Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][N:8]1[C:20](=[O:31])[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:23].CO>O.O1CCCC1>[C:16]([O:15][C:13]([NH:12][C@H:10]1[CH2:9][N:8]([C:20](=[O:31])[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH3:23])[C@H:7]([C:6]([OH:32])=[O:5])[CH2:11]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(=O)N1C[C@H](NC(=O)OC(C)(C)C)C[C@H]1C(=O)O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 92.4 %

Procedure:
A solution of lithium hydroxide monohydrate (35 mg) in water (2 mL) was added to a solution of trans-4-(N-tert-butoxycarbonylamino)-1-(N-tert-butoxycarbonyl-N-methylglycyl)-L-proline methyl ester (E, 289 mg) in tetrahydrofuran (6 mL)-methanol (2 mL) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 15 hr, the solvents were removed in vacuo. The residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (258 mg) as a colorless oil. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 9H), 1.38 (s, 9H), 2.03-2.30 (m, 1.5H), 2.62-2.94 (m, 3.5H), 3.20-4.02 (m, 4H), 4.07-4.42 (m, 1H), 4.46-4.62 (m 1H), 5.24-5.62 (m, 0.5H), 5.70-5.82 (m, 0.5H), and 8.60 (br s, 1H).
Reaction SMILES: C([N:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH:29][C:30]3C=C[C:33](OC)=[CH:32][CH:31]=3)=[CH:28][C:23]=2[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:48]1([CH2:54][CH2:55]Br)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[CH2:57]1[CH2:61][O:60][CH2:59][CH2:58]1>O>[CH3:59][O:60][C:61]1[CH:57]=[CH:58][C:31]([CH2:30][N:29]([CH2:55][CH2:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:27]2[CH:26]=[CH:25][C:24]3[NH:20][CH:21]=[N:22][C:23]=3[CH:28]=2)=[CH:32][CH:33]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(Nc2ccc3c(c2)ncn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Product: COc1ccc(CN(CCc2ccccc2)c2ccc3[nH]cnc3c2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
N1-Trityl-N-(4-methoxyphenyl)benzimidazol-5-amine (990 mg; 2 mmol; 1 eq.) was dissolved in THF (5 ml), cooled to 0° C. and treated with lithiumbis(trimethylsilyl)amide 1M in THF (2.4 ml; 2.4 mmol; 1.2 eq.). Phenylethylbromide (0.330 ml; 2.4 mmol; 2.4 eq.) was added and the mixture was stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH (5 ml) and treated with TFA (1 ml). After heating to reflux for 1 h the mixture was poured into saturated NaHCO3-solution and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.058 g (8.1%); MS m/z: 358.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 2.85 (t, 2H, 3J=7.9 Hz); 3.57 (t, 2H, 3J=7.9 Hz); 3.69 (s, 3H); 4.44 (s, 2H); 6.77-6.79 (m, 2H); 6.83-6.86 (m, 2H); 7.14-7.16 (m, 2H); 7.18-7.21 (m, 1H); 7.23-7.25 (m, 2H); 7.28-7.30 (m, 2H); 7.38-7.39 (m, 1H); 7.92 (s, 1H); 11.92 (br s, 1H); HPLC (METHOD [A]): rt 16.74 min (96.3%)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].CC(C)([O-])C.[K+].[C:21]([S:29][CH2:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(SC[C@@H](C)C(O)=O)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([C:32](=[O:33])[C@H:31]([CH3:35])[CH2:30][S:29][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]1=[O:14]
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Agent: CC(C)(C)[O-]
Agent: C[C@H](CSC(=O)c1ccccc1)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Temperature: -30 °C
Yield: 73.9 %

Procedure:
3.0 g of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 20 ml of tetrahydrofuran. 1.7 g of potassium tert.-butoxide are added to the solution under cooling at about -30° C. and stirring, and the mixture is further stirred at the same temperature for 10 minutes. A solution of (2S)-3-benzoylthio-2-methylpropionyl chloride (prepared by heating the mixture of 3.4 g of (2S)-3-benzoylthio-2-methylpropionic acid and 10 ml of thionyl chloride at 50°-60° C. for 2 hours and then evaporating excess thionyl chloride under reduced pressure) in 10 ml of tetrahydrofuran is added dropwise to the mixture under ice-cooling and stirring. Then, said mixture is further stirred at room temperature overnight. After the reaction, the mixture is condensed under reduced pressure, and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and an aquous sodium bicarbonate solution, dried and then evaporated to remove solvent. The oily residue thus obtained is purified by silica gel column chromatography (Solvent, toluene-ethyl acetate(20:1)). 4.5 g of tert-butyl (4S)-1-methyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 73.9% M.p. 128° C.
Reaction SMILES: C(=O)C.[OH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13](=[O:15])[CH3:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13](=[O:15])[CH3:14])[CH3:22]
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: CCOC(=O)CBr
Agent: CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OC)ccc1C(C)=O
Temperature: 90 °C

Procedure:
Into a Round bottom flask was added Ethanone, 1-(2-hydroxy-4-methoxyphenyl)-ethanone (40.01 g, 0.241 mol), ethyl bromoacetate (28.17 mL, 0.2540 mol), potassium carbonate (69.6 g, 0.504 mol), and N,N-Dimethylformamide (200 mL, 2 mol). The reaction was heated at 90° C. for 6 h before cooling to RT overnight. The reaction was poured into ice/water and extracted with ethyl ether (twice). The combined ether extracts were dried, filtered and concentrated. The resulting solid was triturated in hexanes, filtered and dried. The product was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17]C(C)(C)C)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][N:4]=[CH:3]1.[C:22](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:22])[CH2:11][CH2:10]2)=[O:8])=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2cncn2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A homogeneous yellow solution of tert-butyl 4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate (10.1 g, 34.4 mmol; Intermediate 58: step b) in DCM (172 mL) was treated with TFA (26.4 mL, 344 mmol) and stirred at room temperature for 2.5 hours. The reaction was concentrated from toluene (2×100 mL), and the resulting clear light amber residue was taken up in DCM (344 mL) and TEA (23.9 mL, 172 mmol). Acetic anhydride (3.91 mL, 41.3 mmol) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under high vacuum and the residue was purified by FCC using 95:5 DCM/MeOH with 2% TEA as eluent. The combined fractions were concentrated, dissolved in DCM (200 mL), and washed with water (2×200 mL) to remove TEA. The organic layer was dried (Na2SO4), filtered, and concentrated, and the residue was triturated with MTBE (75 mL) at reflux for 15 minutes and then allowed to cool to room temperature. The mixture was filtered and the off-white filter cake was washed with MTBE (2×3 mL) to provide the title compound as an off-white fine powder.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1>CC(C)=O>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[NH:14][C:2]([NH:3][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:1]
Reactant: N#C[S-]
Reactant: Nc1cnccn1
Reactant: O=C(Cl)c1ccccc1
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cnccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ammonium thiocyanate (17.8 g, 0.234 mol) in dry acetone (200 ml) at 0° C. under nitrogen is added benzoyl chloride (30 g, 0.213 mol) slowly over a period of 15 min. The reaction mixture is stirred at room temperature for 30min and filtered. To the filtrate is added 2-amino pyrazine (16.2 g, 0.17 mol) dropwise and stirred for 3 h at room temperature. The solvent is removed under vacuum and the residue is diluted with water. The solid precipitated is filtered and dried to afford N-[(pyrazin-2-ylamino)carbonothioyl]benzamide as a solid (33 g; 76%). TLC—Chloroform/methanol (9/1): Rf−0.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: Nc1nccc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: Nc1nccc(Oc2ccccc2-c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)n1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 4-(2-bromophenoxy)pyrimidin-2-amine. MS (ESI): mass calcd. for C23H16FN5O, 397.13; m/z found, 398.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.55-8.45 (m, 1H), 8.18-8.08 (m, 1H), 8.07 (d, J=5.7, 1H), 7.55-7.28 (m, 8H), 7.22 (dd, J=8.0, 1.4, 1H), 6.08 (d, J=5.7, 1H), 4.95 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(-c3ccccc3OC)cccc2c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 8-bromoquinoline-3-carboxylate (2.01 g, 10 mmol), prepared as described in Patent WO 2001047891, 2-methoxyphenylboronic acid (2.79 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:31][N:32]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)cn1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 61.1, 181 mg, 0.5 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (133 mg, 0.6 mmol), PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol), K2CO3 (138 mg, 1 mmol), water (2 mL) and dioxane (10 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 90° C. for 24 h. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the product which was recrystallized from hot EtOAc to afford the title compound as a beige powder. UPLC-MS (Condition 2) tR 0.89 min, m/z=376.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 6.98 (s, 2H) 7.41 (d, J=8.99 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.50-8.55 (m, 1H) 8.76 (s, 2H) 9.00 (d, J=1.95 Hz, 1H) 9.06 (d, J=1.96 Hz, 1H) 10.62 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([OH:15])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC(C)n1nc(OCc2ccccc2)c(C=O)c1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyloxy-5-bromo-4-formyl-1-isopropyl-1H-pyrazole (0.7 g) was dissolved in tetrahydrofuran (5 mL), and a solution of 4-methoxyphenyl magnesium bromide in tetrahydrofuran (0.5 mL/L, 4.3 mL) was added to the stirred solution. The mixture was stirred at room temperature for 1 hour. A small amount of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was purified by column chromatography on aminopropylated silica gel (eluent:tetrahydrofuran) to give the title compound (0.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([S:13][CH3:14])[CH:5]=1)[CH3:2].O.NN>CCO.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([S:13][CH3:14])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(SC)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOc1ccc(N)c(SC)c1
Temperature: 90 °C

Procedure:
To a solution of 4-ethoxy-2-methylsulfanyl-1-nitro-benzene (1.0 g, 5.4 mmol) in absolute EtOH (25 mL) at rt was added 40 mg of Pd/C (Aldrich, 10 wt. % on active carbon), followed by slow addition of hydrazine hydrate (0.5 mL). The resulting reaction mixture was refluxed at 90° C. for 3 h. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford 4-ethoxy-2-methylsulfanyl-phenyl amine as a pale yellow oil: MS (ESI) 184 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3]1.[CH3:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:22]=[C:21]([CH3:31])[N:20]=1>>[CH3:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:6]4[CH2:5][CH2:4][O:3][C:2]4=[O:1])=[CH:17][CH:16]=3)=[O:13])[CH2:27][CH2:26]2)=[CH:23][CH:22]=[C:21]([CH3:31])[N:20]=1
Reactant: CCOC(=O)c1ccc(N2CCOC2=O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)n1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)n1
Yield: 15.8 %

Procedure:
By reaction and treatment in the same manner as in Example 34 and using ethyl 4-(2-oxooxazolidin-3-yl)benzoate (353 mg) described in Preparation Example 12 and 1-(2,6-dimethylpyridin-3-yl)piperazine (287 mg) described in Preparation Example 153, the title compound (90.2 mg) was obtained.
Reaction SMILES: I[CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:11]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:19]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(C)CI
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CC(C)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Mix ethyl 4-iodo-3-methylbutyrate (4.61 g, 0.18 mol), dibenzylamine (35.5 g, 0.18 mol), potassium carbonate (24.9 g, 0.18 mol) and ethanol (114 mL dried over 4A molecular sieves). Reflux for 24 hours then stir at room temperature for 48 hours. Add methylene chloride (100 mL) and filter. Evaporate the filtrate to a residue and purify by silica gel chromatography to give the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C(O)(=O)C>[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: OC1CCNC1
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)CCN1CCC(O)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Acetic acid (31 μL), pyrrolidin-3-ol (3.47 g, 39.8 mmol) and 3,3-dimethyl-butyraldehyde (3.99 g, 39.8 mmol) were dissolved in THF (100 mL) and stirred at room temperature for 40 min. The solution was then cooled to 0° C. on an ice bath. To the cold solution sodium triacetoxyborohydride (10.98 g, 51.8 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was basified with a 5.0 M solution of NaOH and extracted with CH2Cl2 (3×150 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford 1-(3,3-dimethyl-butyl)-pyrrolidin-3-ol in (6.34 g, 92.5%), which was used without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:29](=[O:30])[NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol) in dry tetrahydrofuran (5 ml) was added to a stirred suspension of sodium hydride (0.024 g. 1 mmol) in dry tetrahydrofuran (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then 3-bromo-phenyl isocyanate (0.237 g., 1.2 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20:80) as eluant to give 2j; yield: 0.25 g. (57.2%), m.p. 117° C., C23H21BrN2O2; 1H NMR δ ppm (CDCl3): 2.00-2.20 (m, 2H), 2.81 (t, 2H), 3.36 (t, 2H), 4.46 (s, 21), 6.46 (d, 1H), 6.79-6.81 (m, 2H), 7.19-7.31 (m, 8H), 7.69 (s, 1H); IR vmax (KBr) (cm−1): 621, 670, 759, 885, 930, 1021, 1117, 1215, 1348, 1420, 1505, 1594, 1743, 2369, 2855, 2928, 3021, 3428; MS: m/z=437 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][OH:19].[C:20]1(O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Oc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Reaction time: 72 h

Procedure:
To a mixture of Example 1B (10.87 g), 1-naphthol (5.77 g) and triphenylphosphine (10.5 g) in THF (100 mL) was added di-tert-butyl azodicarboxylate (9.21 g). The mixture was stirred for 3 days, concentrated, redissolved in dichloromethane, washed with water and brine and dried (MgSO4), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 0-10% ethyl acetate in hexanes. The product was recrystallized from hexanes.
Reaction SMILES: [Br:1][CH:2]([CH2:17][CH2:18][O:19][CH3:20])[C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=O.[NH:21]1[CH2:25][CH2:24][NH:23][C:22]1=[S:26].C(O)C>C(O)(=O)C>[BrH:1].[Cl:16][C:11]1[CH:10]=[C:9]([C:5]2([C:3]3[N:23]4[CH2:24][CH2:25][N:21]=[C:22]4[S:26][C:2]=3[CH2:17][CH2:18][O:19][CH3:20])[CH2:8][CH2:7][CH2:6]2)[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: COCCC(Br)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: S=C1NCCN1
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: COCCC1=C(C2(c3ccc(Cl)c(Cl)c3)CCC2)N2CCN=C2S1
Temperature: 25 °C

Procedure:
A mixture of the crude 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutan-1-one described above, imidazolidine-2-thione (0.68 g), ethanol (15 ml) and acetic acid (10 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The solvents were removed in vacua and the residue was dried by azeotropic distillation with ethanol (50 ml) followed by ethyl acetate (20 ml). The solid remaining after removal of residual solvent in vacuo was crystallised from a 2:1 mixture of ethanol and ethyl acetate. The resulting product was collected by filtration, washed with ethanol (10 ml) and dried in vacuo at 60°0 C. to give 3-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(2-methoxyethyl)-5,6-dihydroimidazo[2,1-b]-thiazole hydrobromide as colourless prisms (1.39 g), m.p. 227-229° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[C:12]([CH2:13][CH3:14])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)C.[CH:17](NC)(C)C>>[CH2:13]([C:12]1[C:4]([N:3]([CH:15]([CH3:16])[CH3:17])[CH3:1])=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])[CH3:14]
Reactant: CCc1cc(C(=O)O)cnc1N(CC)CC
Reactant: CNC(C)C
Product: CCc1cc(C(=O)O)cnc1N(C)C(C)C

Procedure:
The title compound is prepared in analogy to 6-diethylamino-5-ethyl-nicotinic acid using isopropyl-methylamine; LC-MS: tR=0.64 min, [M+1]+=223.14.