Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23].S(Cl)(Cl)=O.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>COCCOC.ClCCl>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)=[O:23]
Reactant: O=C(O)c1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Reactant: Nc1nccs1
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(Nc1nccs1)c1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To 3-(2-hydroxy-6-(3-hydroxyphenyl)naphthalene-1-yl)benzoic acid (79 mg, 0.22 mmol, 1 eq), which is dissolved under a nitrogen atmosphere in 2 ml of dry DME, thionyl chloride (100 μl) is added, and the mixture is stirred at RT for 2 h. After the excess thionyl chloride has been removed in vacuum on a rotary evaporator, the residue is dissolved in dry DME and added dropwise to a suspension of 2-aminothiazole (22.2 mg, 0.22 mmol, 1 eq) in dry dichloromethane cooled at 0° C. The reaction mixture is stirred at RT over night, followed by removing the solvent on a rotary evaporator. Purification of the raw product by column chromatography with dichloromethane/methanol 95/5 as the eluent yielded the desired compound in a yield of 13%, 13 mg.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C-:22]#[N:23].[Na+].[Cl-].[NH4+:26]>[OH-].[NH4+]>[NH2:26][C:15]1([C:22]#[N:23])[CH2:16][CH2:17][CH2:18][CH:14]1[CH2:13][C:12]1[CH:20]=[CH:21][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: CCCCCCCCc1ccc(CC2CCCC2=O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCc1ccc(CC2CCCC2(N)C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
2-(4-Octylbenzyl)cyclopentanone (5) 3.20 g (11.8 mmol), sodium cyanide 1.15 g (23.5 mmol) and ammonium chloride 1.25 g (23.5 mmol) were added to 20 mL of ammonium hydroxide. The mixture was stirred vigorously for 12 hours at room temperature, then poured into a separating funnel and extracted twice with 10 mL of methylene chloride. The organic layers were combined, dried and then concentrated to give a crude yellow oil (3.30 g, ˜100%). The crude product is used for next step without further purification. (See: J. Med. Chem., 1986, 29, 1988-1995).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.Br[CH:33]([CH2:41][CH2:42]Br)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:37]([O:36][C:34]([CH:33]1[CH2:41][CH2:42][N:1]1[C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCN1[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 9 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (300 mg, 0.69 mmol) in DMF (3 mL) were added t-butyl 2,4-dibromobutyrate (322 μL, 1.5 mmol) and DIPEA (297 μL), 1.7 mmol). The reaction mixture was stirred at 60° C. for 9 h. The reaction mixture was then diluted with EtOAc and washed with 1M Na2CO3, water (×4) and brine. The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 116 mg of 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidine-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH2:8].[Mg].[CH3:10][C:11]([CH3:13])=[O:12].C1C[O:17][CH2:16]C1>>[CH3:10][C:11]1([CH3:13])[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[CH2:8])[CH2:1][C:16](=[O:17])[O:12]1
Reactant: C=C1CCCCC1=C
Reactant: CC(C)=O
Reactant: C1CCOC1
Agent: [Mg]
Product: C=C1CCCCC12CC(=O)OC2(C)C
Temperature: -78 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
In a typical reaction 1,2-dimethylenecyclohexane (0.239 g, 2.21 mmol) was added via a disposable syringe to the highly reactive magnesium (3.53 mmol) in THF (20 mL). After being stiffed at room temperature for 4 hours, the reaction mixture was allowed to stand until the solution became transparent (approximately 2 hours). The yellowish gold THF solution of the complex was then separated from the excess magnesium by cannulating the solution to another flask under argon. The THF solution of newly formed magnesium complex of 1,2-dimethylenecyclohexane was cooled to -78° C. using a dry ice/acetone bath, and acetone (0.122 g, 2.10 mmol) was added via a disposable syringe. The mixture was stirred at -78° C. for 10 minutes, then gradually warmed to 0° C. Carbon dioxide was then bubbled through the reaction mixture for 10 minutes at 0° C., and another 10 minutes at room temperature. An aqueous solution of 1.5 N HCl (10 mL) was added at 0° C. The reaction mixture was slightly heated at 40° C. for 1 hour. After cooling to room temperature, the mixture was extracted with diethyl ether (3×20 mL). The combined organic phases were washed with saturated aqueous NaHCO3 (2×20 mL) and brine (20 mL) and dried over anhydrous MgSO4. Removal of solvents and flash column chromatography gave 4,4-dimethyl-6-methylene-3-oxaspiro[4.5]decan-2-one (0.279 g) in 68% yield. The following scheme illustrates this route for spiro γ-lactone synthesis. ##STR35##
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([O:11][CH2:12][CH:13]1[O:15][CH2:14]1)(=[O:10])[C:7]([CH3:9])=[CH2:8]>C(OCC1OCCC1)(=O)C(C)=C>[C:6]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: CNCCO
Agent: C=C(C)C(=O)OCC1CCCO1
Product: C=C(C)C(=O)OCC(O)CN(C)CCO

Procedure:
10.0 g (133.1 mmol) of 2-(methylamino)ethanol and 85 g of tetrahydrofurfuryl methacrylate were weighed into a 250 ml three-neck flask with magnetic stirrer bar, thermometer and reflux condenser. At room temperature, 19.5 g (137.1 mmol) of glycidyl methacrylate were slowly added dropwise while stirring constantly. In the course of this, slight exothermicity was observed, but the temperature never exceeded 70° C. After stirring at 70° C. for 6 hours, it was possible to detect only small traces of 2-(methylamino)ethanol by means of a gas chromatograph. This approx. 25% product solution in tetrahydrofurfuryl methacrylate was transferred into a glass bottle and used in the model formulations without further workup.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[N:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:13]([CH2:31][C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
A mixture of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 10 min. After addition of 1-(bromomethyl)naphthalene (1.511 g, 6.83 mmol), the mixture was warmed to 80° C. and stirred for 3 h at this temperature. The resulting mixture was cooled to rt and poured over ice. The precipitate formed was collected by filtration and air dried (2.4 g total). The crude material was purified on silica gel (ISCO, 0-5% MeOH in DCM) to give methyl 6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate (1.48 g, 3.15 mmol, 69.2% yield). A portion of this material (138 mg) was purified by reverse phase-HPLC (25 to 95% AcCN in water, plus 0.1% TFA) to give the desired product (93.4 mg, 0.195 mmol, 4.28% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, J=8.34 Hz, 1H), 8.01 (d, J=7.33 Hz, 1H), 7.85 (d, J=8.08 Hz, 1H), 7.60-7.73 (m, 3H), 7.39 (d, J=2.27 Hz, 1H), 7.31 (t, J=7.83 Hz, 1H), 6.24 (br. s., 1H), 6.22 (s, 2H), 3.95 (s, 3H), 3.64-3.73 (m, 4H), 3.06-3.19 (m, 4H). MS (ES+) m/e 470 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH:2]([CH3:4])[CH3:3].C(=O)(O)[O-:23].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH2:1]([C:5]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20]([CH3:21])=[O:23])[N:15]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CSc1nccc(-c2c(CC(C)C)nn3ccccc23)n1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cc1nn2ccccc2c1-c1ccnc(S(C)=O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
To a cold (0° C.) solution of 2-isobutyl-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (890 mg, 2.98 mmol) in dichloromethane (25 mL) was added sodium bicarbonate solid (500 mg), and m-chloroperbenzoic acid (734 mg, ˜70% pure, 2.98 mmol). The mixture was stirred at 0° C. for 20 minutes and then quenched by the addition of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The biphasic mixture was allowed to warm to room temperature and stirred vigorously for 15 minutes. The layers were separated and the organic layer washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration in vacuo provided 2-isobutyl-3-[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (930 mg, 99%) as a yellow solid. 1H NMR (CDCl3) δ 8.73 (d, 1H), 8.63 (d, 1H), 8.47 (d, 1H), 7.48 (d, 1H), 7.43 (t, 1H), 6.94 (t, 1H), 3.00 (d, 2H), 2.99 (s, 3H), 2.16 (m, 1H), 1.01 (d, 6H); MS m/z 315 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:12][C:11](=[O:13])[CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[O:23])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[O:23]=[C:9]1[CH:8]([CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:12][C:11]([O:13][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:10]1[C:14]1[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)CC(CC3CCOCC3)C2=O)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(CC3CCOCC3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a solution of 4-(tetrahydro-pyran-4-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (100 mg, 0.25 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added the pivaloyl chloride (91 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethyl-propionic acid 3-oxo-4-(tetrahydro-pyran-4-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester (102 mg).
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][CH2:5][C@H:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11].C(Cl)Cl.[Si:18](Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[CH3:12][C@@H:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:13])([O:1][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: C[Si](C)(C)Cl
Reactant: C[C@H](CCCC=O)CCCC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CCCC=O)CCCC(C)(C)O[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
3.10 g of (S)-9-hydroxy-5,9-dimethyl-decanal was dissolved in 60 ml of abs. CH2Cl2 and treated successively at 0° with 57 mg of DMAP, 7.0 ml of NEt3 and 3.1 ml of TMS-Cl. The reaction mixture was kept for 30 minutes at RT and then poured onto crushed ice, extracted twice with ether, washed twice with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=95/5) yielded 3.90 g of (S)-5,9-dimethyl-9-trimethylsilanyloxy-decanal as colorless oil, 98.6% pure according to GC.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]1[C:15]([C:35]2[CH:36]=[N:37][C:38](F)=[CH:39][CH:40]=2)=[CH:16][C:17]2[C:18]3[N:26]([CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:25](=[O:33])[N:24]([CH3:34])[C:19]=3[CH:20]=[N:21][C:22]=2[CH:23]=1>C1COCC1>[F:13][C:14]1[C:15]([C:35]2[CH:36]=[N:37][C:38]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:39][CH:40]=2)=[CH:16][C:17]2[C:18]3[N:26]([CH:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[C:25](=[O:33])[N:24]([CH3:34])[C:19]=3[CH:20]=[N:21][C:22]=2[CH:23]=1
Reactant: OCCCN1CCCCC1
Reactant: Cn1c(=O)n(C2CCOCC2)c2c3cc(-c4ccc(F)nc4)c(F)cc3ncc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(C2CCOCC2)c2c3cc(-c4ccc(OCCCN5CCCCC5)nc4)c(F)cc3ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
3-(Piperidin-1-yl)propan-1-ol (0.053 mL, 0.35 mmol) was added slowly to a slurry of sodium hydride (31.5 mg, 0.79 mmol) in THF (7 mL) and the solution stirred at ambient temperature for 30 minutes. 7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one (125 mg, 0.32 mmol) in THF (3 mL) was added to the reaction mixture via syringe over a period of 1 minute and the reaction stirred for 24 h. The reaction was quenched with water then extracted into DCM, the organic phase separated and concentrated in vacuo. The crude product was purified by FCC, elation gradient 0 to 10% 1M methanolic ammonia in DCM, and the resultant oil triturated with Et2O to afford the desired material as a white solid (92 mg, 56%). NMR Spectrum: 1H NMR (500 MHz, CDCl3) δ 1.38-1.52 (2H, m), 1.61 (4H, p), 1.92 (2H, dd), 2.03 (2H, dt), 2.43 (4H, s), 2.47-2.58 (2H, m), 2.94 (2H, d), 3.53-3.63 (5H, m), 4.22 (2H, dd), 4.42 (2H, t), 5.01 (1H, s), 6.89 (1H, dd), 7.85-7.96 (2H, m), 8.26 (1H, s), 8.44 (1H, s), 8.71 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=520.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:16])=[C:5]([CH3:15])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:17][C:18](=O)[CH2:19][C:20](=[O:22])[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:16][C:4]1[S:3][C:2]2=[N:1][C:18]([CH3:17])=[C:19]([C:20](=[O:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[C:5]=1[CH3:15]
Reactant: Cc1sc(N)c(C(=O)c2ccccc2)c1C
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc(C)c(C)c2c1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a stirred solution of 70 mg (0.30 mmol) (2-Amino-4,5-dimethyl-thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.02 ml (0.30 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 10 mg (11%) 1-(2,3,6-trimethyl-4-phenyl-thieno[2,3-b]pyridine-5-yl)-ethanone as an orange solid. ES-MS m/e (%): 296 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:16]([O:23][NH:24][CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][N:24]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCNOCc1ccccc1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Product: CCCNc1nc(NCCC)nc(N(CC)OCc2ccccc2)n1
Yield: 38 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and O-benzyl-N-ethyl-hydroxylamine (LXVII) were reacted as described in Example 13 to afford O-benzyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII, 38% yield). 400 MHz 1H NMR (DMSO-d6, ppm) 7.51-7.45 (2H, m), 7.40-7.30 (3H, s), 6.97-6.85 (1H, m), 6.79-6.67 (1H, m), 4.97-4.87 (1H, m), 3.72-3.53 (2H, m), 3.23-3.11 (4H, m), 1.56-1.43 (4H, m), 1.13-1.00 (3H, m), 0.89-0.80 (6H, m). ESI-MS (m/z): 345 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([C:14](=[O:18])[CH2:15][NH:16][CH3:17])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>CCOCC.O.CN(C)C=O>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH2:23]([N:16]([CH2:15][C:14]([N:12]1[C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[S:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:18])[CH3:17])[CH:24]=[CH2:25]
Reactant: CNCC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Reactant: C=CCBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C)CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2-(4-chlorophenyl)-4-(N-methylaminoacetyl)-3,4-dihydro-2H-1,4-benzothiazine (1.80 g), allyl bromide (0.52 ml), potassium carbonate (2.25 g) and dimethylformamide (20 ml) is stirred at room temperature for 3.5 hours. The reaction mixture is poured into water, and the mixture is extracted with ethyl acetate. After the solvent is distilled off, the residue is purified by silica gel column chromatography (solvent, chloroform:methanol=40:1). The caramel thus obtained is dissolved in ether and thereto is added 1.1 equivalent of oxalic acid. The resulting precipitate is washed with ether and dried to give 4-(N-allyl-N-methylaminoacetyl)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine oxalate as powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:14])([F:15])[F:16])[C:7]([O:9][CH2:22][CH3:23])=[O:8])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1

Procedure:
3-Nitro-4-(trifluoromethyl)benzoic acid (10 g, 43 mmol) was taken up in 100 ml of ethanol and sulfuric acid (11 ml) was added to the mixture. The reaction was heated to reflux for 12 hours. The volatiles were removed in vacuo. The residue obtained was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with an aqueous solution of saturated sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate and the volatiles removed in vacuo to give ethyl 3-nitro-4-(trifluoromethyl)benzoate a clear yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[C:30]=2[CH3:36])[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:31]1[C:30]([CH3:36])=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:37])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:16])([F:15])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)c1C

Procedure:
The title compound was prepared from (2-{3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M127) (0.27 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (100 mg, 48%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][CH:10]=1.[C:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].CO>N1C=CC=CC=1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:23]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1
Reactant: OCCC1=CC=Nc2ccccc2S1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a mixture of 2-(2-hydroxyethyl)-1,5-benzothiazepine as prepared in Example 2 (3 g, 14.4 mM) in pyridine (30 ml) was slowly added N-acetylsulfanilyl chloride (6.7 g, 28.7 mM). The resulting mixture was stirred at room temperature for 16 hours and the excess pyridine was removed under reduced pressure. The residual semi-solid was diluted with H2O (80 ml) and extracted with CH2Cl2 (2×80 ml). The combined methylene chloride extracts were dried (MgSO4), filtered and evaporated in vacuo to give a crude oil. Flash column chromatography (EM silica gel 60; 2% MeOH in CH2Cl2) gave the desired product as a white solid (2.9 g, 50%). m/z (MH+)407
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C:3]#[C:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1.O>O1CCCC1>[CH2:1]([O:6][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:2][C:3]#[C:4][CH3:5]
Reactant: CC#CCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-pentyn-1-ol (750 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu]I.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.O1CCCC1>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=[CH:4][C:5]=2[O:12][C:9]2([CH2:11][CH2:10]2)[CH2:8]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC2(CC2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC2(CC2)Oc2ccc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and using 6-bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 36, 0.44 g, 1.65 mmol), triethyl amine (4 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.95 g, 0.5 mmol), trimethylsilyl acetylene (1.62 g, 16.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.4 g, 0.56 mmol), the title compound was obtained as a brown oil (0.4 g, 86%).