Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N[NH:8][C:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH:10]=2)C=CC=CC=1.S(=O)(=O)(O)O.[OH-].[Na+].[C:23](O)(=O)[CH3:24]>>[C:11]1(=[O:15])[C:10]2[C:24]3[CH:23]=[CH:11][CH:10]=[CH:9][C:14]=3[NH:8][C:9]=2[CH2:14][CH2:13][NH:12]1
Reactant: CC(=O)O
Reactant: O=C1C=C(NNc2ccccc2)CCN1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCCc2[nH]c3ccccc3c21
Reaction time: 2 h

Procedure:
A solution of 5,6-dihydro-4-(2-phenylhydrazino)-2(1H)-pyridinone (8.0 g) in acetic acid (16 ml) was added over 30 min to concentrated sulphuric acid (16 ml) at 10°-20°. The reaction mixture was stirred for 2 h, then added over 10 min to 2N sodium hydroxide (150 ml) at 15°-25°. The solid product was filtered off, triturated with water (50 ml), then recrystallised from ethanol (20 ml) and dried in vacuo to give the title compound (3.79 g), m.p. 255°, t.l.c. (System B, 100:8:1) Rf 0.2.
Reaction SMILES: C[O:2][C:3](=[O:21])/[C:4](/[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([Cl:20])[CH:11]=1)=[N:5]/[O:6][CH:7]([CH3:9])[CH3:8].[OH-].[Li+]>CO.C(Cl)(Cl)Cl>[Cl:20][C:12]1[CH:11]=[C:10](/[C:4](=[N:5]\[O:6][CH:7]([CH3:9])[CH3:8])/[C:3]([OH:21])=[O:2])[CH:15]=[CH:14][C:13]=1[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: COC(=O)/C(=N/OC(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)O/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
This estimated 80% pure (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid methyl ester (0.52 g, <1.5 mmol) was dissolved in methanol (14 mL) and cooled to 0° C. An aqueous solution of lithium hydroxide (2.0 N, 1.86 mL, 3.72 mmol) was added dropwise. After stirring 1.25 h, the reaction mixture was diluted with chloroform (175 mL) and washed with 0.2 M aqueous potassium bisulfate solution (50 mL). The aqueous phase was extracted with chloroform (75 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid (506 mg, quant.) as a slightly yellow paste that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH2:28][CH3:29])[CH3:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCOCC1>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:16]1[N:15]=[C:14]2[NH:13][C:12](=[O:24])[N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH2:20][C:19]2=[CH:18][N:17]=1)[CH3:26]
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Reactant: CCN(CC)CCCCN
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Product: CCN(CC)CCCCNc1ncc2c(n1)NC(=O)N(c1cc(OC)cc(OC)c1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A suspension of 0.2261 g (0.65 mmol) of 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.103 g (0.71 mmol) of diethylaminobutylamine in 10 mL of dry dioxane was warmed to 60° C. and stirred overnight. To the reaction mixture was added 0.306 g (2.13 mmol) of diethylaminobutylamine and 0.1658 g (0.71 mmol) of camphorsulfonic acid. The reaction mixture was stirred for another 18 hours at 60° C. The reaction solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate. The ethyl acetate layer was washed with a saturated solution of sodium bicarbonate, then with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed down silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) to give 0.173 g (62%) of the title compound: mp 203-207° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][NH2:21].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:21]([CH2:20][CH2:19][CH2:18][OH:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: Cc1occc(=O)c1OCc1ccccc1
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with 3-hydroxypropylamine under substantially similar conditions to those described under Example 9 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one as white crystals, m.p. 111°-113° C.; νmax (nujol) 1630, 3150, 3350 cm-1, δ(d6DMSO) 1.8 (m, 2H), 2.4 (s, 3H), 3.35 (t, 2H), 4.33 (t, 2H), 7.3 (d, 1H), 8.2 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([SH:11])[NH:8][C:7]=2[CH:12]=1.[H-].[Na+].[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16]>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][S:11][C:9]1[NH:8][C:7]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:10]=1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1nc2ccc(OC)cc2[nH]1
Yield: 99.3 %

Procedure:
6-Methoxy-1H-benzoimidazole-2-thiol (10.00 g, 55.56 mmol) was dissolved in DMF (300 mL). NaH (2.44 g, 60 w/w % in mineral oil, 61.11 mmol) was added in small portions at room temperature. The resulted mixture was stirred for one h then bromo-acetic acid ethyl ester (10.21 g, 61.11 mmol) was added. After 12 h the mixture was evaporated and the resulted slurry was diluted with HCl (340 mL, 2N) and was stirred for a 0.5 h at room temperature then was filtered, washed with water and n-hexane respectively. The title compound (14.70 g, 99%) was isolated as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[CH:25]2[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=CCc1ccccc1
Reactant: Oc1cccc(CCNc2ccc(Cl)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1)CCN(c1ccc(Cl)cc1)C2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 3-{2-[(4-chlorophenyl)amino]ethyl}phenol (0.20 g, 0.8 mmol) and phenylacetaldehyde (0.194 g, 1.6 mmol) in CH2Cl2 (6 mL) was added trifluoroacetic acid (0.148 g, 1.6 mmol). After stirring at room temperature overnight, the reaction was quenched with saturated sodium bicarbonate and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.203 g, 72% yield): 1H NMR (CDCl3) 7.19-7.24 (m, 4H), 7.16 (m, 1H), 7.14 (m, 1H), 6.70 (m, 2H), 6.71 (m, 2H), 6.61 (m, 2H), 6.54 (dd, 1H), 4.77 (t, 1H), 3.58 (ddd, 1H), 3.47 (ddd, 1H), 3.17 (dd, 1H), 2.86-2.99 (m, 2H), 2.67 (m, 1H); ES−MS (m/z) 350 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O.[BH4-].[Na+].O>C(O)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[O:19][CH3:18])=[C:3]([CH:13]=1)[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11]
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(Cl)cc2C(O)c2ccccc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 2-amino-5-chloro-α-(2-chloro phenyl)benzyl alcohol (5.0 g) and 2,4-dimethoxy benzaldehyde (3.72 g) in acetic acid (50 ml) was added, under ice-cooling, sodium borohydride (0.94 g). The mixture was stirred for one hour at room temperature, which was poured into water (200 ml), followed by extraction with ethyl acetate (200 ml×2). The ethyl acetate layer was washed with 1N sodium hydroxide, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=5:1) to give 5-chloro-α-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzyl alcohol (7.5 g) as an oily product.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.C(O[C:14](=[O:29])[CH2:15][CH2:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:19][CH:18]=1)C.O>O1CCCC1>[CH2:22]([N:21]1[C:17]([CH2:16][CH2:15][C:14]([C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=2)([C:3]2[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=2)[OH:29])=[CH:18][N:19]=[CH:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CCOC(=O)CCc1cncn1Cc1ccccc1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(O)(CCc2cncn2Cc2ccccc2)c2cc(C)cc(C)c2)c1
Temperature: 25 °C

Procedure:
1,06 g of magnesium turnings are covered with 30 ml of dry tetrahydrofuran. To the mixture is then added dropwise a solution of 5-bromo-m-xylene (8,14 g) in 10 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 1-benzyl-5-imidazole propionic acid ethyl ester (5,0 g) in 40 ml of tetrahydrofuran at 60° C. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and to the solution is added conc. hydrochloric acid. The solution is cooled, some ether is added and the precipitate which contains the product as hydrochloride salt is removed by filtration, washed and dried. Yield 4,1 g. M.p. 120°-124° C.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.98 g (22.43 mmol) of tert-butyl 1-[3-(benzylamino)benzyl]cyclopropanecarboxylate were dissolved in 50 ml of ethanol and 50 ml of THF, and 0.48 g (0.45 mmol) of palladium (10% on carbon) were added. At RT, the mixture was stirred under an atmosphere of hydrogen at atmospheric pressure for 2 h. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.66 g (65.9% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[F:23][CH:24]([F:35])[O:25][C:26]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].O>CN(C)C=O>[F:23][CH:24]([F:35])[O:25][C:26]1[CH:33]=[C:32]([O:10][CH:7]([C:6]2[S:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][CH3:9])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(F)cc1OC(F)F
Reactant: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1ccc(C#N)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
To a solution of 1.7 g of 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in 4.7 mL of dimethylformamide at 5° C. was added 250 mg of a 55% suspension of sodium hydride in mineral oil. The reaction volume was completed with dimethylformamide to about 8.5 mL. The reaction mixture was stirred for 30 minutes at 5° C. 4.3 mL of the resulting mixture was slowly added to a solution of 450 mg of 2-difluoromethoxy-4-fluoro-benzonitrile in 2 mL of dimethylformamide at 5° C. The resulting mixture was stirred at 5° C. allowing the temperature to warm up to room temperature. It was then heated in a sealed tube to 60° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 50/ethyl acetate 50) to give 490 mg of 2-difluoromethoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:14]=4[N:15]=3)[C:6]=2[CH:23]=1.Cl[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>>[CH3:22][C:17]1([CH3:21])[CH2:16][C:14]2[N:15]=[C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][C:25]5[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)[S:12][C:13]=2[C:19](=[O:20])[CH2:18]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOc4ccc(N)cc43)nc2C1
Reactant: Cc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)CC(C)(C)C4)CCO3)nn1
Reaction time: 20 h
Yield: 26.6 %

Procedure:
A mixture of Example 12 (44 mg, 0.134 mmol), 3-chloro-6-methylpyridazine (15 mg, 0.116 mmol) and DIPEA (0.5 mL, 67.0 mmol) was heated to 180° C. under microwave irradiation for 2 h. A further portion of 3-chloro-6-methylpyridazine (15 mg, 0.116 mmol) was added and heating continued for a further 20 h. The solvent was removed in vacuo and the residue purified by prep HPLC to give the title compound (13 mg, 23%) as a yellow solid. δH (CDCl3) 1.15 (6H, s), 2.42 (2H, s), 2.58 (3H, s), 2.76 (2H, s), 4.13-4.18 (2H, m), 4.32-4.38 (2H, m), 6.93-7.20 (5H, m), 8.03 (1H, d, J 2.4 Hz). LCMS (ES+) 422 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.CCN(C(C)C)C(C)C>C(#N)C>[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: BrCc1ccccc1Br
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3Br)CC2)cc1

Procedure:
A mixture of EXAMPLE 1A (23.43 g), 2-bromobenzyl bromide (26.24 g), and DIEA (20.94 mL) in acetonitrile (200 mL) at 25° C. was stirred for 2 hours and filtered.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.Br[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:15][CH2:14][CH2:13][CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: C1=CC2(CCC1)CCCNC2
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCCC1NCCCC12C=CCCC2
Yield: 72 %

Procedure:
A mixture of 2-azaspiro-[5.5]-undec-7-ene (30.2 g.; 0.20 mole), 2-bromoethanol (25 g.; 0.20 mole) and triethylamine (20.2 g.) in toluene (250 ml.) is heated under reflux for 5 hours. The solution is cooled, filtered to remove triethylamine hydrobromide and the filtrate concentrated under reduced pressure. The residual liquid was distilled under reduced pressure to afford 28 g. (72% yield) of 2-hydroxyethyl-2-azaspiro-[5.5]-undec-7-ene, b.p. 90°-91° C./0.45 mm.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=O.Br[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].[OH-].[Na+].[Cl-].[Na+]>CO.C(Cl)Cl>[NH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[CH:11][CH:12]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: O=C(NCc1ccc(O)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cccc(Oc2ccc(CN)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15 %

Procedure:
Use a method similar to Preparation 40 (Step 2), using 2,2,2-trifluoro-N-(4-hydroxybenzyl)-acetamide (1.0 g, 5.5 mmol) and 3-bromobenzonitrile (673 mg, 3.7° mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3:1). Concentrate in vacuo. Dissolve the residue (287 mg, 0.89 mmol) in methanol (25 mL) and add 5N NaOH (7 mL). Stir at room temperature for 4 h. Dilute with DCM and add solid sodium chloride to the mixture. Extract the aqueous layer three times with DCM. Combine organic extracts, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (94:6) to obtain the title compound (124 mg, 62%). MS (ES+) m/z: 500 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25]Br>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:25][C:24]5[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:23]=5[F:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cc([C@H]2CC[C@H](N3CCNCC3)CC2)cc2c1OCO2
Reactant: Fc1ccc(F)c(CBr)c1
Product: Fc1ccc(F)c(CN2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]piperazine and 2,5-difluorobenzyl bromide by the method described in example to give the product (59%, mp: 110°-111° C.). Calc'd for C24H28F2N2O2 : C, 69.55%; H, 6.81%; N, 6.76%. Found: C, 69.55%; H, 6.74%; N, 6.63%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.F[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]([N+:26]([O-:28])=[O:27])=[C:18]([N:14]2[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)[CH:23]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Product: COc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cccc(C)n3)CC2)c1
Yield: 48.2 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (20 mg, 0.93 mmol) and 2-fluoro-4-methoxynitrobenzene (21.3 mg, 0.12 mmol) was stirred at 120° C. for 0.5 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 1:1) affording the title product (21 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[CH:35]=[CH:34][N:33]=[C:27]2[S:28][C:29]=1[C:30](O)=[O:31]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[S:28][C:27]3=[N:33][CH:34]=[CH:35][N:26]3[C:25]=2[CH3:24])=[O:31])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: Cc1c(C(=O)O)sc2nccn12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2sc3nccn3c2C)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3-Methyl-imidazo[2,1-b]thiazole-2-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=512.3.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9].Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:8](=[O:9])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Temperature: -25 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a solution of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-proline (3.01 g) in DMF (25 ml) were added L-proline methyl ester hydrochloride (2.07 g), HOBt (2.54 g) and N-methylmorpholine (1.38 ml). The mixture was cooled to -25° C., added with DCC (2.85 g), and stirred at a temperature of -25°-0° C. for 3 hours and at room temperature for 15 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 2.56 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-proline methyl ester.
Reaction SMILES: [CH3:1][O-:2].[Na+].C([C@H]1COC(=O)N1[C:17](=[O:40])[C@@H:18]([O:37][CH2:38][CH3:39])[C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][C:22]=1[CH2:35][CH3:36])[OH:20])C1C=CC=CC=1>CO>[CH3:1][O:2][C:17](=[O:40])[C@@H:18]([O:37][CH2:38][CH3:39])[C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:23][C:22]=1[CH2:35][CH3:36])[OH:20]
Reactant: C[O-]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1CC
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1CC
Temperature: 0 °C
Yield: 64.5 %

Procedure:
A 5.4 M solution of sodium methoxide (640 μl, 3.5 mmol) was added to an ice-cooled and stirred suspension of (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one (1.58 g, 3.1 mmol) in dry methanol (9 ml). The mixture was stirred at 0° C. for 15 min, quenched and neutralized by the addition of dilute aqueous hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure and the residue dissolved in ice water/ethyl acetate 1/1. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with ice water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 730 mg (2.0 mmol, 65%) of the title compound as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.