Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=[CH:5]2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=[CH:5]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)Nc1cccc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
A mixture of N-(6-hydroxy-naphthalen-1-yl)-acetamide (5.72 grams, 28 mmol), benzyl bromide (4.78 grams, 28 mmol) and potassium carbonate (4.14 grams, 30 mmol) in DMF (50 mL) was stirred at room temperature for 20 hours. The reaction was diluted with ether (250 mL) and was washed with saturated aqueous NaHCO3 (2×30 mL) and saturated aqueous NaCl (2×30 mL), dried MgSO4) and concentrated in vacuo. The crude residue was azeotroped with heptane (2×100 mL) to give a colored solid. The solid was filtered and washed with hexanes to give 5.0 grams of a colorless product. 1NMR (250 MHz, CDCl3): d 7.25 (m, 11 H), 4.4 (s, 2 H), 2.16 (s, 3 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].[OH-].[Na+]>C(OCC)C.C(O)C>[NH2:12][C@@H:13]([CH2:14][S:15][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[C:16]([OH:18])=[O:17]
Reactant: COc1ccc(CO)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(CSC[C@H](N)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solvent mixture of diethylether (400 ml) and conc. hydrochloric acid (400 ml) was added in drops 4-methoxybenzylalcohol (280 g, 1780 mmol) dissolved in diethylether (400 ml) for 2 h, and the mixture was stirred for 1 h. The organic layer was separated, and added to a solution prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 ml) in ethanol (1890 ml). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was cooled to 0° C., and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered, and dried to give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid (250 g, 1035 mmol, Yield: 64%).
Reaction SMILES: [C:1]([N:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br-].[C:21]([O:24][C@@H:25]1[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:30]([O:36][C:37](=[O:39])[CH3:38])[C@@H:29]([C:40]([O:42][CH3:43])=[O:41])[O:28][C@@H:26]1[OH:27])(=[O:23])[CH3:22]>C(#N)C.[Ag]=O>[C:1]([N:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C@:26]1([O:28][C@H:29]([C:40]([O:42][CH3:43])=[O:41])[C@@H:30]([O:36][C:37](=[O:39])[CH3:38])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:25]1[O:24][C:21](=[O:23])[CH3:22])[OH:27])[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)c1cc([N+](=O)[O-])ccc1O
Agent: O=[Ag]
Agent: [Br-]
Solvent: CC#N
Product: COC(=O)[C@H]1O[C@](O)(c2ccc([N+](=O)[O-])cc2N(C)C(=O)OC(C)(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Silver oxide (0.23 g, 0.992 mmol) and 2-(N-BOC,N-methylamino)-4-nitrophenol (3) were added to a solution of methyl 2,3,4-tri-O-acetyl-a-D-glucuronate bromide (4) (126 mg, 0.317 mmol) in acetonitrile (5 ml). The reaction mixture was stirred at room temperature for 1 hour, filtered through Celite and concentrated in vacuo. The product was chromatographed on silica gel (eluent dichloromethane/methanol 97.5/2.5). Yield 165 mg (89%).
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Br.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[C:18]([OH:24])=[N:19][CH:20]=[C:21]([CH3:23])[N:22]=1>CC(O)C.CCOCC>[CH3:23][C:21]1[N:22]2[CH:1]=[CH:2][N:16]=[C:17]2[C:18]([OH:24])=[N:19][CH:20]=1
Reactant: Cc1cnc(O)c(N)n1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cnc(O)c2nccn12
Reaction time: 8 h
Yield: 35.4 %

Procedure:
Bromoacetaldehyde diethyl acetal (12.2 mL, 81.4 mmol) and a solution of 48% HBr (0.94 mL) are heated at reflux for 1.5 hours, then poured into a suspension of NaHCO3 (1.92 g) in propan-2-ol (31.3 mL). The resulting solid is filtered off and 3-amino-5-methyl-pyrazin-2-ol (3.13 g, 25.0 mmol) is added. The solution is refluxed for 2 hours then left to stand overnight and the solid formed washed with IPA and ether. The solid is added to a solution of DCM (60 mL) and NaHCO3 sat. (30 mL), the two layers are separated and the aqueous phase is extracted with DCM. The combined organic layers are dried with MgSO4 anh., filtered and evaporated to give a brown solid product. The aqueous phase is again extracted with a CHCl3/IPA 9/1, dried with MgSO4 anh., filtered and concentrated to give a brown solid product. The IPA and Ether used previously for washing the solid are combined, evaporated and submitted to the same process described previously to give a brown solid quite impurified from the DCM extraction and a brown solid with the CHCl3/IPA of similar purity to the one obtained beforehand. The products resulting from the first DCM extraction and the two CHCl3/IPA extraction are combined and washed with cold MeOH to give 5-Methyl-imidazo[1,2-a]pyrazin-8-ol as a pale yellow solid (1.32 g) that is submitted into the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH2:27][CH3:28])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH2:27][CH3:28])[C:24]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CCC(C(=O)NCc1ccc(C(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 371 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.91 (m, 1H), 2.19 (m, 1H), 4.38 (m, 2H), 7.38 (d, J 8.5, 2H), 7.64 (d, J 8.5, 2H), 7.96 (t, J 7.8, 1H), 8.20 (d, J 7.1, 1H), 8.39 (d, J 8.1, 1H), 8.72 (s, 1H), 9.02 (t, J 6.8, 1H), 9.81 (s, 1H), 10.12 (br s, 1H); Anal. Calcd for C21H19F3N2O: C, 67.73; H, 5.14; N, 7.52. Found: C, 67.46; H, 4.90; N, 7.90.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:6].[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C1COCC1.O>[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][N:9]([S:14](=[O:16])(=[O:15])[N:13]([CH3:18])[CH3:12])[N:8]=1)=[O:6]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccn(S(=O)(=O)N(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Sodium hydride (1.57 g, 41.03 mmol) was added to a solution of 1H-pyrazole-3-carboxylic acid methyl ester (3.45 g, 27.36 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then dimethylsulfamoyl chloride (4.41 mL, 41.03 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water and the product extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield 1-dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methyl ester (4.8 g, 75% yield) as a colourless oil.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+].C(#N)C>Cl[Pd-2](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.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[CH:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:17]([F:16])[CH:18]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=Cc1ccc(B(O)O)cc1F
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(C=O)c(F)c3)n2n1
Temperature: 160 °C
Yield: 69.9 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (300 mg, 1.1 mmol), 3-fluoro-4-formylphenylboronic acid (230 mg, 1.3 mmol), dichloro-bis(triphenylphosphino) palladium (II) (40 mg, 0.055 mmol), potassium carbonate (230 mg, 1.7 mmol), acetonitrile (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 1000 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzaldehyde (240 mg, 68%) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.39 (s, 1H), 8.28 (dd, J=12.9, 1.5 Hz, 1H), 7.91-8.01 (m, 3H), 7.73 (d, J=9.6 Hz, 1H), 6.54 (d, J=9.6 Hz, 1H), 3.48 (td, J=7.2, 5.8 Hz, 2H), 1.69-1.80 (m, 2H), 1.46-1.57 (m, 2H), 1.03 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 313.2 [(M+H)+, calcd for C17H18FN4O 313.1].
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.O>[Si:18]([O:6][CH2:7][C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1N[C@@H](CO)CO1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1COC(=O)N1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
Imidazole (1.74 g, 25.6 mmol, 2.0 equiv) was added to a solution of (S)-4-(hydroxymethyl)oxazolidin-2-one (1.5 g, 12.8 mmol) and tert-butylchlorodiphenylsilane (3.95 mL, 15.4 mmol, 1.2 equiv) in DCM (43 mL) at room temperature. A white precipitate formed. The solution was stirred at room temperature for 16 hours and then diluted with water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 65%) provided (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (3.55 g, sticky colorless oil) in 78% yield. 1H NMR (400 MHz, CDCl3) δ 7.64 (m, 4H), 7.50-7.38 (m, 6H), 5.31 (m, 1H), 4.44 (t, J=8.7 Hz, 1H), 4.15 (m, 1H), 4.00 (m, 1H), 3.65 (d, J=5.5 Hz, 2H), 1.07 (s, 9H). MS m/z 356.1 (M+H)+; Rt-1.00 min.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10](OS(C(F)(F)F)(=O)=O)[C:11]2=[O:21])[CH2:3]1.C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[C@H](O)C2=O)C1.FC(F)(F)S(O)(=O)=O.[Cl-:60].[Li+]>CN(C=O)C.O>[CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@@H:10]([Cl:60])[C:11]2=[O:21])[CH2:3]1
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](OS(=O)(=O)C(F)(F)F)C[C@@H]32)C1
Reactant: [Cl-]
Agent: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](O)C[C@@H]32)C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Cl)C[C@@H]32)C1
Reaction time: 21 h
Yield: 96.5 %

Procedure:
800 mg of 3β-methyl-16β-trifluoromethylsulfonyloxy-5-androsten-17-one, prepared from 3β-methyl-16β-hydroxy-5-androsten-17-one and trifluoromethane sulfonic acid was placed in 16 ml DMF and was treated with 100 mg Lithium chloride at room temperature. The reaction mixture was stirred magnetically for 21 hours. Water is then added and the resulting crystalline ppt was collected. The crystals were washed with additional water and were then dissolved in CH2Cl2, filtered through anhydrous sodium sulfate and the solvent was evaporated off. The resulting crystals were recrystallized from CH3OH, yielding 570 mg of final product. m.p. 159°-165° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Na+].[I-:17]>CC(=O)CC.CCOCC>[I:17][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)C1(CCCCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1(CCCCI)CC1
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.6 g, 45.7 mmol) in 2-butanone (50 mL) was added NaI (8.23 g, 54.5 mmol). The reaction mixture was stirred under reflux overnight, diluted with Et2O (100 mL), washed with a mixture of H2O (100 mL) and aqueous Na2S2O4 (0.5 M, 10 mL) and brine (50 mL). The organic phase was dried (Na2SO4) and evaporate in vacuo to give tert-butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate (14.8 g, 94% pure by GC, 94%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=3.18 (t, J=6.9 Hz, 2H), 1.76 (quintet, J=7.1 Hz, 2H), 1.62-1.45 (m, 4H), 1.43 (s, 9H), 1.12 (dd, J=6.7 Hz, 3.8 Hz, 2H), 0.60 (dd, J=6.6 Hz, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=173.9, 80.0, 33.8, 33.3, 28.9, 28.2 (3×), 24.2, 15.5 (2×), 7.2. HRMS calcd for C12H21IO2 (M+): 324.0587, found: 324.0587.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:6](=[O:20])[N:5]([C:21]2[CH2:22][O:23][C:24](=[O:27])[C:25]=2[CH3:26])[CH2:4]1.OC1C2(CCN(C(OC(C)(C)C)=O)CC2)C(=O)N(C2COC(=O)C=2C)C1.IC.[Al]>C(#N)C.[Ag]=O>[CH3:1][O:2][CH:3]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:6](=[O:20])[N:5]([C:21]2[CH2:22][O:23][C:24](=[O:27])[C:25]=2[CH3:26])[CH2:4]1
Reactant: COC1CN(C2=C(C)C(=O)OC2)C(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Agent: O=[Ag]
Agent: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: [Al]
Solvent: CC#N
Solvent: CI
Product: COC1CN(C2=C(C)C(=O)OC2)C(=O)C12CCNCC2
Temperature: 58 °C
Reaction time: 15 h

Procedure:
tert-Butyl 4-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (Enantiomer A and Enantiomer B): To a solution of tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (100 mg, 0.273 mmol) in acetonitrile (1 mL) was added iodomethane (171 μL, 2.73 mmol) and silver oxide (69.6 mg, 0.300 mmol). The vial was sealed, wrapped with aluminum foil, and stirred at 58° C. for 15 h. The reaction mixture was filtered through CELITE®, concentrated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to afford the title compound as a mixture of enantiomers. LC/MS: [(M+1)]+=381. The racemic mixture was separated by SFC-HPLC, using the following conditions: chiralcel AD-H, 2×25 cm, 15% MeOH, 60 mL/min to afford faster eluting Enantiomer A: LC/MS: [(M+1)]+=381; and slower eluting Enantiomer B: LC/MS: [(M+1)]+=381
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23].O>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH3:23])[CH2:11][CH2:10]1
Reactant: Fc1cccc(C2CCNCC2)c1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1CCC(c2cccc(F)c2F)CC1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
To a solution of 4-(2,3-difluorophenyl)piperidine (0.41 g, 2.08 mmol) in acetonitrile (4 ml), was added potassium carbonate (0.57 g, 4.16 mmol) and 1-iodoethane (0.163 ml, 2.12 mmol) and the mixture was heated to 120° C. in a sealed tube under microwave radiation for 1200 s. Water (50 ml) was added and the mixture was extracted with ethylacetate (3×40 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.31 g). MS m/z (reL. intensity, 70 eV) 225 (M+, 20), 224 (14), 211 (13), 210 (bp), 127 (8).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([Br:3])[CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1

Procedure:
25.43 g (0.64 mol) of a 60% strength by weight sodium hydride dispersion in mineral oil are added in portions at room temperature to 100 g (0.58 mol) of commercially available 3-bromophenol in 600 ml of dimethylformamide, the mixture is stirred for a further half an hour, and 66.5 ml (0.58 mol) of commercially available benzyl chloride are added dropwise. The mixture is stirred at room temperature for 1 hour, 11 of water is added, and the solid which precipitates is filtered off, washed with water and recrystallized from 600 ml of isopropanol, giving 108 g of 3-benzyloxybromobenzene. ##STR12##
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[C:4]([OH:12])=[N:3][CH:2]=1.F[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C.C(O)(CC)(C)C>>[F:21][C:20]([F:23])([F:22])[C:19]1[C:14]([N:9]2[CH2:10][CH2:11][C:5]3[C:4]([OH:12])=[N:3][CH:2]=[N:1][C:6]=3[CH2:7][CH2:8]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1ncccc1C(F)(F)F
Reactant: Oc1ncnc2c1CCNCC2
Solvent: CCC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ncnc2c1CCN(c1ncccc1C(F)(F)F)CC2
Yield: 33.9 %

Procedure:
A solution of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (353 mg, 1.76 mmol), 2-fluoro-3-trifluoromethyl-pyridine (582 mg, 3.53 mmol), iPr2NEt (0.9 mL, 5.28 mmol), and t-amyl alcohol (5 mL) was heated in a microwave at 180° C. for 5 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give the title compound (185 mg, 34%), which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[C:17]1(=[O:27])[N:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: Cc1cc(CCCCCCCBr)cc(C)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cc(CCCCCCCN2C(=O)c3ccccc3C2=O)cc(C)n1
Temperature: 125 °C

Procedure:
A mixture of compound (14) (3.54 g, 12.5 mmol), potassium phthalimide (2.54 g, 13.7 mmol) and dimethylformamide (25 ml) was heated at 125° C. for 6 h. DMF was evaporated and the residue coevaporated twice with n-butanol and twice with toluene. The dry crude product was purified by flash chromatography. Yield: 3.54 g (81%) viscous oil Rf=0.46 (System A) H1NMR (60 MHz, CDCl3): 7.60-7.95 (m, 4H), 6.76 (s, 2H), 3.68 (t, 2H, J=7 Hz), 2.48 (s, 6H), 2.36-2.60 (m, 2H), 1.23-1.77 (m, 10H)
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C([O-])([O-])=O.[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+].O1CCOCC1>[CH2:21]([O:20][C:18]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Glutamine (1.84 g, 12.62 mmol) was dissolved in 1 N NaOH (12.58 mL) and the solution was cooled to 0° C. and stirred for 30 min, when Na2CO3 (3.30 g) and benzyl chloroformate (4.38 mL) in dioxane (19.30 mL) were gradually added, in equal portions. Stirring continued at 0° C. for 1 h, then the solution was allowed to stir overnight at room temperature and was extracted with ethyl ether (2×20 mL). The aqueous solution was acidified with 2N HCl to pH 5 and extracted with ethyl acetate (3×50 mL), which was dried over sodium sulfate, and evaporated to give an oil which crystallized overnight. Recrystallization of the crude product gave a white crystalline material (3.07 g, 87%); FABMS 319.1 (M+K), 281.1 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][C:11](O)([CH3:13])C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(CC(O)[CH2:26][O:27]CC)C1C=CC=CC=1)C.C(N(CC(O)COC)C1C=CC=CC=1)C>>[CH2:1]([N:3]([CH2:10][CH2:11][CH2:13][CH2:26][OH:27])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCN(CC(C)(C)O)c1ccccc1
Reactant: CCOCC(O)CN(CC)c1ccccc1
Agent: CCN(CC(O)COC)c1ccccc1
Product: CCN(CCCCO)c1ccccc1

Procedure:
N-ethyl-N-(2-hydroxyisobutyl)aniline 3N-ethyl-N-(2-hydroxy-3-methoxypropyl)aniline N-ethyl-N-(2-hydroxy-3 -ethoxypropyl)aniline
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[IH:11].CS[C:14]1[NH:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>C(#N)C>[IH:11].[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][NH:23][C:14]=1[NH:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC1=Nc2ccccc2CN1
Reactant: NCCOc1ccccc1
Agent: I
Solvent: CC#N
Product: c1ccc(OCCNC2=Nc3ccccc3CN2)cc1
Temperature: 80 °C
Yield: 64.8 %

Procedure:
2-Phenoxyethylamine (21 mg, 0.16 mmol) was added to a solution of 2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (50 mg, 0.16 mmol, prepared as under example 1 [c]) in acetonitrile (1 ml), and the mixture was heated overnight (80° C.) in a screw-capped vial. The solvent was then evaporated and the mixture was suspended in diethyl ether. The title compound (41 mg, 95%) was obtained from this mixture by filtration.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[C:10]([NH2:29])=[CH:11][C:12]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31]>C1COCC1>[CH:1]1([CH2:7][N:8]2[C:9]3[CH:14]=[C:13]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:12]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:11][C:10]=3[NH:29][C:30]2=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(c2cc(NCC3CCCCC3)c(N)cc2Nc2ccccc2)CC1
Solvent: C1CCOC1
Product: CN1CCN(c2cc3c(cc2Nc2ccccc2)[nH]c(=O)n3CC2CCCCC2)CC1
Yield: 66.7 %

Procedure:
A solution of N1-cyclohexylmethyl-5-(4-methyl-piperazin-1-yl)-N4-phenyl-benzene-1,2,4-triamine (0.10 g, 0.25 mmol) and 1,1′-carbonyldiimidazole (0.12 g, 0.76 mmol) in THF (3 mL) was stirred at room temperature for 17.5 h. The solvent was evaporated and the resulting residue was chromatographed (FCC, 5% MeOH/CH2Cl2) to give the title compound as a white solid (0.07 g, 61.6% yield). M+, 420.