Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C)C=O.S(Cl)(Cl)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>ClCCl.O1CCCC1>[CH2:20]([N:22]([CH2:23][CH3:24])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([F:1])[CH:3]=1)[CH3:21]
Reactant: O=C(O)c1ccnc(F)c1
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a stirred suspension of compound 27 (6.00 g, 42.5 mmol) in anhydrous dichloromethane (200 mL) were successively added, under argon, anhydrous N,N-dimethylformamide (2 mL) and thionyl chloride (12.4 mL, 0.17 mol). The mixture was refluxed for 3 h. After cooling to room temperature, the solvent was evaporated under reduce pressure and the residue was dissolved in anhydrous toluene (40 mL). The solvent was evaporated under vacuum and the residue was dissolved in anhydrous tetrahydrofuran (40 mL). A solution of diethylamine (8.79 mL, 85.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, at 0° C. The mixture was then stirred at room temperature for 12 h. The solvent was evaporated under reduce pressure and the residue was dissolved in water (80 mL) before addition of a 5% aqueous sodium carbonate solution (10 mL). The mixture was extracted with dichloromethane (4×80 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (Al2O3, AcOEt) to give compound 86 (5.66 g, 28.8 mmol) as a yellow liquid. Yield 68%; Rf (Al2O3, AcOEt) 0.78; IR (CCl4) ν 1298, 1401, 1433, 1562, 1612, 1647, 2936, 2978 cm−1: 1H NMR (200 MHz, CDCl3) δ 1.00 (t, 3H, J=7.1 Hz), 1.12 (t, 3H, J=7.1 Hz), 3.09 (q, 2H, J=7.1 Hz), 3.42 (q, 2H, J=7.1 Hz), 6.80 (m, 1H), 7.05 (ddd, 1H, 5JH-F=1.9 Hz, J=1.3, 5.1 Hz), 8.15 (d, 1H, J=5.1 Hz); MS m/z 196 (M+, 22), 195 (26), 124(100), 96 (36), 76 (11), 69 (12).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:5]([S:12][CH2:13][CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COC(=O)[C@H](N)[C@H](SCC)C1C=CC=CC=1.C(N(CC)CC)C.FC1C=CC(C2C=CC(S(Cl)(=O)=O)=CC=2)=CC=1>C(Cl)Cl>[CH2:13]([S:12][C@H:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C@@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:3]([OH:32])=[O:2])[CH3:14]
Reactant: CCS[C@H](c1ccccc1)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)OC
Agent: CCS[C@H](c1ccccc1)[C@@H](N)C(=O)OC
Agent: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS[C@H](c1ccccc1)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S,3R)-3-Ethylsulfanyl-2-(4′-fluoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid methyl ester. To a solution of (2S,3R)-2-amino-3-ethylsulfanyl-3-phenyl-propionic acid methyl ester 4a (49 mg, 0.20 mmol) in methylene chloride (2.0 mL) is added triethylamine (0.060 mL, 0.43 mmol) and 4′-fluoro-4-biphenylsulfonyl chloride (66 mg, 0.24 mmol). This mixture is stirred under argon overnight at room temperature. The reaction is diluted with methylene chloride and washed with 1.0 N aq. HCl. The aqueous layer is extracted with methylene chloride. The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, 20% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([OH:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(O)c23)c1
Reactant: OC1CCCCC1
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCCCC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 1, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-hydroxyquinazoline (0.53 g) was reacted with cyclohexanol to give 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxyquinazoline (0.25 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.3-1.4 (m, 1H), 1.4-1.55 (m, 2H), 1.55-1.65 (m, 1H), 1.7-1.85 (m, 4H), 2.15 (m, 2H), 3.82 (s, 3H), 4.95 (m, 1H), 5.4 (s, 2H), 7.0 (d, 1H), 7.05 (m, 1H), 7.2 (s, 1H), 7.4-7.65 (m, 7M, 8.9 (s, 1H); Mass Spectrum: M+H+ 490 and 492.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]([C:16]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][O:17]1)([CH3:15])[CH3:14]>CN(C)C=O>[CH3:14][C:13]([CH3:15])([C:16]([CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([OH:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:12]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(CCCOc2ccccc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)(CCCOc1ccccc1)Cn1cncn1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
5.6 g (0.082 mol) of 1,2,4-triazole are added to a suspension of 11.3 g (0.082 mol) of potassium carbonate in 50 ml of dimethylformamide. 8.8 g (0.038 mol) of 2-(1,1-dimethyl-ethyl)-2-(3-phenoxypropyl)-oxirane are then added dropwise to the mixture, and the mixture is heated at 130° to 140° C. for 12 hours. After cooling to room temperature, the reaction mixture is filtered. The filtrate is concentrated under reduced pressure and the residue which remains is dissolved in methylene chloride. The organic phase is washed three times with water and, after drying, is concentrated. The residue is recrystallized from n-hexane. 8.1 g (70.3% of theory) of 2,2-dimethyl-6-phenoxy-3-(1,2,4-triazol-1-yl-methyl)-hexan-3-ol of melting point 106° C. are obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][C:17]1[CH:22]=[N:21][C:20]([CH3:23])=[C:19]2[O:24]C(C)(C)[O:26][CH2:27][C:18]=12.[ClH:30]>C(O)C>[ClH:1].[ClH:30].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][C:17]1[C:18]([CH2:27][OH:26])=[C:19]([OH:24])[C:20]([CH3:23])=[N:21][CH:22]=1
Reactant: Cc1ncc(CON2CCNC2=Nc2c(Cl)cccc2Cl)c2c1OC(C)(C)OC2
Agent: Cl
Solvent: CCO
Product: Cc1ncc(CON2CCNC2=Nc2c(Cl)cccc2Cl)c(CO)c1O
Reaction time: 48 h

Procedure:
3.7 g. of 5-[{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}methyl]-2,2,8-trimethyl-4H-m-dioxino[4,5-c]pyridine are dissolved in 50 ml. of ethanol, 50 ml. of 3 N hydrochloric acid are added at room temperature and the mixture is left to stand for two days. The solution is evaporated and the residue is recrystallized from methanol/acetonitrile, whereupon 5-[{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}methyl]-3-hydroxy-2-methyl-4-pyridinemethanol dihydrochloride, m.p. 216°-218°, is obtained.
Reaction SMILES: [CH3:1][O:2][P:3]([C@@H:6]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:7])(=O)[OH:4].C(Cl)(=O)C(C)(C)C.[OH:26][C@@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][CH3:31])=[O:29].NCCCCC(O)C(O)=O>O1CCCC1.C(N(CC)CC)C>[CH2:12]([O:11][C:9]([NH:8][C@H:6]([P:3]([O:2][CH3:1])([O:26][C@@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][CH3:31])=[O:29])=[O:4])[CH3:7])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H](O)CCCCNC(=O)OC(C)(C)C
Reactant: COP(=O)(O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: NCCCCC(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)OP(=O)(OC)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
(R)-1-(benzyloxycarbonylamino)ethylphophonic acid monomethyl ester (40.7 mg) described in Biochemistry, 6294(1989) was dissolved in tetrahydrofuran (1 ml), and pivaloyl chloride (71.8 mg) and triethylamine (90.4 mg) were added. The mixture was stirred at room temperature for 30 minutes, then added with a tetrahydrofuran (1 ml) solution of methyl (S)-2-hydroxy-6-(tert-butoxycarbonylamino)hexanoate (38.9 mg), which is obtainable from 6-amino-2-hydroxyhexanoic acid described in Chem. Pharm. Bull., 621(1976) by a conventional method, and stirred at room temperature overnight. The organic substances were extracted with ethyl acetate and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel thin-layer chromatography to obtain methyl (S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(methoxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoate (9.7 mg, 13%). This compound was subjected to the measurement of molecular weight and then used in the following reaction.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:11][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Reactant: Nc1ccc(CCO)cc1
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Temperature: 150 °C
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-4,6-dimethyl-3-nitropyridine (step 2, 1.3 g, 7.0 mmol) and 4-aminophenylethyl alcohol (1.4 g, 10.2 mmol) was placed in a sealed tube and heated at 150° C. for 3 h. The reaction mixture was cooled and purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 1.6 g (80%) of the title compound as orange solids: 1H-NMR (CDCl3) δ 9.55 (1H, br.s), 7.57 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 6.52 (1H, s), 3.84 (2H, t, J=6.4 Hz), 2.85 (2H, t, J=6.4 Hz), 2.54 (3H, s), 2.42 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[C:11]([CH2:13][O:14]C3C=CC(C)=CC=3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:32]O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[C:11]([C:13](=[O:14])[CH3:32])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2cn(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(Cl)cc3)n2)cc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1

Procedure:
A suspension of ethyl [2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl] carboxylate (Example 159) (929 mg, 2.29 mmol) in 16 ml of methanol and 16 ml of 1N aqueous sodium hydroxide was stirred at reflux for one hour. After cooling, the mixture was concentrated, water was added, and the resulting mixture was acidified with acetic acid. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Acetic acid was removed by azeotropic distillation with toluene to give the title compound, 520 mg, as a white crystalline solid: mp (DSC) 121° C. Anal. Calc'd. for C17H13ClN2O4S.H2O (MW 394.83): C, 51.71; H, 3.32; N, 7.10. Found: C, 51.89; H, 3.29; N, 6.97.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])(C)(C)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:16][C:14]([CH:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[C:6]([OH:5])=[O:7])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCC(=O)N1C(=O)O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A suspension containing (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (10.00 g, 0.044 mol, 1.0 equivalent), benzyl bromide (7.88 g, 0.046 mol, 1.05 equivalents), and potassium carbonate (15.20 g, 0.11 mol, 2.5 equivalents) in DMF (200 ml) was allowed to stir at 65° C. overnight. The reaction was allowed to cool to room temperature and the mixture was filtered through Celite. The solid was rinsed with ethyl acetate (100 ml) and the resulting filtrate was partitioned between ethyl acetate and saturated brine solution. The organic layer was washed with saturated brine (3×100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude, colorless oil was chromatographed on silica to afford 5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester, 1-tert-butyl ester as a colorless oil (8.20 g, 0.026 mol, 59% yield). Analysis H1 NMR (400 Hz CDCl3): 7.36 (5H, broad s), 5.20 (2H, d), 4.64 (1H, dd), 2.44-1.96 (4H, m), 1.41 (9H, s). MS (LC-MS): Calculated for C17H21NO5 319.14, found 320.19 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([C@@H:10]([CH:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[C:11](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:12])=[N+]=[N-]>C1COCC1>[NH2:7][C@@H:10]([CH:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:11][OH:12]
Reactant: CCCCC(CCCC)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC(CCCC)[C@H](N)CO
Temperature: 36 °C
Reaction time: 2 h

Procedure:
To a slurry of LAH (1.219 g, 32.13 mmol) in THF (60 mL) was added (4R)-3-[(2S)-2-azido-3-butylheptanoyl]-4-benzyl-1,3-oxazolidin-2-one (3.6 g, 9.37 mmol) dropwise at 0° C. over 20 min. The reaction was heated to 36° C. for 18 h. The reaction slurry (brown) was cooled to 0° C. and the reaction was quenched with H2O (15 mL) and washed with 1N NaOH (30 mL) and H2O (15 mL). It was let stir for 2 h to obtain an off-white slurry. The slurry was filtered and the mother liquor was further dried over MgSO4, filtered, and concentrated in vacuo to obtain (2S)-2-amino-3-butyl-1-heptanol as a crude yellow oil (1.93 g, 73.75%). Mass Spectrum (+ESI): 188 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1C=C(C#CC2CC3(CCN(C(OC(C)(C)C)=O)C3)ON=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[CH2:15][CH2:25]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Product: CN(C)C(=O)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 95 but replacing Compound 22d for Compound 27c. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 3:7 to 0:1) giving pale yellow solid of the title compound. Yield: 66.2%.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])(=O)=O>C(Cl)Cl>[Cl:16][CH:8]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH2:10][C:11]#[N:12]
Reactant: N#CCCCSc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: N#CCCC(Cl)Sc1ccccc1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a solution of 50 g (0.28 mole) of 4-phenylthiobutyronitrile in 200 ml of methylene chloride is added 40.5 g (0.3 mole) of sulfuryl chloride dropwise during a period of six hours. Stirring is continued overnight. Solvent and excess sulfuryl chloride is then evaporated under vacuum to give 61 g of a crude product. This material is used in the next experiment without further purification.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([C:16]([O:18]C)=[O:17])[NH:13]2)=[CH:9][CH:8]=1.Cl>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([C:16]([OH:18])=[O:17])[NH:13]2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(O)c1cc2ccc(O)cc2[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
146 ml (146 mmol) of 1M boron tribromide in methylene chloride are added slowly, at 0° C., to a solution of 10 g (48.73 mmol) of methyl 6-methoxy-2-indole carboxylate in 500 ml of methylene chloride. The reaction medium is stirred at 0° C. for 1 h and at ambient temperature for 2 h. The reaction medium is cooled to 0° C. and 100 ml (100 mmol) of 1M boron tribromide in methylene chloride are added slowly, at 0° C. The reaction is stirred at 0° C. for 1 h and at ambient temperature for 16 h. The reaction medium is then cooled to approximately 0° C. and a 1N hydrochloric acid solution (247 ml) is added slowly with stirring. The mixture obtained is filtered over sintered glass. The organic phase (methylene chloride) of the filtrate is separated and the aqueous phase is then acidified with 5N hydrochloric acid and extracted with ethyl acetate. The organic phase (ethyl acetate) is dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure, to give 6.39 g of 6-hydroxy-1H-indole-2-carboxylic acid in the form of a brown solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccncc4)c3)cnc2n1
Yield: 58 %

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 4-fluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 1 to give 2-[3-(4-fluoro-3-(pyridin-4-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid (240 mg, 58%). Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 1.56 (6H, s), 7.77 (1H, dd, J 11 and 9), 7.85 (1H, d, J 7), 7.94-7.98 (1H, m), 8.12-8.15 (3H, m), 8.55 (1H, s), 8.95 (2H, d, J 6), 9.38 (1H, d, J 7); m/z (ES+) 349 (M++H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4][CH:3]1[OH:13].C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl>[CH:7]1([N:5]2[CH2:4][C@@H:3]([OH:13])[C@H:2]([NH:1][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)[CH2:6]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CN(C2CCCCC2)CC1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@@H]1CN(C2CCCCC2)C[C@H]1O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.84 g (0.01 mole) of 4-amino-1-cyclohexyl-3-pyrrolidinol in 50 ml of methylene chloride was cooled to 5° C. and 2 g of powdered, anhydrous potassium carbonate was added. The mixture was stirred while a solution of 1.86 g of p-nitrobenzoyl chloride in 20 ml of methylene chloride was added dropwise. The mixture was then allowed to warm to room temperature and was stirred for one hour. The slurry was filtered, and the residue, after solvent evaporation, crystallized immediately and was recrystallized from acetone. Yield was 3.0 g (90%), m.p. 155.5°-157.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>[Br-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.O.C(O)C.C(Cl)Cl>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC1=NCCn2c1ccc2-c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Br-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC1=NCCn2c1ccc2-c1ccc(OCc2ccccc2)cc1
Yield: 19 %

Procedure:
3,4-Dihydro-6-(4-hydroxyphenyl)-1-methylpyrrolo[1,2-a]pyrazine (5.0 g), 100 ml of methylene chloride, 5.3 ml of benzyl bromide and 0.8 g of benzyltributylammonium bromide was added in succession to a solution of 1.8 g of sodium hydroxide in 100 ml of water under argon. The mixture was boiled under reflux overnight and stirred and subsequently cooled. After the addition of 100 ml of methylene chloride and 100 ml of water the phases were separated and the aqueous phase was extracted twice with 100 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 10.3 g of brown oil, was chromatographed on 500 g of silica gel with methylene chloride/methanol mixtures (99:1 to 9:1) as the eluent. The crude product, 4.9 g of brown, amorphous material, was dissolved in a 10-fold amount of hot ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. The product, 2.2 g of yellow crystals, was recrystallized from a 20-fold amount of ethanol. There were obtained 1.8 g (19%) of 6-[p-(benzyloxy)phenyl]-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 165°-168° C. (dec.).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[CH:18]=1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)Nc1cnc(-c2cccnc2)cn1
Temperature: 150 °C
Yield: 36.2 %

Procedure:
Methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 200 mg, 0.694 mmol) was dissolved in N,N-dimethylformamide (4.5 mL) in a microwave vial and 3-pyridyltributylstannane (0.833 mmol, 0.29 mL) and tetrakis(triphenylphosphine) palladium(0) (0.069 mmol) were added. Argon was bubbling through the mixture for ca. 5 min and the vial was heated under microwave irradiations for 10 min at 150° C. The solvent was evaporated and the residue was diluted with acetonitrile, washed with cyclohexane (2×) and evaporated. The product was purified by flash chromatography (RF-machine, AcOEt/cyclohexane: 1/1→1/0) to give methyl 4-oxo-4-[[5-(3-pyridyl)pyrazin-2-yl]amino]butanoate (compound A39) (0.072 g, 36% Yield). LCMS (Method F): RT 0.53 min, 287 (M+H+).