Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[CH2:9]1>O1CCCC1>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:9]1
Reactant: C=C1CC(=O)O1
Reactant: CC1CCCC(N)C1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCC(C)C1
Temperature: 20 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
A solution of 7.5 g of diketene in 30 ml of tetrahydrofuran was added to a mixture of 10 g of 3-methylcyclohexylamine and 60 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 4 hours and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 12 g of N-(3-methylcyclohexyl)-acetylacetamide. 12 g of the latter product and 0.3 g of p-toluene sulfonic acid were added to a mixture of 10.6 g of methyl orthoformate and 20 ml of methanol and the mixture was stirred at 20° C. for 1 hour and stood still for 16 hours at 20° C. 0.6 g of quinoline were added thereto and the mixture was evaporated to dryness under reduced pressure. The residue was added to 50 ml of toluene and the mixture was heated at 145° C. for 3 hours while distilling a toluene-methanol azeotrope and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with an 8-2 methylene chloride-acetone mixture gave 9.2 g of N-(3'-methylcyclohexyl)-3-methoxy-crotonamide whose RMN spectra showed it to be the E isomer.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)=O)[CH3:2].[C:21]1([CH:28]=CC=[C:24](O)[CH:23]=1)[OH:22].P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[OH:22][C:21]1[CH:28]=[C:1]2[C:2]([C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=4)[CH:9]=3)=[CH:5][C:4](=[O:20])[O:3]2)=[CH:24][CH:23]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccc2cc(OC)ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2cc(-c3cc(=O)oc4cc(O)ccc34)ccc2c1
Temperature: 0 °C
Yield: 68.8 %

Procedure:
A stirred solution of ethyl(6-methoxy-2-naphthoyl)acetate (36 g, 0.132 mole), resorcinol (14.6 g, 0.132 mole) and phosphoryl chloride (32 ml) in benzene (200 ml) was refluxed for 3 hours. The reaction mixture was allowed to cool, poured into ice/water and filtered to give the crude product as a red solid. Recrystallisation from ethanol gave 7-hydroxy-4(6-methoxy-2-naphthyl)coumarin (28.9 g, 69%) m.p. 223°-225° C.
Reaction SMILES: [Cl:1][C:2]([CH:4]([Cl:8])[CH:5]([CH3:7])[CH3:6])=[CH2:3].Cl[C:10]1[CH:19]=C[C:13](NC(=S)[S-])=[C:12]([CH3:20])[CH:11]=1.C([NH+](CC)CC)C.C(=[O:32])C(C)C.[Br-]>>[Cl:1][C:2]([CH:4]([Cl:8])[CH:5]([CH3:7])[CH3:6])=[CH2:3].[CH3:13][CH:12]([CH3:20])[CH:11]([OH:32])[C:10]#[CH:19]
Reactant: Cc1cc(Cl)ccc1NC(=S)[S-]
Reactant: CC(C)C=O
Agent: C=C(Cl)C(Cl)C(C)C
Agent: CC[NH+](CC)CC
Agent: [Br-]
Product: C#CC(O)C(C)C

Procedure:
By the procedure of Example 2, the reactant 2-chloro-1-isopropylallyl 4-chloro-2-methyl dithiocarbanilate is prepared by the reaction of 2,3-dichloro-4-methyl-1-pentene and triethylammonium 4-chloro-2-methyldithiocarbanilate. The 2,3-dichloro-4-methyl-1-pentene is prepared by the reaction of isobutyraldehyde with acetylenemagnesium bromide to yield 4-methyl-1-pentyn-3-ol, which is converted to 2-chloro-4-methyl-1-pentene-3-ol by treatment with hydrogen chloride in the presence of mercuric chloride. The required 2,3-dichloro-4-methyl-1-pentene is then obtained by treating 2-chloro-4-methyl-1-pentene-3-ol with phosphorus trichloride.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2c(c1)NCCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinolin-7-ol (200 mg, 1.34 mmol) from step 1 in anhydrous N,N-dimethyl-formamide (5 mL) was added bromomethyl-benzene (229 mg, 1.34 mmol), and potassium carbonate (556 mg, 4.02 mmol). The reaction mixture was stirred at 60° C. overnight. Added some water to the reaction mixture and extracted it with methylene chloride several times. The organic layer was combined, dried over magnesium sulfate, and filtrated. The solution was evaporated under vacuum. The crude residue was purified by MPLC (biotage) to afford 297 mg (93%) of the title compound. 1H-NMR (CDCl3) δ 7.35-7.20 (m, 5H), 6.81 (d, J=8.1 Hz, 1H), 6.05 (dd, J=7.8 Hz, 2.2 Hz, 1H), 5.98 (d, 2.5 Hz, 1H), 4.53 (bs, 1H), 4.44 (s, 2H), 3.34 (t, J=5.0Hz, 2H), 2.73 (t, J=5.8Hz, 2H) 1.98 (m, 2H); MS LC-MS (MH+=240.1), LC MS RT: 3.08 min.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) (Example 11b) in chloroform (2 mL) was added pyridine (0.099 mL, 1.226 mmol) followed by benzenesulfonyl chloride (0.059 mL, 0.460 mmol). The reaction mixture was stirred at room temperature for 1 hr. The saturated solution of NH4Cl was added, and layers were separated. Organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at the room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. trans-2-phenyl-N-((1-(phenylsulfonyl)piperidin-4-yl)methyl)cyclopropanamine (10 mg, 0.026 mmol, 8.37% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.76-7.85 (m, 2H), 7.65-7.73 (m, 1H), 7.52-7.66 (m, 2H), 7.15-7.28 (m, 2H), 7.06-7.16 (m, 1H), 6.97-7.05 (m, 2H), 3.77 (d, J=12.13 Hz, 2H), 2.57 (dd, J=1.26, 6.82 Hz, 2H), 2.13-2.35 (m, 3H), 1.72-1.97 (m, 3H), 1.36-1.54 (m, J=3.73, 3.73, 7.33, 7.33, 14.78 Hz, 1H), 1.14-1.35 (m, 2H), 0.90-1.10 (m, 2H); LC-MS Rt=0.76 min; MS (ESI): 370.9 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]1[N:15]2[C:10]3[C:11](=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]=3[CH2:8][CH2:7]1)[C:12](=[O:19])[C:13]([C:16]([OH:18])=[O:17])=[CH:14]2>>[CH3:5][CH:6]1[N:15]2[C:10]3[C:11](=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][C:26]([N+:1]([O-:4])=[O:2])=[CH:25][CH:24]=4)[C:9]=3[CH2:8][CH2:7]1)[C:12](=[O:19])[C:13]([C:16]([OH:18])=[O:17])=[CH:14]2
Reactant: O=[N+]([O-])O
Reactant: CC1CCc2c(-c3ccccc3)ccc3c(=O)c(C(=O)O)cn1c23
Product: CC1CCc2c(-c3ccc([N+](=O)[O-])cc3)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (5° C.) 400 ml portion of 90% nitric acid was added 2.3 g of 6,7-dihydro-5-methyl-1-oxo-8-phenyl-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. The solution was stirred at 5°-10° C. for one hour, then diluted with 1.5 liters of ice-water. The solid was separated by filtration and dried to provide 6,7-dihydro-5-methyl-8-(4-nitrophenyl)-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >300° C. Analysis: Calculated for C20H16N2O5 : %C, 65.9; %H, 4.4; %N, 7.7; Found: %C, 65.3; %H, 4.6; %N, 7.4. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:3]1([CH3:12])[CH3:11])=[O:18]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)OC1CC(C)(C)N(OC(=O)C(C)(C)C)C(C)(C)C1
Yield: 67 %

Procedure:
Using 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, prepared as described by: Paleos C. M. et al., loc. cit., and pivaloyl chloride in a procedure otherwise similar to the preparation of the compound 101 gives a 67% yield of the compound 108 which is obtained in the form of colourless crystal; melting point: 43-46° C. (pentane).
Reaction SMILES: [Si:1]([O:18][C@H:19]([C@H:22]1[O:26][C:25](=[O:27])[CH2:24][CH2:23]1)[CH2:20][CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Si:1]([O:18][C@H:19]([C@H:22]1[O:26][C:25](=[O:27])[C@H:24]([CH3:28])[CH2:23]1)[CH2:20][CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1CCC(=O)O1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1C[C@@H](C)C(=O)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (5S)-5-[(1S)-1-[tert-butyl(diphenyl)silyl]oxypropyl]tetrahydrofuran-2-one (Compound 28e-S, 3.0 g, 7.8 mmol) in THF (60 mL) at −78° C. was added lithium diisopropylamide (2M in THF, 5.9 mL, 11.8 mmol) dropwise. After addition, the reaction was stirred at −78° C. for 1 hour. To the mixture was added iodomethane (5.5 g, 39 mmol) and the mixture was stirred at −78° C. for another 1 hour. The mixture was quenched with saturated NH4Cl solution (40 mL), extracted with EtOAc (100 mL) twice. The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:10 EtOAc in petroleum ether) to afford 2.7 g of (3R,5S)-5-[(1S)-1-[tert-butyl(diphenyl)silyl]oxypropyl]-3-methyl-tetrahydrofuran-2-one (compound 28f) as a colourless oil. (Refer to Tetrahedron. 1997, 53, 6281-6294).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.O>C1COCC1>[N:9]1[CH:8]=[C:7]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:23][CH2:13][CH2:14][O:15]3)[CH2:17][CH2:18]2)[CH:12]=[N:11][CH:10]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2cncnc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 12.1 %

Procedure:
A solution of n-butyllithium (4.32 mL of 1.6 M solution in hexane, 6.92 mmol) was added to 5-bromopyrimidine (1.0 g, 6.29 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (0.982 g, 6.29 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe and stirred for 4 h at −78° C. Water (5 mL) was added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and chromatographed to yield 0.18 g of 8-pyrimidin-5-yl-1,4-dioxaspiro[4,5]decan-8-ol in 12% yield. MS (EI) calcd: (M+H)+=237.1. Found: 237.2.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16](=[O:23])[CH:17]=[C:18]([CH2:21][OH:22])O[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[OH:26][N:25]1[CH:20]=[C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:16](=[O:23])[CH:17]=[C:18]1[CH2:21][OH:22]
Reactant: NO
Reactant: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1cc(CO)n(O)cc1OC(c1ccccc1)c1ccccc1
Yield: 44 %

Procedure:
17.5 g (0.0568 mol) of the product of Step (1) was added and dissolved in a mixture of ethanol (60 ml) and water (60 ml). Then, 39.5 g (0.568 mol) of hydroxylamine hydrochloride and 77.2 g (0.568 mol) of sodium acetate trihydrate were added thereto, and the mixture was reacted at 60° C. for 18 hours under stirring. Formed precipitates were collected by filtration, washed sequentially with water, ethanol and ethyl ether, and then dried to obtain 8.1 g (yield: 44.0%) of the above identified compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=CC=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(CC)C>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH:48]([CH3:53])[CH2:49][CH3:50])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CCC(C)N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C)NC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and sec-butylamine (12.12 uL, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (3.2 mg, 9%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([N:18]1[C@@H:22]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20][C@H:19]1[C:29]([O:31]C)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O.P([O-])([O-])([O-])=O>C1COCC1>[CH2:11]([N:18]1[CH:22]2[CH2:21][CH2:20][CH:19]1[C:29]([OH:31])=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH2:23]2)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CC[C@H]1CC[C@@H](C(=O)OC)N1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(O)C2CCC(C1)N2Cc1ccccc1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
A solution of LiHMDS (1.0 M in THF, 0.908 ml, 0.980 mmol) was slowly added to a solution of (2S,5R)-methyl 1-benzyl-5-(3-methoxy-3-oxopropyl)pyrrolidine-2-carboxylate (126, mg, 0.413 mmol) in THF (4 ml) at −78° C. The reaction mixture was stir at −78° C. for 6 hrs. Then the reaction mixture was poured into a 0° C. stirring mixture of EtOAc (10 mL) and pH 7.0 aqueous phosphate buffer. The organic phase was separated, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) to give the product methyl 8-benzyl-2-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-3-carboxylate (74 mg, 0.271 mmol) as a syrup. Anal. Calcd. for C16H19NO3 m/z 273.1, found: 274.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.21 (5 H, m), 3.80-3.73 (4 H, m), 3.70 (2 H, d, J=3.0 Hz), 3.36 (1 H, t, J=5.2 Hz), 3.32 (1 H, d, J=5.6 Hz), 2.63 (1 H, dd, J=15.9, 4.8 Hz), 2.18-2.11 (2 H, m), 2.02-1.95 (1 H, m), 1.85 (1 H, d, J=15.9 Hz), 1.59-1.48 (1 H, m).
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[C:36]([N:24]1[CH2:25][CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:22]([CH2:21][N:13]([CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]1)=[O:37]
Reactant: O=Cc1ccccc1Cl
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(c1cccc2ccccc12)N(CC1CN(C(=O)c2ccccc2Cl)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
A mixture of 9.9 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[4-phenylpyrrolidin-3-yl]methyl}carbamate, 4.9 mg of 2-chlorobenzaldehyde, 50 μl of acetic acid and 0.5 ml of DMF was mixed at room temperature with 75 mg of MP-Triacetoxyborohydride (mfd. by Argonaut Technologies, USA) and stirred for 15 hours. At room temperature, the reaction solution was mixed with 50 mg of PS-Isocyanate (mfd. by Argonaut Technologies, USA) and stirred for 4 hours, and the reaction solution was filtered. The filtrate was concentrated under a reduced pressure to obtain tert-butyl {[1-(2-chlorobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}[1-(1-naphthyl)ethyl]carbamate as a crude product. A 0.5 ml methanol solution of the thus obtained crude product was mixed with 0.5 ml of 4 M hydrogen chloride/ethyl acetate solution at room temperature and stirred for 4 hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a fractional high performance liquid chromatography (methanol-0.1% formic acid aqueous solution) to obtain 3.3 mg of N-{[1-(2-chlorobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)c1cc2c(cc1O)CCC2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4c(cc3C(C)=O)CCC4)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
1-(6-Hydroxyindan-5-yl)-ethanone (275 mg), 4-chloro-6,7-dimethoxyquinoline (173 mg), and 4-dimethylaminopyridine (286 mg) were suspended in o-dichlorobenzene (5 ml) to prepare a suspension which was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (37 mg, yield 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](I)=[N:6][CH:7]=1.C1([Mg]Cl)C=CC=CC=1.[CH3:20][C:21]1[C:26]([CH:27]=[O:28])=[C:25]([CH3:29])[CH:24]=[CH:23][N:22]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH:27]([C:26]2[C:21]([CH3:20])=[N:22][CH:23]=[CH:24][C:25]=2[CH3:29])[OH:28])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1I
Reactant: Cc1ccnc(C)c1C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccnc(C)c1C(O)c1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-Chloro-2-iodo-3-nitro-pyridine (2.5 g, 8.77 mmol) in anhydrous THF (20 mL) at −78° C. was added 2 M phenylmagnesiumchloride in THF (4.8 mL, 9.6 mmol) and stirred at the same temperature for 30 minutes and then 2,4-Dimethyl-pyridine-3-carbaldehyde (1.82 g, 13.15 mmol) was added in one portion and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc. The combined extracts were washed with aqueous NaHCO3, brine, and then dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography to (5-Chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanol. Mass spectrum m/z: 294.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3Cl)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4Cl)c3)S2)CC1

Procedure:
5-[1-(2,4-Dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O.[S:43]1[C:51]2[C:46](=[N:47][C:48]([CH2:52][CH2:53]O)=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>C1COCC1>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:53][CH2:52][C:48]3[N:47]=[C:46]4[CH:45]=[CH:44][S:43][C:51]4=[CH:50][CH:49]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1
Reactant: O=c1[nH]ncc2scc(Br)c12
Reactant: OCCc1ccc2sccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2c(Br)csc2cnn1CCc1ccc2sccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a mixture of 3-bromothieno[2,3-d]pyridazin-4(5H)-one (100 mg, 0.433 mmol) from Example 3.3 and triphenylphosphine (227 mg, 0.866 mmol) in THF (2 mL) was added (E)-diethyl diazene-1,2-dicarboxylate (151 mg, 0.866 mmol) dropwise at 0° C. After the addition, the mixture was stirred for 1 h at 0° C. Then 2-(thieno[3,2-b]pyridin-5-yl)ethanol from Example a3 (78 mg, 0.433 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at room temperature overnight. The solution was filtered to obtain the title compound (80 mg, yield 47.1%).