Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH3:16]>CO>[CH3:1][O:2][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH3:16]
Reactant: CCc1ccc([N+](=O)[O-])cc1CCl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc([N+](=O)[O-])cc1COC
Temperature: 3 °C

Procedure:
Sodium methoxide is added portionwise to a solution of 150.0 g of α-chloro-2-ethyl-5-nitrotoluene in 1.15 l. of methanol maintained between 18° C. and 30° C. The mixture is refluxed for 2 hours, cooled to 3° C., and filtered. The filtrate is concentrated under vacuum and the resulting slurry shaken with saturated aqueous sodium chloride and methylene chloride. The methylene chloride layer is washed, filtered through sodium sulfate, and stirred over magnesium sulfate. The filtered solution is concentrated under vacuum to yield 133.89 g. of a dark brown liquid. The crude product is fractionated by vacuum distillation to yield a yellow liquid with boiling point 113° C. to 115° C. at 0.35 mm Hg which solidifies to light yellow prisms with mp 21.5° C. to 23.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Br:22]Br>CN(C=O)C>[Br:22][C:5]1[S:1][C:2]([C:6]2([C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=3)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[N:3][CH:4]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C2(c3nccs3)CCOCC2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(c3ncc(Br)s3)CCOCC2)cc1
Reaction time: 2 h

Procedure:
To the mixture of methyl 4-(4-(thiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate (570 mg, 1.88 mmol) in DMF (5 mL) was added a 1M solution of bromine in DMF (1.9 mL, 1.88 mmol). After 2 hours, additional 1M solution of bromine in DMF (1.9 mL, 1.88 mmol) was added. The reaction mixture was then concentrated to half its volume and poured into water (25 mL). The resulting solid was filtered and washed with water and dried to give methyl 4-(4-(5-bromothiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate. 1H NMR (400 MHz, dmso-d6): δ 7.99 (d, J=8.0 Hz, 2H); 7.58 (s, 1H); 7.41 (d, J=8.0 Hz, 2H); 3.87 (s, 3H); 3.91-3.84 (m, 2H); 3.73-3.68 (m, 2H); 2.63-2.59 (m, 2H); 2.41-2.37 (m, 2H); MS found for C16H16BrNO3S (m/z): 3840.3 [M++1].
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9]C(=O)C)[C:3]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[OH-].[Na+].C(O)(=O)/C=C/C(O)=O>CN(C)C=O.O.CO>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[C:3]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CC(=O)OCCN1CCN(C)C1=Nc1ccccc1N1CCOCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CN1CCN(CCO)C1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 4-((2-[1-methyl-3-(2-acetoxyethyl)-2-imidazolidinylideneamino]phenyl))morpholine (2.7 g) in dimethylformamide (10 ml) with sodium hydroxide (0.4 g) in water (10 ml) for one hour at 10° C. gave an oil which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give 4-((2-[1-methyl-3-(2-hydroxyethyl)-2-imidazolidinylideneamino]phenyl))morpholine (m.p. 129°-131° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].[CH3:31][O:32][CH2:33][C:34](O)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([NH:25][S:22]([C:20]1[S:21][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:28])[C:2]([CH3:1])([CH3:29])[CH3:30])=[C:7]([CH3:27])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:26])(=[O:24])=[O:23])=[O:35]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Reactant: COCC(=O)O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NC(=O)COC)s1
Yield: 84 %

Procedure:
Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide and methoxy-acetic acid give the title compound (84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1sccc1NC(=O)c1cccc(OC)c1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
To a solution of methyl-3-amino-2-thiophenecarboxylate (8.00 g, 50.9 mmol) in acetonitrile (100 mL) was added potassium carbonate (1.1 eq., 56.0 mmol, 7.73 g) followed by m-anisoyl chloride (1.05 eq., 53.4 mmol, 7.51 mL) and the mixture heated under reflux for 1 hour. A white precipitate forms. The mixture was cooled in ice-water, diluted with water (100 mL) and the white solid collected by filtration and dried to yield compound 1 (12.78 g). Upon standing, an additional quantity of product precipitated from the water-acetonitrile solution; this was collected in the same fashion. (Total yield: 14.08 g, 95%).
Reaction SMILES: CO.[CH2:3]([N:10]([CH2:29][CH2:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:11][CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>[Cl-].[Na+].O>[CH2:3]([N:10]([CH2:29][CH2:30][CH:31]([OH:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:11][CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCN(CCC(=O)c3ccccc3)Cc3ccccc3)cc2)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CCN(CCC(O)c3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 0 °C
Yield: 12.7 %

Procedure:
Add methanol (10 mL) to 6-(4-{2-[benzyl-(3-oxo-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide (0.1871 g, 0.3901 mmol) and cool to 0° C. Add sodium borohydride (0.0664 g, 1.756 mmol) and stir for 1.5 h at (0° C. under nitrogen. Pour the reaction into brine (50 mL) and extract with diethyl ether (3×50 mL). Dry the diethyl ether extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 100% ethyl acetate to yield 0.0239 g (13%) of 6-(4-{2-[benzyl-(3-hydroxy-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.07 minutes, Purity: 99.9%; mass spectrum (ion spray): m/z=482.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=4)[N:12](C(OC(C)(C)C)=O)[C:11]=3[C:10]2=[O:31])=[C:4]([F:32])[C:3]=1[O:33][C:34]1[CH:39]=[C:38]([C:40]#[N:41])[CH:37]=[C:36]([Cl:42])[CH:35]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:42][C:36]1[CH:37]=[C:38]([CH:39]=[C:34]([O:33][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([CH2:8][N:9]3[CH2:21][CH2:20][C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=5)[NH:12][C:11]=4[C:10]3=[O:31])[C:4]=2[F:32])[CH:35]=1)[C:40]#[N:41]
Reactant: COc1ccc2c(c1)c1c(n2C(=O)OC(C)(C)C)C(=O)N(Cc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c3c(c2c1)CCN(Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F)C3=O
Reaction time: 1 h
Yield: 78.4 %

Procedure:
1,1-Dimethylethyl 2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-6-(methyloxy)-1-oxo-1,2,3,4-tetrahydro-9H-β-carboline-9-carboxylate (0.03 g, 0.05 mmol), was dissolved in CH2Cl2 (1.0 mL) and TFA (1.0 mL) was added dropwise. The reaction mixture was stirred 1 h and the solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized with saturated NaHCO3 and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.02 g, 80%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.50 (br. s., 1H), 7.80 (s, 1H), 7.47-7.55 (m, 3H), 7.39 (t, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.86 (dd, 1H), 4.76 (s, 2H), 3.75 (s, 3H), 3.66 (t, 2H), 2.97 (t, 2H). MS: m/z 510.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.[CH:26]([NH2:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28].CS(O)(=O)=O>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:35][CH:26]([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])=[CH:4][CH:3]=1
Reactant: NC(C(F)(F)F)C(F)(F)F
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CON(C)S(=O)(=O)c1c(Cl)ccc(Nc2c(NC(C(F)(F)F)C(F)(F)F)c(=O)c2=O)c1O

Procedure:
6-Chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide (Intermediate A) (50 mg, 0.102 mmol) and 1,1,1,3,3,3-hexafluoroisopropylamine (34.0 mg, 0.203 mmol) were dissolved THF (1 ml). To the solution was added methanesulfonic acid (7 μl, 0.108 mmol) and the resultant mixture was heated at 50° C. overnight (˜18 hr). The solution was concentrated in vacuo and the residue was re-dissolved in DMSO (900 μl). The solution was transferred to a HPLC vial and purified using mass-directed prep system using 50-98% acetonitrile in water (0.1% TFA). The solvent was removed from the purified fraction in vacuo. The residue was re-dissolved in MeOH the solvent was removed in vacuo to afford the title compound as an orange solid;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[CH:34]2>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[CH:34]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 35.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (360 mg, 1.00 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (215 mg, 1.56 mmol) and 5-hydroxy-2-methylindole (162 mg, 1.10 mmol) in DMF (8.0 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluting with methanol (2.5 to 5%) in dichloromethane. The resulting solid was recrystallised from ethyl acetate, filtered and washed with diethyl ether to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (166 mg, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(C)n1c([C@H](C)N)nc2ccc(F)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C(C)C
Temperature: 100 °C
Yield: 27 %

Procedure:
(S)-1-(6-Fluoro-1-isopropyl-1H-benzoimidazol-2-yl)ethylamine (0.5 g, 2.26 mmol) was dissolved in n-butanol (5 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.54 g, 2.26 mmol) and DIPEA (2 mL, 11.3 mmol) added. The resultant dark red solution was heated to 100° C. overnight. The mixture was allowed to cool to RT and was concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-10% MeOH in DCM) to afford 379 as a pale red solid (207 mg, 27%). LCMS (Method K): RT 2.68 min [M+H]+ 340.1 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (1H, s), 8.15 (1H, s), 8.00-7.90 (1H, m), 7.64-7.55 (2H, m), 7.02 (1H, td, J=9.31, 2.40 Hz), 5.96-5.77 (1H, m), 4.98-4.85 (1H, m), 1.67 (3H, d, J=6.71 Hz), 1.57 (3H, d, J=6.91 Hz), 1.46 (3H, d, J=6.78 Hz)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH:10]([CH:16]=[N:17]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].ClC1C=CC=CN1C.CCN(CC)CC.Cl>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH:10]([C:16]#[N:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CC(C=NO)CN(Cc2ccccc2)C1
Agent: CN1C=CC=CC1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1CC(CO)CN(Cc2ccccc2)C1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To 1-benzyl-5-(hydroxymethyl)piperidine-3-carbaldehyde oxime (3.3 g, 13.30 mmol) in CH2Cl2 (15 mL) at 23° C. was added 2-chloro-1-methylpyridine iodide (3.73 g, 14.62 mmol) in one portion and the resulting mixture stirred at 23° C. for 10 min. Et3N was then added and the reaction mixture stirred for 3 hours (color changed from light yellow to light brown). The solution was neutralized with HCl (5%), to approximately pH 6 and the organic material was extracted with CH2Cl2 (3×25 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to afford 3.06 g (95% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.37 (5 H, m), 3.51-3.60 (4 H, m), 3.11 (1 H, ddd, J=11.0, 1.9, 1.8 Hz), 2.98 (1 H, d, J=7.6 Hz), 2.73-2.82 (1 H, m), 2.12-2.22 (2 H, m), 1.80-1.92 (2 H, m), 1.45 (1 H, br s), 1.27-1.38 (1 H, m). LCMS (+ESI, M+H+) m/z: 231.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:23][N:24](C)[CH:25]=[O:26]>>[CH3:23][NH:24][C:25](=[O:26])[NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrochloride (1.0 g) was suspended in dimethylformamide (30 ml) and triethylamine (1.2 ml) was added. The dark solution was filtered. Methyl isocyanate (0.53 ml) was added and the mixture was stirred for 17 hours at room temperature. The mixture was evaporated to dryness and the black residue washed with water; the insoluble material was collected by filtration and then reprecipitated from dimethylformamide solution with water. The precipitate was filtered off and the filtrate evaporated to dryness. The cream-coloured residue was collected to afford the title compound, m.p.>300° C.; C12H12N4O2Calculated: C 59.01; H 4.95; N 22.94: Found: C 59.09; H 4.94; N 22.90: νmax (liquid paraffin) 1675, 1642 cm-1 ; N.m.r. δ(DMSO-d6) 2.76 (d, 3H, CH3), 5.98 (q, 1H, --NHCH3), 7.91, 8.08 (2d, 2H, pyridine H's).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]#[N:20].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]=[O:30])=[C:24]([Cl:31])[CH:23]=1.CC(C1C=CC(Br)=CC=1Cl)=O>C1COCC1.O>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:1])[CH:29]([C:17]2[S:16][C:15]([C:19]#[N:20])=[C:14]([CH3:13])[CH:18]=2)[OH:30])=[C:24]([Cl:31])[CH:23]=1
Reactant: O=CCc1ccc(Br)cc1Cl
Reactant: [Li]CCCC
Reactant: Cc1ccsc1C#N
Agent: CC(=O)c1ccc(Br)cc1Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1cc(C(O)C(C)c2ccc(Br)cc2Cl)sc1C#N
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium (1.6M) in hexanes (0.18 ml) was added to a solution of diisopropylamine (0.212 ml) in THF (2 ml) at 0° C. The mixture was stirred for 5 min and then cooled to −78° C. 3-Methylthiophene-2-carbonitrile (184 mg, CAS Reg. No. 55406-13-8) was added at −78° C. and then stirred for 30 min. A solution of 2-(4-bromo-2-chlorophenyl)ethanone (248 mg, CAS Reg. No. 749932-89-6, prepared in analogy to Example 58, step 2, from 2-chloro-4-bromoacetophenone [CAS Reg. No. 252561-81-2]) in THF (1 ml) was added at −78° C. The mixture was stirred for 20 min, then water (0.2 ml) was added. The mixture was filtered over celite and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 100% EtOAc/heptane) to give the title compound (100 mg) as a colorless oil. MS (m/e)=370.0 [M+H+].
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][CH:6]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[CH3:7].O.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[CH3:5][CH:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][CH2:14][CH2:15][C:16](=[O:19])[NH:1][C:17]=2[CH:18]=1)[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Oc1ccc2c(c1)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)Oc1ccc2c(c1)NC(=O)CCC2
Yield: 14.4 %

Procedure:
900 mg of sodium azide are added at ambient temperature to a solution of 2.24 g of 7-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in 35 ml of trifluoroacetic acid. The reaction medium is refluxed for 3 hours and is then brought back to ambient temperature. The reaction medium is poured into 100 ml of water and the pH is adjusted to pH 7 by adding sodium carbonate. The mixture is extracted twice with 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel, elution being carried out with dichloromethane and then a dichloromethane/methanol (9/1) mixture, so as to obtain 346 mg of 8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of an orangey-coloured oil.
Reaction SMILES: [C:1]([C:9]1([OH:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22]O.OS(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][O:16][C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:18])=[O:17]
Reactant: O=C(O)C1CCCCC1(O)C(=O)c1ccccc1
Reactant: CC(C)CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)CCOC(=O)C1CCCCC1(O)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
10 g (0.04 mol) of 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid (of example 1), 7.05 mol 3-methyl-butan-1-ol and 0.5 g H2SO4 are dissolved in 200 ml CHCl3 and heated to reflux during 18 hours using a water separator to remove the water formed during the reaction. The reaction mixture is then cooled to room temperature, washed with sodium bicarbonate and water and dried over Mg2SO4. After distillation of the solvent, the crude reaction product is purified by flash chromatography (silica gel, eluant petroleum ether/ethyl acetate 1:1) to give 3 g 2-benzoyl-2-hydroxy-cyclohexanecarboxylic acid 3-methyl-butyl ester as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[O:36]([CH2:43][CH2:44]Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][CH2:44][CH2:43][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:4][CH:5]=2)[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]1[CH2:12][CH2:13]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Reactant: BrCCOc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCCOc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86 (eee)] with phenoxy-ethyl bromide there was obtained tert-butyl (1RS,2RS,3RS,5SR)-2-(naphthalen-2-ylmethoxy)-3-[4-(2-phenoxy-ethoxymethyl)-phenyl]-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless oil; MS: 611 (M+NH4)+.
Reaction SMILES: [C:1]1([C@@H:7]([N@:9]2[CH2:11][CH:10]2[CH2:12][OH:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C@@H:7]([N@:9]2[CH2:11][CH:10]2[CH:12]=[O:13])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](c1ccccc1)[N@]1CC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)[N@]1CC1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
A three neck, 250 mL round bottom flask was equipped with a low temperature thermometer and two (2) equalizing dropping funnels. One of these was connected to a nitrogen line and charged with a solution of ((R)-1-((S)-1-phenylethyl)aziridine-2-yl)methanol EBE 06046 (7.0 g, 39.5 mmol) in CH2Cl2 (75 mL), the other was charged with a solution of DMSO (9.25 g, 118.5 mmol) in CH2Cl2 (11 mL). To a solution of oxalyl chloride (7.5 g, 59.3 mmol) in CH2Cl2 (90 mL) under N2 at −78° C., the DMSO solution was added dropwise during 20 min and stirred for 20 min. EBE 06046 (7.0 g, 39.5 mmol) in CH2Cl2 (75 mL) was added dropwise over 50 min. then the dropping funnel was charged with DIEA (42.6 mL, 237 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred for 30 min at −45° C. The DIEA solution was added over 5 min with the reaction mixture at −78° C. and the reaction was allowed to warm to room temperature. The reaction mixture was washed with H2O (3×50 mL), dried over MgSO4, filtered, evaporated. The crude product obtained was purified by column chromatography on silica with a gradient of 0-20% [v/v] EtOAc in cyclohexane to give (R)-1-((S)-1-phenylethyl)aziridine-2-carbaldehyde EBE 06048 as a yellow oil (5.59 g, 81% yield).