Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:26](=[O:27])[NH:25][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:20]([O:19][CH3:18])[CH:21]=1)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)cccc1Cl
Reactant: COc1cc(C(=O)N=C=O)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1cc(C(=O)NC(=O)N(NC(=O)OC(C)(C)C)c2c(Cl)cccc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of tert-butyl 2-(2,6-dichlorophenyl)hydrazinecarboxylate (Intermediate-44, 1.2 g, 4.5 mmol) in DCM (20 mL) was added 3-methoxy-4-nitrobenzoyl isocyanate (1.0 g, 4.5 mmol). The reaction mass was stirred at RT for 2 h. Excess of solvent was removed under vacuum to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.35 (s, 9H), 3.97 (s, 3H), 7.89 (m, 1H), 7.27-7.35 (m, 2H), 7.55 (d, 1H), 7.62-7.75 (m, 1H), 7.94 (d, 1H), 8.26 (s, 1H), 9.03 (s, 1H); MS (m/z): 496.78 (M−H)−.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[N+:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].Cl>CN(C)C1C=CN=CC=1.ClCCl>[N+:21]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cccc([N+](=O)[O-])c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-nitrophenyl isocyanate (0.33 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 72 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield an orange oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.20 g, 29% yield), mp=100–102° C.; MS (−) ESI m/z=343 (M−H)−; [α]D25=−26.3° (c=1, DMSO).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[CH3:33][C:34]1[NH:38][N:37]=[C:36]([C:39](O)=[O:40])[CH:35]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]3[N:7]=[CH:8][C:9]4[N:10]=[C:2]([NH:1][C:39]([C:36]5[CH:35]=[C:34]([CH3:33])[NH:38][N:37]=5)=[O:40])[S:3][C:4]=4[N:5]=3)[CH:13]=2)=[O:32])[CH:26]=[CH:25][CH:24]=1)([CH3:29])[CH3:28])#[N:31]
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)Nc2nc3cnc(Nc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)ccc4C)nc3s2)n[nH]1
Temperature: 90 °C
Reaction time: 16 h
Yield: 41.3 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (80 mg, 180 μmol) produced in Example D25(iii) in pyridine (3 mL) were added 5-methyl-1H-pyrazole-3-carboxylic acid (45 mg, 360 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (205 mg, 540 μmol), and the mixture was stirred at 90° C. for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from N,N-dimethylformamide and diethyl ether to give the title compound (41 mg, 41%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH2:27][CH2:28]3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(N2CCN(c3ccccn3)CC2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 1-(2-pyridyl)piperazine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [Mg].BrCCBr.Br[CH:7]([CH3:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCN=C1.[CH3:21][C:22]1([CH3:39])[CH2:26][O:25][C:24]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[CH:29][C:28]=2OC)=[N:23]1>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:36][O:35][C:30]1[C:31]([O:33][CH3:34])=[CH:32][C:27]([C:24]2[O:25][CH2:26][C:22]([CH3:21])([CH3:39])[N:23]=2)=[C:28]([CH:7]([CH3:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:29]=1
Reactant: CC(Br)Cc1ccccc1
Reactant: COc1cc(OC)c(C2=NC(C)(C)CO2)cc1OC
Agent: C1=NCCO1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: BrCCBr
Solvent: CCCCCC
Product: COc1cc(C2=NC(C)(C)CO2)c(C(C)Cc2ccccc2)cc1OC
Temperature: 40 °C
Yield: 60.9 %

Procedure:
To a rapidly stirring suspension of magnesium turnings (1.32 g, 54.5 mol) and in 35 mL tetrahydrofuran (THF) was added 1,2-dibromoethane (0.10 mL) in one portion. 2-bromo-1-phenylpropane (10.86 g, 54.5 mmol) was added at a rate that maintained the internal temperature at 40° C. After 2.5 hours the cloudy suspension was transferred via canula to a solution of 4,4-dimethyl-2-(2,4,5-trimethoxy-phenyl)-4,5-dihydro-oxazole oxazoline (10.013 g, 36.4 mmol) in 50 mL THF. After 18 hours the solution cooled to 0° C. and quenched by the slow addition of 10% NH4Cl. 500 mL H2O was added and the mixture was extracted with ethyl acetate, washed with H2O, and washed with brine. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. Purifications via flash chromatography (4:1 hexane/ethyl acetate) afforded 2-[4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-4,4-dimethyl-4,5-dihydro-oxazole as a clear viscous oil (7.833 g, 41%).
Reaction SMILES: [OH:1][C@H:2]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][NH:4][C@H:5]([CH3:24])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][C@@H:17]([CH3:23])[C:18]([O:20]CC)=O)[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C@H:2]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][NH:4][C@H:5]([CH3:24])[CH2:6][C:7]1[C:15]2[C:10]3=[C:11]([O:16][C@@H:17]([CH3:23])[C:18](=[O:20])[N:9]3[CH:8]=1)[CH:12]=[CH:13][CH:14]=2
Reactant: CCOC(=O)[C@H](C)Oc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](Cc1cn2c3c(cccc13)O[C@@H](C)C2=O)NC[C@H](O)c1cccnc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of ethyl (2S)-2-((3-((2R)-2-(((2R)-2-hydroxy-2-pyridin-3-ylethyl)amino)propyl)-1H-indol-7-yl)oxy)propanoate.2 hydrochloride (205 mg, 0.423 mmol) in acetonitrile (8.7 ml) is added potassium carbonate (294 mg, 2.13 mmol), and the mixture is stirred at 60° C. for 4 hours. After the reaction is completed, the mixture is cooled to room temperature, and filtered. The filtrate is evaporated under reduced pressure to remove the solvent, and the obtained residue is purified by preparative thin layer chromatography (chloroform/methanol=10/1) to give the title compound (131 mg, yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:12]=C)=[N:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.C[OH:15]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH:12]=[O:15])=[N:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CO
Reactant: C=Cc1nc([N+](=O)[O-])ccc1OC
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])nc1C=O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 0.63 g (3.5 mmol) 3-methoxy-6-nitro-2-vinyl-pyridine in 50 ml of CH2Cl2 and 10 ml of methanol was cooled to −70° C. Ozone was bubbled into the solution until a blue color persisted. The mixture was stirred for 60 minutes at −70° C. and then quenched with excess dimethyl sulfide. The reaction was warmed to room temperature and the solvent evaporated. The residue was dissolved in ethyl acetate and water. The pH of the solution was adjusted to 2.0 with 1N HCl and the mixture stirred for 30 minutes. The pH of the solution was then adjusted to 8.0 with 1N NaOH. The mixture was extracted with excess ethyl acetate. The ethyl acetate extracts were combined, dried (Na2SO4) and evaporated to yield 0.6 g of 3-methoxy-6-nitro-pyridine-2-carbaldehyde as a tan solid. TLC. Rf=0.2 (1.1 ethyl acetate/hexane). 1H NMR (CDCl3) δ 10.1 (s, 1H), 8.5 (d, 1H), 7.85 (d, 1H), 4.15 (s, 3H).
Reaction SMILES: [CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][C:9]([C@H:13]4[C@@H:17]([C:18]5[C:26]6[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=6)[NH:20][CH:19]=5)[C:16](=[O:27])[NH:15][C:14]4=[O:28])=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][C:9]([C@H:13]4[C@H:17]([C:18]5[C:26]6[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=6)[NH:20][CH:19]=5)[C:16](=[O:27])[NH:15][C:14]4=[O:28])=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)[C@@H](c2cc3c4c(ccn4CCC3)c2)[C@H]1c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NC(=O)[C@@H](c2c[nH]c3ccccc23)[C@@H]1c1cc2c3c(ccn3CCC2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
A solution of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione (760 mg, 2.06 mmol) in anhydrous tetrahydrofuran (10 ml) at room temperature was treated with potassium tert-butoxide (1.0 ml, 1.00 mmol; 1M solution in tetrahydrofuran) then heated to 50° C. and stirred for a further 1 hour. The reaction was quenched with water (10 ml) and acidified with 2M hydrochloric acid, and the mixture extracted with dichloromethane (3×50 ml). The combined organic extracts were dried over anhydrous sulfate and evaporated to dryness. The residue was purified by flash column chromatography (SiO2, 1% to 10% methanol in dichloromethane) to provide (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione as an orange solid (46 mg). M.p=141-145° C.; 400 MHz 1H NMR (CDCl3) δ: 8.12 (s, 1H), 8.05 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.29 (s, 1H), 7.23 (m, 1H), 7.11 (m, 2H), 6.78 (s, 1H), 6.39 (d, J=2.7 Hz, 1H), 4.48 (d, J=5.9 Hz, 1H), 4.32 (d, J=5.5 Hz, 1H), 4.16 (t, J=5.5 Hz, 2H), 2.98 (t, J=6.3 Hz, 2H), 2.25 (t, J=6.3 Hz, 2H); LCMS: 370 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: CC1Cc2cc(Br)ccc2C(=O)O1
Reactant: CCN(CC)CC
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C=Cc1ccc2c(c1)CC(C)OC2=O
Temperature: 100 °C

Procedure:
A solution of 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 9.96 mmol) and triethylamine (2.78 ml, 19.91 mmol) in EtOH (39.8 ml) was added to a microwave vial containing Cl2Pd(dppf)2-DCM (0.406 g, 0.498 mmol) and potassium vinyltrifluoroborate (2.000 g, 14.93 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[C:1]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
After benzoic acid (300 mg, 2.46 mmol), triphenylphosphine (775 mg, 2.95 mmol), (2R,4R)-2,4-pentanediol (308 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (691.1 mg, 2.95 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for one hour. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-benzoyloxypentane-2-ol as a colorless oily substance (379 mg, yield: 74%/benzoic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[F:10].Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:12]2[CH:22]=[C:16]3[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]3[C:14](=[O:23])[N:13]=2)=[CH:4][C:3]=1[F:10]
Reactant: NCc1ccc(Cl)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(NCc1ccc(Cl)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (4-chloro-3-fluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]([SH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O-]CC.[Na+].[C:16](#[N:19])[CH:17]=[CH2:18]>C(O)C>[CH2:1]([S:11][CH2:18][CH2:17][C:16]#[N:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCS
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCSCCC#N
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a 250 mL round-bottomed flask fitted with an overhead mechanical stirrer, a thermometer and an addition funnel were charged 87 g of 1-decanethiol and 20 drops of a 21% by weight solution of sodium ethoxide in ethanol. The mixture was cooled to 10° C. using an ice bath. Then the dropwise addition of 53 g of acrylonitrile was started. After addition of a portion of the acrylonitrile, 10 drops of 21% by weight solution of sodium ethoxide in ethanol were added. The temperature of the reaction mixture during the addition of the remaining acrylonitrile ranged between 30° C. and 35° C. The reaction mixture was then kept at room temperature overnight (~19 hours). The unreacted acrylonitrile was then removed by distillation at atmospheric pressure. The remaining material was then distilled at ~1 mm pressure. A first fraction was collected from 150° C. to 160° C. Fraction one had a strong odor of thiol. A second and final fraction was collected at 160° C. The second fraction had a faint odor of thiol. An NMR spectrum indicated the second fraction to be the desired product 83.5% of theoretical (94.9 g) based upon the weight of 1-decanethiol employed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[OH:30].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:6][C:5]=1[O:30][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1O
Reactant: BrCc1ccccc1
Product: COC(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Yield: 58 %

Procedure:
The reaction of 2-hydroxy-5-[(12-phenoxydodecyl)oxy]benzoic acid methyl ester with benzyl bromide as described in Example 102 gave 5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy) benzoic acid methyl ester (58% yield, mp 46°-48° ).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:8]=1.[F:23][C:24]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=1[CH:26]=[O:27]>CCCCCC.O.C(OCC)C>[Si:16]([O:15][CH2:14][C:9]1[CH:8]=[C:7]([CH:26]([C:25]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:24]=2[F:23])[OH:27])[C:12]([CH3:13])=[CH:11][N:10]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Cc1cnc(CO[Si](C)(C)C(C)(C)C)cc1Br
Reactant: O=Cc1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cnc(CO[Si](C)(C)C(C)(C)C)cc1C(O)c1cc(F)ccc1F
Reaction time: 1 h
Yield: 74.2 %

Procedure:
Under an argon atmosphere, n-butyl lithium (a 1.58M hexane solution, 400 μl, 0.632 mmol) was added to a diethyl ether (3 ml) solution of 4-bromo-2-[(t-butyldimethylsilyloxy)methyl]-5-methylpyridine (200 mg, 0.632 mmol) at −78° C. The resulting mixture was stirred for 1 hour. After 2,5-difluorobenzaldehyde (69 μl, 0.632 mmol) was added dropwise, the reaction mixture was stirred for 1 hour. To the reaction mixture were added water and a saturated aqueous solution of sodium bicarbonate, followed by extraction with diethyl ether. The extract was washed with brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (178 mg, 0.469 mmol, 74%) as a white powder.
Reaction SMILES: [CH:1](=[N:10][NH:11][C:12]([NH2:14])=[S:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=O>>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:14]=[C:12]([NH:11][N:10]=[CH:1][CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[S:13][CH:16]=2)=[CH:24][CH:23]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: NC(=S)NN=CC=Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2csc(NN=CC=Cc3ccccc3)n2)cc1
Yield: 42 %

Procedure:
The compound is prepared according to the method described in Example 1B from cinnamaldehyde thiosemicarbazone (0.5 mmol) (Eur. J. Med. Chem. 25(7), 581-588, 1990) and from 2-bromo-4′-trifluoromethylacetophenone (0.5 mmol) (Tet., 59(8) 1317-1325, 2003). Yield 42%.
Reaction SMILES: CS(O[CH2:6][CH:7]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1)(=O)=O.[H-].[Na+]>C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH:7]1[CH2:8][C:9]2([CH2:11][CH2:10]2)[O:12][CH2:6]1
Reactant: CS(=O)(=O)OCC(CC1(O)CC1)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1CCC(OC2COC3(CC3)C2)OC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
A mixture of 3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate (1.3 g, 4.63 mmol) and NaH (0.15 g, 6 mmol, Aldrich) in 20 mL of THF was stirred at rt for 4 hrs. The reaction mixture was quenched with 5 mL of methanol. The mixture was diluted with 10 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:10 (v/v) EtOAc/petrolum ether) to give the title compound as colorless oil (380 mg, 42%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.C([O-])(=O)C.[K+].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH2:34][CH2:35][C:36]2[NH:45][C:39]3=[N:40][CH:41]=[C:42](I)[CH:43]=[C:38]3[N:37]=2)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:42]3[CH:43]=[C:38]4[N:37]=[C:36]([CH2:35][CH2:34][C:30]5[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=[CH:32][N:31]=5)[NH:45][C:39]4=[N:40][CH:41]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)Nc5ccc(N(C)C)cc5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 15.5 %

Procedure:
A mixture of 0.400 g of N-(4-dimethylamino-phenyl)-4-bromo-benzenesulfonamide, 0.315 g of bis-(pinacolato)-diboron, 0.019 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.025 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.332 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.278 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.085 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.202 g of potassium carbonate and 0.062 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-15:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.06 g of the title compound as a solid of m.p. 221-222° C. The mass spectrum shows the molecular peak MH+ at 529.2 Da.