Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:20](=O)([O-:24])[O:21][CH2:22][CH3:23]>O>[O:3]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:5]=1)[CH2:1][C:20]([O:21][CH2:22][CH3:23])=[O:24]
Reactant: CCOC(=O)[O-]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-trifluoromethylacetophenone (57.8 g, 0.307 mol) and ethanol (1 ml) in ethyl carbonate (300 ml) was added sodium hydride (24.5 g, 60% in oil, 0.63 mol) by small portions. Because heat was generated gradually, the reaction solution was ice-cooled and thereafter stirred at room temperature for 2 hrs. 6N Hydrochloric acid was added thereto to stop the reaction. The mixture was diluted with water (300 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionate (71.2 g, 89%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]=2[CH:18]=1
Reactant: CC(C)n1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1c([C@H](C)N)nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
[(S)-1-(6-Fluoro-1-isopropyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.0 g, 3.11 mmol) was dissolved in DCM (10 mL) and TFA (5 mL) added. The reaction mixture was stirred at RT for 30 minutes. The resultant mixture was concentrated in vacuo and the residue dissolved in DCM (40 mL) and stirred vigorously with saturated aqueous NaHCO3 (20 mL), for 10 minutes. The layers were separated and the organic fraction washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.5 g, 72%). 1H NMR (CDCl3, 400 MHz): δ 7.65 (1H, dd, J=8.83, 5.01 Hz), 7.20 (1H, dd, J=9.40, 2.46 Hz), 6.97 (1H, ddd, J=9.58, 8.80, 2.43 Hz), 4.92-4.82 (1H, m), 4.37-4.28 (1H, q, J=6.68 Hz), 1.64 (6H, d, J=6.98 Hz), 1.58 (3H, d, J=6.65 Hz).
Reaction SMILES: [C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([CH3:28])[N:22]=1>C1COCC1>[C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][O:17][C:25]1[CH:26]=[C:21]([Cl:20])[N:22]=[C:23]([CH3:28])[N:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C2C(CO)C2OC(C)(C)C)nc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C2C(COc3cc(Cl)nc(C)n3)C2OC(C)(C)C)nc1
Yield: 55.8 %

Procedure:
To a solution of (2-tert-butoxy-3-(5-methylpyridin-2-yl)cyclopropyl)-methanol (12-5) (130 mg, 0.55 mmol) in THF, sodium hydride (28 mg, 0.69 mmol) was added at 0° C. and it was allowed to stir for 30 min whereupon a solution of 4,6-dichloro-2-methylpyrimidine (113 mg, 0.69 mmol) in THF was added. The solution was heated to reflux overnight. After cooling, it was quenched with water, extracted with EtOAc, dried over sodium sulfate, concentrated under reduced pressure and purified by Pre-TLC (PE/EA=1:1) to afford the product as a white solid (111 mg, 56%). 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 7.41 (d, J=6.6 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.59 (s, 1H), 4.49-4.40 (m, 2H), 3.62 (dd, J=6.9, 3.6 Hz, 1H), 2.60 (s, 3H), 2.30 (s, 3H), 2.27 (m, 1H), 2.04 (dd, J=6.7, 3.7 Hz, 1H), 1.08 (s, 9H); LRMS (ES) calculated M+H for C19H25ClN3O2: 362.8. Found: 362.1.
Reaction SMILES: N#N.O[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=1.CCN(CC)CC.S([Cl:24])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(CO)on1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-isoxazol-3-yl)-ethanone (262 mg, 1.86 mmol) in dry CH2Cl2 (2.6 mL) was treated at 0° C. with Et3N (0.34 mL, 2.41 mmol) followed by DMAP (23 mg, 0.19 mmol) and Ms-Cl (0.17 mL, 2.23 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure to give crude 1-(5-chloromethyl-isoxazol-3-yl)-ethanone as a pale yellow oil. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 1-(5-chloromethyl-isoxazol-3-yl)-ethanone in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (210 mg, 1.84 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.63 mL, 3.68 mmol) and the reaction mixture was stirred for 16 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (2:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.90 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6](O)[CH2:7][O:8][C:4]=2[CH:3]=1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:26]([CH:6]1[C:5]2[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=2[O:8][CH2:7]1)=[N+:27]=[N-:28]
Reactant: OC1COc2cc(Br)ccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1COc2cc(Br)ccc21

Procedure:
In analogy to the procedures described for the preparation of intermediates A-2 [B] and A-2 [C], (rac)-6-bromo-2,3-dihydro-benzofuran-3-ol was treated with diphenylphosphoryl azide, DBU in toluene to give (rac)-3-azido-6-bromo-2,3-dihydro-benzofuran, which was subsequently reduced with triphenylphosphine in THF/water to yield the title compound as light yellow oil. MS: 213 (M+, 1Br).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11](Br)=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.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>[S:1]1[C:5]([C:6]2[C:11]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3ccccc3s2)n1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2ccccc2)c(-c2cc3ccccc3s2)n1
Temperature: 140 °C
Yield: 16.9 %

Procedure:
A 5 mL Personal Chemistry microwave tube was charged with 1-(2-(4-(benzo[b]thiophen-2-yl)-5-bromopyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (103 mg, 0.22 mmol), phenyl boronic acid (55 mg, 0.44 mmol), a 2 M aqueous solution of sodium carbonate (0.22 mL, 0.44 mmol), dioxane (2 mL) and tetrakis(triphenylphosphine)palladium (0) (52 mg, 0.044 mmol). The vessel was sealed and heated to 140° C. for 20 min with stirring. After cooling to r.t. the mixture was diluted with ethyl acetate (10 mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (10 mL). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography (chloroform/methanol 99:1 to 96:4 followed by a second column: ethyl acetate/hexane/methanol 50:48:2) to afford the title compound (17 mg, 17%). 1H NMR: δ (CDCl3, 400 MHz) 1.47 (s, 6H), 3.60-3.68 (m, 2H), 3.81-3.92 (m, 2H), 6.32 (br. s., 1H), 6.92 (s, 1H), 7.26 (t, J=7 Hz, 1H), 7.32 (t, J=7 Hz, 1H), 7.36 (dd, J=3 Hz, 2H), 7.44-7.47 (m, 3H), 7.50 (d, J=8 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 8.22 (s, 1H): HRMS (M+H)+ Calcd. C25H23N5O2S 458.1650. found 458.1616.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=O.[CH:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[CH:20][CH:21]=1>C(#N)C>[C:19]1([NH:22][C:23]2[N:25]=[C:5]([C:7]3[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=3)[C:10]#[N:11])[CH:4]=[CH:3][N:24]=2)[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CN(C)C=CC(=O)c1cccc(C#N)c1
Solvent: CC#N
Product: N#Cc1cccc(-c2ccnc(Nc3ccccc3)n2)c1

Procedure:
To a solution of 3-(3-dimethylamino-acryloyl)-benzonitrile (30.4 g, 152 mmol) in acetonitrile (250 mL) was added a solution of phenylguanidine (21.0 g, 155 mmol) in acetonitrile (250 mL) and the mixture was heated at reflux for two hours. The solution was cooled and the resulting solid was filtered and washed with acetonitrile to afford the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:51])[CH2:49][CH3:50]>CN(C=O)C>[N:33]1([C:31]([NH:30][C@@H:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:17]3[N:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH:5]5[CH2:6][CH2:7][N:2]([C:48](=[O:51])[CH2:49][CH3:50])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)[N:16]=3)[CH2:25]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCC(=O)Cl
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (70 mg, 0.13 mmol) was dissolved in 4 mL DMF. To it were added DIEA (230 μL, 1.30 mmol) and then propionyl chloride (36 μL, 0.39 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (498), as HCl salt (45 mg). LC-MS (ESI): m/z (M+1) 564.3. UV: λ=263, 329, 338 nm.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(C)CCOc1ccc(C=O)c(O)c1

Procedure:
A mixture containing 0.8 mole of 2,4-dihydoxy-benzaldehyde, 0.8 mole of 2-chloro-1-dimethylaminoethane and 1.6 mole of potassium carbonate in 1200 ml of anhydrous methyl ethyl ketone is refluxed for 1 hour 30 minutes with stirring. After cooling, the precipitate formed is filtered and washed with methyl ethyl ketone. The filtrate is then evaporated and leads to a brown oil which is purified by chromatography of a silica column using a dichloromethane-methanol mixture (90/10) as eluting solvent. The expected product is then obtained after recrystallization from isopropanol.
Reaction SMILES: [C:1]([C:3]1([CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[OH-].[Na+]>CO.O>[C:1]([C:3]1([CH:9]([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)C(C(=O)OCC)C1(C#N)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CC1(C(C(=O)O)C(=O)O)CCCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
50 g Diethyl (1-cyanocyclohexyl)-malonate are dissolved in 175 mL methanol at 40° C. At this temperature, a solution of 29.9 g sodium hydroxide in 150 mL water is added dropwise. The reaction mixture is stirred for 30 minutes at 40° C. After cooling to 20° C., the precipitated product (sodium salt) is filtered off with suction, the filter cake is washed with 50 mL methanol and the product is dried at 60° C. to constant weight. The product is dissolved in 500 mL of water at 10° C., and adjusted to a pH of one to two at 10-15° C. with concentrated hydrochloric acid. The substance which precipitates out is extracted three times with, in each case, 300 mL ethyl acetate. The combined ethyl acetate phases are dried and evaporated on a rotary evaporator at 35° C. The white residue obtained is dried to constant weight at 35° C. in a vacuum drying cabinet. 35.5 g of the title compound are obtained (89.8% of theory); m.p. 99.9° C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:33][CH2:32][C:29]3([CH2:31][O:30]3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1)#[N:17]>O>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][N:26]2[CH2:33][CH2:32][C:29]([CH2:31][O:9][C:8]3[CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=3)([OH:30])[CH2:28][CH2:27]2)=[CH:22][CH:23]=1)#[N:17]
Reactant: Oc1ccc(O)cc1
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Yield: 9 %

Procedure:
60% sodium hydride (46 mg) was added to an anhydrous dimethylformamide solution (4 mL) of hydroquinone (0.18 g) under cooling with ice-water and the mixture was stirred at room temperature for fourty minutes under nitrogen atmosphere. The compound (0.40 g) obtained in Step 3 was added to the mixture, and the reaction mixture was stirred at 80° C. for four hours under nitrogen atmosphere. Water (40 mL) was added to the mixture under cooling with ice-water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over anhydrous sodium sulfate and then, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=49:1 to 19:1) and the obtained fractions were concentrated and washed with ether-ethyl acetate to obtain the titled compound (52 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[C@H:10]([O:23]C(=O)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([OH:23])[C@H:11]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(=O)c1ccc(Cl)s1
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2ccc(Cl)s2)[C@H](O)C1

Procedure:
79.5 A solution of (3S,4R)-3-acetoxy-4-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (20 mg) in 1 ml of a 2M NH3 solution in MeOH was stirred at 22° C. for 1 h and evaporated to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale brown oil. MS 305.1 ([M-isobutene+H]+)
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O>>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=[CH:15][C:14]([C:3]1[N:4]2[C:5]([S:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=32)=[N:1][CH:2]=1)=[O:16]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Product: O=C(C=Cc1ccc2ccccc2c1)c1cnc2sc3c(n12)CCCCC3

Procedure:
1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)ethanone (Formula O-1), 1.37 g, was condensed with 2-napthaldehyde by non-critical variations of EXAMPLE 15 to yield 3-(2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula O-2), 2.24 g, m.p. 185-188°.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1)[CH2:4]C.NC(CO)C[OH:36]>>[OH:36][CH2:4][CH:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][CH:20]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:31])[CH3:32])=[C:9]2[N:8]=1)[CH2:2][OH:1]
Reactant: CC[C@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Reactant: NC(CO)CO
Product: CC(C)c1cnn2c(NCc3ccc(-c4ccccn4)cc3)nc(NC(CO)CO)nc12
Yield: 30 %

Procedure:
According to the same conditions resulting in the preparation of the compound 2, the compound 17 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of serinol. Yield=30%. Oil. 1H NMR (300 MHz, CDCl2): δ 8.68 (d, 1H, J=4.4 Hz, Harom), 7.96 (d, 2H, J=8.3 Hz, Harom), 7.79-7.69 (m, 2H, Harom) 7.64 (s, 1H, Harom) 7.45 (d, 2H, J=8.3 Hz, Harom) 7.26-7.21 (m, 1H, Harom), 6.80 (bs, 1H, NH), 5.71 (bs, 1H, NH), 4.77 (d, 2H, J=5.9 Hz, CH2), 4.08-4.95 (m, 1H, CH), 3.92-3.80 (m, 4H, 2 CH2), 3.02 (hept, 1H, J=7.0 Hz, CH), 1.28 (d, 6H, J=7.0 Hz, 2 CH3). MS (ESI): m/z 434 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)[O:31][C:32]=2[CH3:33])=[C:24]([O:41][CH3:42])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:35]1[CH:36]=[CH:37][CH:38]=[C:34]1[C:30]1[O:31][C:32]([CH3:33])=[C:28]([CH2:27][O:26][C:25]2[CH:39]=[CH:40][C:22]([CH2:21][O:1][C:2]3[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:3]=3)=[CH:23][C:24]=2[O:41][CH3:42])[N:29]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)CCc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)propionate (0.40 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (0.57 g), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]propionate (420 mg, yield 44%) was obtained as colorless crystals-from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 97–98° C.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:18]=[CH:17][C:8]2[S:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[C:7]=2[CH:6]=1.[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][Cl:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[ClH:29].[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][O:16][C:13]2[CH:14]=[CH:15][C:10]3[S:9][C:8]4[CH:17]=[CH:18][C:5]([O:4][CH2:28][CH2:27][CH2:26][N:20]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]5)=[CH:6][C:7]=4[C:11]=3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Oc1ccc2sc3ccc(O)cc3c2c1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2sc3ccc(OCCCN4CCCCC4)cc3c2cc1OCCCN1CCCCC1

Procedure:
To 200 ml of water containing 12.0 g (0.3 mole) of sodium hydroxide and 8.5 g (0.039 mole) of 2,8-dihydroxydibenzothiophene are added 200 ml of toluene and 19.8 g (0.1 mole) of 3-piperidinopropyl chloride hydrochloride, and the heterogeneous reaction mixture is stirred and heated to reflux for 16 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The free base is chromatographed on alumina, using chloroform as the eluant. After removing the chloroform from the fraction collected, the oily residue is dissolved in ether and treated with ethereal hydrogen chloride. The resulting solid is purified by two recrystallizations from methanol-butanone to give 2,8-bis(3-piperidinopropoxy)dibenzothiophene dihydrochloride, M.P. 240°-242°C.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:3].C(O[CH2:13][CH2:14][C:15]#[N:16])C>C(O)C>[NH2:16][C:15]1[CH2:14][CH2:13][N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:3]=1
Reactant: CCOCCC#N
Reactant: NNc1ccccn1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccccn2)CC1

Procedure:
A 0.58 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 14.0 g. of 2-hydrazinopyridine is added followed by 12.7 g. of betaethoxypropionitrile. The reaction mixture is refluxed on a steam bath for 16 hours, then the solvent is removed in vacuo. Water is added and the solid collected by filtration. The solid is recrystallized twice from acetone to give 5.55 g. of the product of the Example as tan colored crystals, m.p. 168.5°-171° C.