Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21]C(C)([O-])C.[K+].IC>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=1)([CH3:21])[C:3]([O:2][CH3:1])=[O:20]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)Cc1cccc(C(C(=O)OC)C(=O)OC)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1cccc(C(C)(C(=O)OC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
The compound of step 1 (0.353 g, 1.26 mmol) was dissolved in DMF (1.5 ml), potassium tert-butoxide (151 mg, 1.32 mmol) was added, the mixture stirred at room temperature for 10 min, and then iodomethane (0.542 g, 3.78 mmol) was added. The mixture was stirred at room temperature for 3 h and partitioned between EA and 2 N hydrochloric acid. The combined extracts were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to yield 0.128 g of the title compound.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(O)C(N)(CO)CO>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:3]2[CH2:2][CH2:1][C:14]3[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[NH:7][C:6]=3[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]2)=[O:26])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (Example 1, 52 mg, 0.2 mmol) in DCM was added 4-fluorobenzoyl chloride (36 μL, 0.2 mmol) and TEA (56 μL, 0.4 mmol) and the mixture was shaken overnight at 20° C. Trisamine resin (50 mg) was added and the suspension was shaken for 2 hours at 20° C. The resin was removed by filtration through a Florisil® cartridge. Evaporation of solvent gave a crude product, which was purified by trituration with methanol to give the title compound (28 mg); 1H-NMR (CDCl3): δ 10.31 (1H, br s), 7.79 (1H, s), 7.41 (2H, m), 7.36 (1H, d), 6.90-7.04 (5H, m), 3.99-4.06 (4H, m), 3.06 (2H, t), 1.02 (3H, t); MS (ES): 379 (MH+).
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:5]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Reactant: NC(=O)C1C2C=CC(C2)C1Nc1nc(Cl)ncc1Cl
Product: CC(C)N1C(=O)CCCc2cc(Nc3ncc(Cl)c(NC4C5C=CC(C5)C4C(N)=O)n3)ccc21
Yield: 57 %

Procedure:
In an analogous procedure to Example 651, part c, 1-isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was combined with 3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield 3-[5-Chloro-2-(1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (55.01 mg, 57% yield) as a white powder. 1H-NMR (DMSO-d6) δ 9.35 (s, 1H), 7.77 (m, 2H), 7.62 (m, 2H), 7.27 (m, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.36 (s, 1H), 6.24 (s, 1H), 4.60 (m, 1H), 4.15 (m, 1H), 2.88 (s, 1H), 2.87 (s, 1H), 2.64 (m, 1H), 2.55 (m, 1H), 2.10 (m, 4H), 1.82 (m, 1H), 1.41 (d, J=8.3 Hz, 1H), 1.32 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H). LC/MS (ESI+)=481 (M+H). MP=260° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:10]=[C:11]=[O:12])[CH2:8][CH3:9].[CH3:13][C:14]1[NH:18][N:17]=[C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:21]=2)[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:10][C:11]([N:18]1[C:14]([CH3:13])=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:21]=2)=[N:17]1)=[O:12])[CH2:8][CH3:9]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n[nH]1
Reactant: CCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Potassium carbonate (0.30 g, 2.2 mmol) and propyl isocyanate (0.17 g, 2.0 mmol) were added to a solution of 5-methyl-3-(4-nitro-3-trifluoromethylphenyloxy)pyrazole (0.57 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellow viscous substance of N-propyl-5-methyl-3-(4-nitro-3-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.64 g, yield: 69.0%). 1H-NMR (CDCl3, TMS, ppm): δ 0.97 (t, J=7.3 Hz, 3H), 1.62 (q, J=7.3 Hz, 2H), 2.64 (s, 3H), 3.32 (dt, J=7.3 and 7.3 Hz, 2H), 5.85 (m, 1H), 6.80˜7.05 (m, 1H), 7.45 (dd, J=2.6 and 9.0 Hz, 1H), 7.64 (d, J=2.6 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13].S(Cl)(Cl)=O>C(Cl)Cl>[F:13][C:7]1[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:6]=1[C:5]1[O:14][CH2:2][CH2:3][N:4]=1
Reactant: O=C(NCCO)c1cc(Br)ccc1F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(Br)cc1C1=NCCO1
Temperature: 25 °C

Procedure:
A solution of N-(2-hydroxyethyl)-5-bromo-2-fluorobenzamide (956 mg, 3.65 mmol) in methylene chloride was treated with thionyl chloride (0.35 ml, 4.75 mmol). The resulting mixture was stirred at ambient temperature as the progress of the reaction was monitored by thin layer chromatography. After one hour of stirring, no starting material was visible. The reaction mixture was diluted with methylene chloride, and the reaction was quenched by the addition of water and 1 N sodium hydroxide. The organic fraction was dried over sodium sulfate, and concentrated to a white solid. The solid was dissolved in 80% aqueous acetonitrile (25 ml) and an excess of potassium carbonate was added. The resulting mixture was stirred for about 72 hours at ambient temperature, heated to reflux for thirty hours, and worked up as before. The desired title product was then further purified by liquid chromatography, yielding 260 mg as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:5]1[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(OC)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) was mixed with trimethyl orthoformate (4 mL, 36.10 mmol) and p-toluenesulfonic acid (5 mg). The reaction was stirred at room temperature for 3 h and then quenched by adding excess of sodium bicarbonate solid and stirred for 1 h. The solid was removed by filtration and the filtrate was concentrated to yield 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100%). A mixture of 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 4.31 mmol), cesium carbonate (1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladium tetrakis(triphenyl)phosphine (0.25 g, 0.216 mmol) in toluene (60 mL) and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C. for 28 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), concentrated to afford a solid residue. Purification by column chromatography left 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60%). A solution of 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20 mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at room temperature for 2 h. The reaction mixture was then neutralized with 1 N sodium bicarbonate aqueous to pH 9 and extracted with DCM (3×100 mL), to afford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][O:8][C:9](=[O:24])[CH:10]([CH3:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH3:21])=[CH:15][CH:14]=1>CCOCC>[CH3:7][O:8][C:9](=[O:24])[CH:10]([CH3:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([Cl:2])=[CH:20][CH3:21])=[CH:15][CH:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCC(=O)c1ccc(CCC(C)C(=O)OC)cc1
Solvent: CCOCC
Product: CC=C(Cl)c1ccc(CCC(C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
193 g of phosphorus pentachloride are added to a solution of 76.8 g of 2-methyl-4-(4-propionylphenyl)butyric acid methyl ester in one liter of anhydrous ether, and the mixture is stirred at room temperature for 16 hours and is subsequently heated at reflux for one hour. The mixture is slowly poured on ice, is stirred for one hour and extracted with ether. The 4-[4-(1-chloro-1-propenyl)phenyl]-2-methylbutyric acid methyl ester obtained after evaporating the ether extract, is distilled in a vacuum (bulb type). B.P. 160°-170° at 0.06 mm of Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([Cl:13])([Cl:12])[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]([Cl:12])([Cl:13])[CH2:5][N:6]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C(Cl)(Cl)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cl)(Cl)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 143.7 %

Procedure:
A solution of 1.5 g (0.0063 mole) of 2,2-dichloro-3-cyclopentylamino-propionic acid methyl ester in 3 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 0.81 g (0.0042 mole) of 2,4-dichloro-5-nitro-pyrimidine, 1.76 g (0.02 mole) of sodium bicarbonate and 15 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 24 hours at room temperature and then 24 hours at 75 degrees. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 2.4 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dichloro-propanoic acid methyl ester (IV-298) as a yellow thick oil. This material was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[C:12]12([NH2:17])[CH2:16][CH:14]([CH2:15]1)[CH2:13]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:12]12([NH:17][C:5]3[N:4]=[C:3]([S:9][CH3:10])[C:2]([Br:1])=[CH:7][N:6]=3)[CH2:16][CH:14]([CH2:15]1)[CH2:13]2
Reactant: NC12CC(C1)C2
Reactant: CSc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CSc1nc(NC23CC(C2)C3)ncc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 104.5 %

Procedure:
To a stirring solution of 5-bromo-2-chloro-4-(methylthio)pyrimidine (1.0 g, 4.18 mmol) in NMP (10.0 mL) was added bicyclo[1.1.1]pentan-1-amine hydrochloride (749 mg, 6.26 mmol, prepared according to Org. Lett., 13(17): 4746-4748 (2011)) and DIEA (2.19 mL, 12.53 mmol). The mixture was stirred at 100° C. for 16 h and then the solvent was removed under reduced pressure. The residue was diluted in 100 mL ethyl acetate and 50 mL 1M aqueous solution of sodium hydrogen phosphate. The layers were separated and the aqueous layer was extracted with 50 mL ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford N-(bicyclo[1.1.1]pentan-1-yl)-5-bromo-4-(methylthio)pyrimidin-2-amine (1250 mg, 4.37 mmol, 105% yield) as a solid that was used without further purification. MS (ESI) m/z 286.0 [M+1]+ and 288.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[N:9]=2)=[CH:5][C:4]([CH3:17])=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].O>O1CCCC1>[F:30][C:31]1[CH:32]=[C:33]([NH:34][C:14]([C:10]2[N:9]=[C:8]([O:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:17])[CH:5]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:35]=[CH:36][CH:37]=1
Reactant: Nc1cccc(F)c1
Reactant: Cc1cc(Oc2cccc(C(=O)O)n2)n(C)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2cccc(C(=O)Nc3cccc(F)c3)n2)n(C)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1',3'-dimethyl-pyrazol-5-yloxy)-pyridine-6-carboxylic acid (2.2 g, 9.6 mmol) (from Example 53) in anhydrous tetrahydrofuran (20 ml) was added carbonyldiimidazole (1.6 g, 10.6 mmol) and stirred for 30 minutes, maintaining the temperature up to 40° C. 3-fluoroaniline (1.1 ml, 10.6 mmol) was added and the reaction mixture heated to 50° C. After 2 hours, the clear mixture was poured into water (100 ml) and extracted three times with ethyl acetate (50 ml each). The combined extracts were dried with anhydrous magnesium sulphate and the solvent was removed in vacuo. The crude product was purified by flash silica gel column chromatography using hexane/ethyl acetate 1/1. The title compound was obtained as a white solid (1.7 g, 54%), mp 110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[CH:20][CH:21]=1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)COc4ccccc4C)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3ccc(NCCOc4ccccc4C)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenyl}-2-(2-methylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [N:1]([C@@H:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-]>CO.[Pd]>[Si:7]([O:6][CH2:5][C@H:4]([C:14]1[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=1)[NH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N=[N+]=[N-])c1ccncc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
10% Pd/C (10 mg) was added to (S)-4-(1-azido-2-(tert-butyldimethylsilyloxy)ethyl)pyridine (58 mg, 0.208 mmol) in methanol. The reaction was degassed, and then charged with hydrogen. The reaction was stirred at room temperature overnight and filtered. The filtrate was concentrated to give the title compound (50 mg) without further purification.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#N.[CH2:11]([N:15]([CH2:24][CH2:25][CH2:26][CH3:27])[C:16]1[CH:21]=[CH:20]C=[C:18]([O:22][CH3:23])[CH:17]=1)[CH2:12][CH2:13][CH3:14]>CN(C)C=O>[C:5]([C:4](=[C:3]([C:1]1[CH:20]=[CH:21][C:16]([N:15]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:18]=1[O:22][CH3:23])[C:9]#[N:10])[C:7]#[N:8])#[N:6]
Reactant: CCCCN(CCCC)c1cccc(OC)c1
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C(C#N)=C(C#N)C#N)c(OC)c1
Yield: 76.9 %

Procedure:
In 8 ml of N,N-dimethylformamide, 0.5 g (3.9 mmol) of tetracyanoethylene was dissolved. With stirring under ice cooling, 0.8 g (3.4 mmol) of dibutyl(3-methoxyphenyl)amine was dissolved in 2 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 35 minutes. After the ice bath was removed, the mixture was further stirred for 2 hours. After the reaction mixture was poured into 100 ml of water, extraction with chloroform, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography and washed with hexane to give 0.88 g of a black crystal having a mp of 86° C. (yield: 77.2%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[CH3:12][CH:13]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH3:14].N1C=CN=C1>CCOC(C)=O>[CH3:8][O:7][C:6]1[C:4]([O:5][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:12])=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COc1cccc(C=O)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 100 °C

Procedure:
O-vanillin (26.3 mmol) is mixed with TIPSCl (39.6 mmol) and imidazole (78.7 mmol) in a microwave vessel. The mixture is heated in the microwave at 100° C. for 3 minutes. The oily mixture is diluted with EtOAc (100 mL) and washed with NaHSO4 (1 M) (2×50 mL) and brine (50 mL). After drying with MgSO4, the filtrate is concentrated. The resultant crude mixture is purified by silica flash chromatography (2% EtOAc/hexane) to yield 3-methoxy-2-triisopropylsilanyloxy-benzaldehyde as an oil: 1H NMR (400 MHz, CDCl3) δ 10.6 (s, 1H), 7.38 (dd, J1=1.6 Hz, J2=8 Hz, 1H), 7.04 (dd, J1=1.6 Hz, J2=8 Hz, 1H), 6.93 (td, J1=8 Hz, J2=0.8 Hz, 1H), 3.82 (s, 3H), 1.34-1.25 (m, 3H), 1.1 (s, 18H); LC/MS (ES+): 309 (M+1)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH:17]([CH2:20][S:21]([OH:24])(=O)=[O:22])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[Cl:3][S:21]([CH2:20][CH:17]1[CH2:18][CH2:19][N:15]([C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:14])[CH2:16]1)(=[O:24])=[O:22]
Reactant: O=S(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(CS(=O)(=O)O)C1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CS(=O)(=O)Cl)C1

Procedure:
Thionyl chloride (5 ml) was added to a solution of 1-[(benzyloxy)carbonyl]-3-pyrrolidinylmethanesulfonic acid (600 mg) [Preparation 57] in dimethylformamide (50 ml). The reaction mixture was heated to reflux for 20 mins after which time the cooled mixture was evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford benzyl 3-(chlorosulfonylmethyl)-1-pyrrolidinecarboxylate (560 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[CH2:11][Cl:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: Cc1c(N)cccc1Br
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1CCl
Yield: 44 %

Procedure:
A solution of 3-bromo-2-methylaniline (10 g, 53.7 mmol) in DCM (200 mL) at 0° C. was treated with TEA (14.98 mL, 107 mmol), followed by dropwise addition of 2-(chloromethyl)benzoyl chloride (10.16 g, 53.7 mmol) in DCM (50 mL) over 1 h. The mixture was diluted with DCM (ca. 1 L), washed with NaHCO3 (aq) and water, and concentrated to remove most of the solvent. The precipitate was collected by filtration and washed with DCM (2×10 mL) to provide N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (8.0 g). The filtrate was concentrated further, resulting in additional precipitate which was collected by filtration and washed with DCM (2×10 mL) to provide additional N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (3.06 g), for a combined yield of 61%. Mass spectrum 338, 340, 342 The filtrate was concentrated and purified by column chromatography (hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (2.0 g, 12%). A solution of the N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide (11.06 g, 32.7 mmol) in DMF (50 mL) was cooled to 0° C. and treated with a mixture of sodium hydride (60% oil dispersion, pre-washed with hexane, 1.70 g, 42.5 mmol) and DMF (10 mL). The mixture was stirred at 0° C. for 1.5 h, then was treated with water. The precipitate was collected by filtration, dried and combined with the material purified by column chromatography (see above) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (9.41 g, 95%). 1H NMR (400 MHz, chloroform-d) δ 7.96 (1H, d, J=7.5 Hz), 7.58-7.67 (2H, m), 7.49-7.57 (2H, m), 7.20-7.25 (1H, m), 7.15 (1H, t, J=7.9 Hz), 4.72 (2H, s), 2.31 (3H, s). Mass spectrum m/z 302, 304 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=S)[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH3:16]>>[NH2:16][C:9]1[CH:8]2[CH2:13][CH2:14][CH2:15][CH:7]2[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:11]=2[N:10]=1
Reactant: Fc1cccc2c1NC(=S)C1CCCC21
Reactant: N
Product: NC1=Nc2c(F)cccc2C2CCCC12
Yield: 64 %

Procedure:
Analogously to Example 4, 6-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (100 mg, 0.45 mmol) in 7N methanolic ammonia solution (15 ml) is reacted to form 59 mg (64%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(CC(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][CH:10]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
0.75 mole (175 g) of 4'-chloro-4-hydroxy-benzophenone, 1.5 l of methylisobutyl ketone, 0.975 mole (134 g) of K2CO3 and 0.8 mole (145 g) of ethyl 2-bromopropionate are placed in a 2-liter flask. The mixture is heated at reflux for 8 hours with vigorous agitation whereupon the reaction mixture is cooled and filtered on a Buchner funnel. The solvent is then evaporated under vacuum and the residue distilled; the desired ester is recovered at 198° to 201° C under 0.1 mm of mercury. Yield 190 g (76%).