Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([S:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([CH3:16])=[N:10]2.CO.[OH-].[Li+]>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:26])=[O:2])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:16])[C:8]([S:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:7]2[CH3:25]
Reactant: COC(=O)Cc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(Cl)ccc(CC(=O)O)c2c(C)c1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of [8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-yl]acetic acid methyl ester (0.040 g), methanol (2.0 mL), water (0.4 mL) and saturated aqueous lithium hydroxide solution (0.2 mL) was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue diluted with water (2.0 mL) and then the pH adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a grey-brown solid, 0.038 g.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])[CH2:8][CH2:7]1)([CH3:4])=[O:3]>C(O)C.[Pd]>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:22]([F:25])([F:23])[F:24])[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CP(C)(=O)CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CP(C)(=O)CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reaction time: 3 h
Yield: 161.5 %

Procedure:
Palladium (10 wt. %) on activated carbon (wet, 450 mg) was added to a solution of 1-[(dimethylphosphoryl)methyl]-4-[4-nitro-2-(trifluoromethyl)benzyl]piperazine (740 mg, 1.95 mmol) in 25 mL of ethyl alcohol. The reaction suspension was stirred under a hydrogen atmosphere (30 psi.) for 3 hours. The reaction mixture was then filtered through a short pad of celite. The celite pad was washed by 10 mL ethyl alcohol three times. The organic fractions were combined and evaporated to remove solvent and gave the desired compound as light yellow solid (1.10 g crude).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:5][C:6](=[O:10])[N:7]([CH3:9])[N:8]=1)[CH3:2].Cl[C:12]1[N:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([O:10][C:6]2[N:7]([CH3:9])[N:8]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:13]=[N:14][CH:15]=1
Reactant: COc1cnnc(Cl)c1
Reactant: CCOC1=NN(C)C(=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(Oc2cc(OC)cnn2)n(C)n1
Reaction time: 42 h
Yield: 20 %

Procedure:
5-Ethoxy-2,4-dihydro-2-methyl-3H-pyrazol-3-one (0.63 g, 0.0044 mole), 3-chloro-5-methoxypyridazine (0.64 g, 0.0044 mole), potassium carbonate (1.50 g, 0.010 mole), cuprous bromide (0.05 g, 0.0003 mole) and anhydrous dimethyl sulfoxide (10 mL) were heated and held at 90° C. for 42 hours. The mixture was cooled, treated with 1% hydrochloric acid solution and extracted with ethyl acetate. The combined extracts were washed with 2% sodium hydroxide, dried with magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using ethyl acetate/cyclohexane gave a tan solid, which was recrystallized from ethyl acetate/methylcyclohexane to give 5-methoxy-3-[(3-ethoxy-1-methyl-1H-pyrazol-5-yl)oxy]pyridazine (0.22 g, 22% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(O)=O>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:31][C:30]#[N:29])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: CC(=O)O
Product: N#CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Temperature: 90 °C
Yield: 51.8 %

Procedure:
To a screw-cap vial equipped with a magnetic stir bar, ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (105.9 mg, 0.2467 mmol), 4-isoxazoleboronic acid pinacol ester (Aldrich, 75.8 mg, 0.389 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Aldrich, 20.5 mg, 0.0260 mmol) and cesium carbonate (257.9 mg, 0.7915 mmol) were added. The vial was sealed with a Teflon®-lined septum, and then evacuated and backfilled with nitrogen three times. 1,4-Dioxane (2.00 mL) was added via a syringe, followed by deoxygenated water (1.00 mL). The reaction mixture was heated at 90° C. for 2 h and was then allowed to cool to room temperature. After cooling, the reaction mixture was diluted with water (50 mL). AcOH (159 mg, 2.66 mmol) was added to adjust the pH to 5. The mixture was extracted with EtOAc (3×50 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give the sub-title compound as a brown solid (46.2 mg, 52%). LCMS calc. for C20H16N3O4 (M+H)+: m/z=362.1. found 362.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[CH3:19][N:20]([CH3:23])[CH:21]=O.COC(OC)N(C)C>CCOCC>[F:8][C:7]1[C:2]([N:1]=[CH:19][N:20]([CH3:23])[CH3:21])=[N:3][C:4](=[O:18])[N:5]([S:9]([C:12]2[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=2)(=[O:11])=[O:10])[CH:6]=1
Reactant: Cn1cnc(S(=O)(=O)n2cc(F)c(N)nc2=O)c1
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Solvent: CCOCC
Product: CN(C)C=Nc1nc(=O)n(S(=O)(=O)c2cn(C)cn2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To an 8 mL screw-cap vial was added 4-amino-5-fluoro-1-(1-methyl-1H-imidazole-4-sulfonyl)-1H-pyrimidin-2-one (80 mg, 0.3 mmol), N,N-dimethylformamide (DMF; 3 mL), and dimethylformamide dimethylacetal (DMF-DMA; 70 mg, 0.6 mmol). The mixture was shaken at room temperature for 16 h, diluted with Et2O and filtered to yield the title product as a light yellow solid (68 mg, 69%): mp 228-232° C. dec; 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.25-8.21 (m, 2H), 7.82 (s, 1H), 3.73 (s, 3H), 3.24 (s, 3H), 3.13 (s, 3H); ESIMS m/z 329 ([M+H]+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][CH3:34])[CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][C@@H:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:33][CH3:34])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](N)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CC[C@@H](CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)NS(C)(=O)=O

Procedure:
N-[(1S)-1-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}propyl]methanesulfonamide was prepared from 3-[(2S)-2-aminobutyl]-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (Example 154) and methanesulfonyl chloride following General Procedure U.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:2].[CH3:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOCCn1c(CN2CCNCC2)nc2ccccc21
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCN1CCN(Cc2nc3ccccc3n2CCOCC)CC1
Reaction time: 6.5 h
Yield: 87.3 %

Procedure:
A mixture of 1-(2-ethoxyethyl)-2-(1-piperazinyl)methylbenzimidazole (3.1 g) obtained in the same manner as described in Example 1, n-propyl bromide (2.0 g) and potassium carbonate (2.25 g) in ethanol (60 ml) is refluxed with stirring for 6.5 hours. The reaction mixture is treated in the same manner as described in Example 5 and the crude product is purified likewise to give 1-(2-ethoxyethyl)-2-(4-n-propyl-1-piperazinyl)methylbenzimidazole (3.1 g) as a pale brown liquid. This liquid is treated with fumaric acid (2.0 g), and the crude crystal thus obtained is recrystallized from ethanol to give 1-(2-ethoxyethyl)-2-4-n-propyl-1-piperazinyl)methylbenzimidazole 3/2 fumarate (3.9 g) as colorless needles, m.p. 178.5°-180° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:12].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:9][C:7]1([F:10])[CH2:6][CH2:5][N:4]([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:12])[C@H:3]([CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[CH2:8]1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC(F)(F)CC2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC(F)(F)C[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using (2-(aminomethyl)-4,4-difluoropiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 482 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[CH:61]=[CH:62][C:63]2[S:67][C:66]([CH2:68]O)=[CH:65][C:64]=2[CH:70]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:68][C:66]2[S:67][C:63]3[CH:62]=[CH:61][C:60]([CH3:59])=[CH:70][C:64]=3[CH:65]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccc2sc(CO)cc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc3cc(C)ccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (5-methyl-1-benzothien-2-yl)methanol (0.75 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 44%).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9](=[O:33])[C@@H:10]([NH:22]C(=O)OCC1C=CC=CC=1)[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([OH:21])([CH2:14]3)[CH2:12]1)[CH2:18]2)#[N:2]>CO>[CH2:8]1[C@@H:3]([C:1]#[N:2])[N:4]([C:9]([C@@H:10]([NH2:22])[C:11]23[CH2:12][C:13]4([OH:21])[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[O:33])[C@@H:5]2[C@H:7]1[CH2:6]2
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Solvent: CO
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
To a solution of benzyl N-[(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate (10 gm) (formula-IX) in methanol 5% Pd/C (50% wet, 1 gm) was added. Hydrogen gas was bubbled through the reaction mass for 2 hrs at 20-25° C. After the starting material was completely converted, the reaction mass was filtered. The filtrate was evaporated to yield SAXAGLIPTIN free base of formula-I as a foamy solid. To the solid ethyl acetate (5 ml), 20 micro liters of water and n-hexane (20 ml) were added, stirred at 0-5° C. and filtered the white solid formed to yield 6.98 gm (94%) of SAXAGLIPTIN MONO HYDRATE. HPLC Purity: 99.5% (A) and the content of the impurity cyclic amidine: 0.09% (A), M.P: 105-108° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31].[Li+].[OH-]>O1CCCC1>[Cl:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:31])[C:24]=1[NH:23][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][C:5]=1[CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)Cc1cc(OCCCCOc2ccccc2)ccc1Nc1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(OCCCCOc2ccccc2)ccc1Nc1c(Cl)cccc1Cl

Procedure:
A solution of the ester of Step A, above (2.0 g, 4.2 mmol) in tetrahydrofuran (100 mL) and 1N LiOH (12.7 mL) is stirred under nitrogen overnight. The solvent is removed and the residue slurried in water. The mixture is acidified using dilute HCl and extracted with ethyl acetate (2×500 mL). The combined organic phases are washed with brine and dried (MgSO4). Removal of the solvent affords a brown oil which crystallizes from acetonitrile (white solid, 0.620 g, approximately 90% pure by HPLC). This material is further purified by HPLC (Dynamax C18, 2"-column, acetonitrileammonium acetate buffer 3:2) to provide pure title compound (0.250 g, white solid, m.p. 128°-131° C., dec.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:22])[CH2:3]1.O[NH:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26].S(Cl)(Cl)=O>O1CCOCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[O:9])[C:4](=[O:22])[CH2:3]1
Reactant: CCCCNC(=O)NO
Reactant: CC1CCN(C(=O)NCCc2ccc(S(=O)O)cc2)C(=O)C1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2CCC(C)CC2=O)cc1
Temperature: 60 °C

Procedure:
0.6 g of 4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfinic acid (crude product m.p. 113°-115° C., prepared by reaction of 4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfochloride with sodium sulfite) and 0.3 g of N-hydroxy-N'-butyl urea are dissolved in 50 ml of dioxan. 0.4 g of thionyl chloride in 10 ml of dioxan is added dropwise to this solution, and the batch is heated for 2 hours at 60° C. Subsequently, the solvent is evaporated under reduced pressure, water is added dropwise to the residue, the oily substance is separated and reprecipitated from ammonia. The N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-butyl urea obtained has a melting point of 155°-157° C., and, with the substance obtained according to Example 8, shows no depression.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:11]1([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:21][CH:22]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3CCCCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 106.3 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (300 mg, 1.89 mmol, 1.00 eq) and 4-cyclohexylphenol (417 mg, 2.37 mmol, 1.25 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (397 mg, 2.87 mmol, 1.52 eq) was added and the reaction mixture was stirred at room temperature for 27 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100 to 1:75) to afford the title compound as colourless solid (600 mg, 2.01 mmol, quant. yield). Rf=0.35 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C17H19N2O3+ [M+H]+ 299.1390. found: 299.1392. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J=2.9 Hz, 1H, aromatic H), 8.46 (dd, J=9.1, 2.9 Hz, 1H, aromatic H), 7.31-7.22 (m, 2H, aromatic H), 7.07 (dd, J=8.7, 2.3 Hz, 2H, aromatic H), 7.00 (d, J=9.1 Hz, 1H, aromatic H), 2.58-2.51 (m, 1H, cyclohexyl H), 2.01-1.64 (m, 5H, cyclohexyl H), 1.56-1.10 (m, 5H, cyclohexyl H). 13C NMR (101 MHz, CDCl3) δ 167.18, 150.71, 145.88, 145.17, 140.22, 134.89, 128.30, 121.12, 111.30, 44.08, 34.59, 26.95, 26.19.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH3:18])=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:14][C@H:13]2[CH3:18])=[N:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1c1nnc(Cl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-chloro-4-(2-methylpiperazin-1-yl)phthalazine (2.94 g, 11.94 mmol) was dissolved in dry DMF (24 mL) and N,N-diisopropylethylamine (3.12 mL, 17.9 mmol). Benzoyl chloride (1.43 mL, 12.3 mmol) was added dropwise and the reaction stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (200 mL), and washed with aqueous K2CO3 (10%), water, and then saturated sodium chloride. The organic phase was dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave an off-white solid. MS (M+H)+=367.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[O:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)O1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of Ethyl (2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate (131) (0.32 g, 0.70 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, the title compound 132 was obtained as a white powder (0.255 g, 85%). mp 118-121° C. 1H NMR (400 MHz, DMSO-d6): δ 1.10 (s, 6H), 1.12 (s, 6H), 2.11 (s, 2H), 2.13 (s, 2H), 6.47 (d, J=15.9 Hz, 1H), 6.85-7.00 (m, 2H), 7.08 (d, J=1.8 Hz, 1H), 7.19 (d, J=8.2 Hz, 2H), 7.54 (d, J=15.9 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 10.15 (s, 1H), 12.36 (s, 1H). LCMS (ESI): m/z 425 (M−H)−. Anal. Calcd for C25H27ClO4.0.2H2O: C, 69.74; H, 6.41; Found: C, 69.82; H, 6.56.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][C:18](=[CH:21][C:22]#[N:23])[CH2:17][CH2:16]1.Cl.C(=O)(O)[O-].[Na+].OC1C=C(O)C=CC=1C1CCC(=CC#N)CC1>[Pd].C(O)C.CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][C:22]#[N:23])[CH2:19][CH2:20]1
Reactant: COCOc1ccc(C2CCC(=CC#N)CC2)c(OCOC)c1
Agent: [Pd]
Agent: Cl
Agent: N#CC=C1CCC(c2ccc(O)cc2O)CC1
Solvent: CO
Solvent: CCO
Product: N#CC[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Reaction time: 17 h

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added {4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetonitrile (408 mg, 1.3 mmol) and methanol (20 ml). The resulting solution was heated to reflux temperature and aqueous hydrochloric acid (20 ml, 1.0M) was added. The solution was heated for 1 hr then cooled and saturated aqueous sodium bicarbonate solution (50 ml) added. The mixture was partitioned between ethyl acetate (100 ml) and water (20 ml) and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording an oil. To a 50 ml round bottomed flask equipped with magnetic stirrer was added crude [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetonitrile (ca. 224 mg, 0.98 mmol) and ethanol (15 ml). To the stirred solution was added palladium (catalytic amount, 10% on activated carbon) in one portion. The reaction vessel was evacuated and then placed under a hydrogen atmosphere. This process was repeated 10 times before leaving the reaction mixture under a hydrogen atmosphere. Vigorous stirring was continued for 17 hr, then the reaction mixture was filtered through celite washing with methanol. The solvent was removed under reduced pressure and the residue was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:1, v/v), furnishing the title compound (226 mg, 80% over 2 steps) as a colourless oil. m/z (ES+) 232 (M+H+); δH(CD3OD) 1.31 (1H, m), 1.52 (1H, m), 1.67 (1H, m), 1.77 (0.5H, m), 1.83 (1H, m), 1.92 (2H, m), 1.98 (2H, m), 2.22 (0.5H), 2.44 and 2.67 (2H, d), 2.84 (1H, m), 6.28 (2H, m), 6.96 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:24][C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: O=Cc1ccncc1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccncc1)CC3
Yield: 53 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 4-pyridinecarboxaldehyde. Yield 53%; mp 119°-122° C.