297 (M+H).
Reaction SMILES: C(OC([N:8]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[P:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH2:26]([O:25][P:24]([CH2:22][C:19]1[CH:18]=[N:17][C:16]([NH2:8])=[CH:21][CH:20]=1)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cn1
Reactant: CCOP(OCC)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOP(=O)(Cc1ccc(N)nc1)OCC
Temperature: 110 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of di-tert-butyl[5-(bromomethyl)pyridin-2-yl]imidodicarbonate (Compound 309B, 1.162 g, 3 mmol) and triethyl phosphite (0.598 g, 3.6 mmol) in dioxane (2 mL) was stirred at 110° C. for 4 h. The cooled reaction mixture (room temperature) was treated with 4 N HCl in dioxane (5 mL) and DCM (10 mL) and allowed to stir at room temperature for 6 h. Sat. NaHCO3 (aq, 15 mL) was added and the mixture was extracted with DCM (3×40 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N ammonia in MeOH in DCM) to afford 227 mg of the title compound (yield: 31%). 1H NMR (CDCl3, 400 MHz): δ=1.29 (t, J=6.8 Hz, 6H), 2.98 (d, J=20.8 Hz, 2 H), 4.02-4.09 (m, 4H), 5.65 (s, br, 2H), 6.58 (d, J=8.8 Hz, 1H), 7.51 (dt, J=2.4, 8.8 Hz, 1H), 7.82 (t, J=2.4 Hz, 1H). MS (ES+): m/z 245.09 [MH+]. HPLC: tR=0.70 min (UPLC TOF, polar—3 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[CH2:31][NH:30][CH2:29][CH2:28]2>O>[Cl:8][C:6]1[N:5]=[C:4]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:31]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Nc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1OC)CN(c1nc(N)nc(Cl)n1)CC2
Reaction time: 1 h

Procedure:
2-amino-4,6-dichloro-1,3,5-triazine (9.7 g, 58.8 mM) was dispersed in water (50 mL), sodium carbonate solution (2N, 60 mL) and dioxane 15 mL) at 0° C. 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (13.9 g, 58.8 mM) was added and the mixture was stirred vigorously for 1 hr. The product was filtered, rinsed with water, dried and recrystallized from methanol; 14.3 g (75%), mp=196°-197° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Si:13]([O:9][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:12][CH:11]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)cc1

Procedure:
Methyl 4-(hydroxymethyl)benzoate was treated with tert-butyldimethylsilyl chloride using the general procedure described in Journal of the American Chemical Society, 1972, 94, 6190. The resulting product was reduced with lithium aluminium hydride to afford 4-(tert-butyldimethylsilyloxymethyl)benzyl alcohol. This alcohol was converted into the required compound using Method C. 1H NMR (CCl4) δ0.08 (12H, s), 0.91 (18H, s), 4.22 (1H, d, J 2 Hz), 4.68 (5H, br s), 4.90 (2H, s), 7.1-7.6 (8H, m); MS (CH4) 483 (M+ -CH3, 52%), 133 100% ).
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9]([C:11]2[CH2:12][N:13]([C:17](OC(C)(C)C)=O)[CH2:14][CH2:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:25]1[C:30](N)=CC=CN=1.COC(C1CN(C(OC(C)(C)C)=O)CCC=1)=O.C[Al](C)C>C(Cl)Cl>[CH2:17]([N:13]1[CH2:14][CH2:15][CH2:16][C:11]2([C:2]3[C:7](=[CH:6][CH:5]=[CH:4][N:3]=3)[NH:8][C:9]2=[O:10])[CH2:12]1)[CH2:25][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC=C(C(=O)Nc2cccnc2Br)C1
Reactant: Nc1cccnc1Br
Agent: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCN1CCCC2(C1)C(=O)Nc1cccnc12
Yield: 85 %

Procedure:
tert-Butyl 3-[(2-bromo-3-pyridyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate. 2-Bromo-3-pyridineamine (3.0 g, 17.3 mmol) and 1,2,5,6-tetrahydro-1,3-pyridinedicarboxylic acid 1-tert-butyl ester 3-methyl ester (5.05 g, 20.8 mmol) were dissolved in DCM (80 ml). To the solution trimethylaluminium (26 mmol, 2M solution) was slowly added at 0° C. The mixture was refluxed overnight. Work-up and purification on silica gel using 60% ethyl acetate in heptane as an eluent gave 5.65 g (85%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[OH-].[K+].[C:13](=S)=[S:14].C>O.C(O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[N:10]=[C:13]([SH:14])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
The procedure of Van Allan, J. A. V. and Deacon, B. D., Organic Synthesis. IV:569 was adapted. A mixture of 1,2-diamino-4,5-dichlorobenzene (510 mg, 2.88 mMol, Aldrich), potassium hydroxide (190 mg, 3.40 mMol), carbon disulfide (260 mg, 3.40 mMol), 95% ethanol (3 mL) and water (0.45 ml) was heated under reflux for 3 h. Activated charcoal (120 mg) was then added cautiously, and after the mixture has been heated at the refluxing temperature for 10 min the activated charcoal was removed by filtration. The filtrate was heated to 60°-70° C., warm water (3 mL) was added, and then acetic acid (0.25 mL) in water (0.5 mL) was added with good stirring overnight. The mixture was placed in a refrigerator for 3 h to get two crystals (brown and white). The brown crystals were removed by washing with chloroform (5 mL). Recrystallization from hot EtOH/H2O gave pure 5,6-dichloro-2-mercaptobenzimidazole (545 mg, 86%) as white long needles. Mp was measured: the color of 5,6-dichloro-2-mercaptobenzimidazole changed to yellow at 303° C.; the decomposition of 5,6-dichloro-2-mercaptobenzimidazole is obvious at 305° C. and it melted to a black liquid at 308°-10° C. IR (KBr, cm-1): 3447; 3107; 3043; 1607; 1496; 1461. NMR (1H, DMSO-d6): δ7.305 (s, 2H); 12.781 (s, 2H). HRMS: calcd for C7H4Cl2N2S (M+) m/z: 217.9425, Found: 217.9482.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH2:24])=[C:19]([Cl:25])[CH:18]=1.O>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH:24][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:19]([Cl:25])[CH:18]=1
Reactant: Cc1cc(Br)cc(Cl)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
3,3-dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of 4-Bromo-2-chloro-6-methyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (7.46 g, 100% yield).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O.O([CH3:21])[Na]>C1COCC1>[C:12]1([CH:17]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:21]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccn1
Reactant: CO[Na]
Reactant: O=C(CO)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 43 %

Procedure:
2.08 g (15.3 mmol) of 2-hydroxyacetophenone, 1.55 g of 2-pyridine-carboxaldehyde (14.5 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 1.4 g (43%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.76 (s, 1H), 8.73 (d, J=4.5 Hz, 1H), 8.29 (d, J=15.3 Hz, 1H), 8.06 (d, d, J=1.5, 8.1 Hz, 1H), 7.78 (d, J=15.0 Hz, 1H), 7.77 (d, d, d, J=1.8, 7.5, 9.3, 1H), 7.56-7.50 (m, 2H), 7.37-7.32 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 7.01-6.94 (m, 1H).