Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:38](=[O:46])([O:42][CH:43]([CH3:45])[CH3:44])[O:39][CH2:40]Cl.[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[CH:43]([O:42][C:38]([O:39][CH2:40][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)=[O:18])=[O:46])([CH3:45])[CH3:44]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Reactant: CC(C)OC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (6 mL) was added chloromethyl isopropyl carbonate (76 mg, 503 μmol), NaI (101 mg, 670 μmol) and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (12 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography ((PE:EtOAc=1:1) to yield the title compound as a white solid (12.8 mg). LC-MS: 641.9 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) δ 1.21 (d, J=6.2 Hz, 6H), 3.21-3.28 (m, 2H), 4.12-4.30 (m, 2H), 4.40-4.52 (m, 1H), 4.77-4.79 (m, 1H), 5.68-5.76 (m, 2H), 7.41-7.45 (m, 1H), 7.50-7.87 (m, 9H), 7.90 (d, J=7.7 Hz, 2H), 9.98 (s, 1H), 12.76 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:24])[CH2:15][CH2:16]2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=[CH:3][CH3:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[CH3:1][C:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)=[CH:3][CH3:4]
Reactant: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
20,21 -Dimethylpregna-5,20-dien-3β-ol (6, 400.3 mg, 1.218 mmol) in 5 ml of methylene chloride was oxidized with pyridinium chlorochromate (525.4 mg 2.437 mmol) for 42 h. Ether (3.5 ml) was added and the suspension was filtered through a 5 mm dia.×60 mm high column of silica gel. The column was further eluted with 3.5 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography of the resin followed by recrystallization from aqueous ethanol gave yellow crystals (43.6 mg, 0.134 mmol l1). m.p. 157-165° C.
Reaction SMILES: [C:1]1(=[CH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH3:17])[C:10]=2[CH3:18])=[O:7])[CH2:4][CH2:3][CH2:2]1>CS(O)(=O)=O>[OH:15][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([CH3:18])[C:11]=1[CH3:17])[NH:8][C:6](=[O:7])[CH2:5][C:1]12[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(NC(=O)C=C2CCC2)c(C)c1C
Agent: CS(=O)(=O)O
Product: Cc1c(O)cc2c(c1C)NC(=O)CC21CCC1
Yield: 53 %

Procedure:
A solution of 2-cyclobutylidene-N-(4-methoxy-2,3-dimethylphenyl)acetamide (5 g) in methane sulfonic acid (20 mL) was refluxed at 120° C. overnight. After cooling down, the solution was poured onto ice. The solid present was collected by filtration and washed with water (×3), giving 6′-hydroxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,4′-quinolin]-2′(3′H)-one (2.5 g) which was used in the next step without further purification. 1H-NMR (300 MHz, CDCl3) δ=6.8 (s, 1H); 3.37 (s, 1H); 2.64 (s, 2H); 2.43 (m, 3H); 2.16 (s, 6H); 2.07 (m, 3H) ppm. MS: (m/z)=232 (100, M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:31]([OH:32])=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:38]([NH2:40])[CH3:39]>>[CH2:38]([NH:40][C:25](=[O:26])[CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]3[C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[C:31]([OH:32])[C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=1)[CH3:39]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O
Agent: Cl
Product: CCNC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1

Procedure:
According to a method similar to Example (49), from (4′-{[2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetic acid (187 mg, 0.374 mmol) obtained in Example (7) and ethylamine hydrochloride (61 mg, 0.75 mmol), the title compound was obtained as a colorless powder (129 mg, yield: 65%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[N:6]=1)(=[O:3])[CH3:2].[CH3:12][C:13]1([CH3:24])[O:18][C:17](=[O:19])[C:16](=[CH:20]OC)[C:15](=[O:23])[O:14]1>C(O)C>[C:1]([NH:4][C:5]1[N:6]=[C:7]([NH:11][CH:20]=[C:16]2[C:15](=[O:23])[O:14][C:13]([CH3:12])([CH3:24])[O:18][C:17]2=[O:19])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: CC(=O)Nc1cccc(N)n1
Solvent: CCO
Product: CC(=O)Nc1cccc(NC=C2C(=O)OC(C)(C)OC2=O)n1
Yield: 22.4 %

Procedure:
A mixture of 2-acetamido-6-aminopyridine (2.9 g, 19 mmol), (Angew. chem. 1995, 107, 2589), and 2,2-dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (4.28 g, 23 mmol), (Montatsh. Chem. 1967, 98, 564), in ethanol (75 ml) was stirred and heated at reflux for 5 hours. The mixture was allowed to cool and the precipitated product was collected by filtration and dried to give 5-((6-acetamido-2-pyridylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.3 g, 22%) as a yellow solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][N:12]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[CH:13]1[CH2:18][CH2:17][N:16](C(OCC=C)=O)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([SiH3])C=CC=CC=1>C(Cl)Cl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:12]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:32][CH:31]=1
Reactant: C=CCOC(=O)N1CCC(N(CCNC(=O)c2ccccc2)CCc2ccc(Cl)cc2)CC1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: O=C(NCCN(CCc1ccc(Cl)cc1)C1CCNCC1)c1ccccc1

Procedure:
The solution of allyl 4-((2-benzamidoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate, PhSiH3 (5 equiv) in DCM (8 mL/mmol) was degassed for 10 min by bubbling argon through the inserted needle, prior to the addition of Pd(Ph3P)4 (5 mol %). After 20 min TLC indicated completion of reaction. The reaction was concentrated and was purified by column chromatography in DCM/MeOH solvent system (gradient 100:1 to 10:1) to give pure product in a form of an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:17]=[N:18][C:19]4[N:20]([N:30]=[CH:31][C:32]=4[C:33](O)=[O:34])[C:21]=3[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:17]=[N:18][C:19]4[N:20]([N:30]=[CH:31][C:32]=4[C:33]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:34])[C:21]=3[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 35.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(4-fluorophenyl)piperidine-1-carbonyl]-7-(3-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.11 mmol) obtained in step 2 and ethanesulfonamide (0.070 g, 0.64 mmol), the title compound (0.022 g, 37%) was obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:31][CH:30]([CH2:32][C:33](OC)=[O:34])[CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH:30]5[CH2:31][O:28][CH2:29]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)CC1COC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (15.4 mg, 51.2%), MS (ISP) m/z=430.5 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and methyl 2-(oxetan-3-yl)acetate prepared from Oxetan-3-ylidene-acetic acid methyl ester as reported on WO2010031735. (example 47)
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([N:10]=[N+:11]=[N-:12])[CH2:8][CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].[Li+].[OH-]>C1COCC1.O>[C:16]([O:15][C:13]([N:6]1[CH2:7][CH2:8][C@@H:9]([N:10]=[N+:11]=[N-:12])[C@H:5]1[C:3]([OH:4])=[O:2])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@@H]1[C@H](N=[N+]=[N-])CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (2S,3R)-3-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [361367-97-7] (210 mg, 0.777 mmol; Sunshine Ltd) in THF (6 mL) was added a solution of LiOH (55.8 mg, 2.33 mmol) in water (3 mL), followed by stirring at RT for 20 h. The reaction mixture was concentrated under reduced pressure and the residual aqueous phase was washed with EtOAc (3×). The water phase was adjusted to pH 2 to 3 by adding 1N aqueous HCl, followed by extraction with EtOAc (3×). The combined organics were dried (Phase separator) and concentrated in vacuo to give the crude title compound as a colorless oil. The crude product was used in the next reaction step without further purification. MS (LC/MS): 279 [M+Na]+, 200 [MH−tBu]+, 157 [MH−Boc]+; tR (HPLC conditions b): 2.77 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([C:14]([OH:16])=[O:15])[CH2:10]2)=[O:5])[CH3:2].[CH:17]1(O)[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH:7]12[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]([C:14]([O:16][CH:22]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)=[O:15])[CH2:8]2
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)C2
Reactant: OC1C=CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)N1C2CCC1CC(C(=O)OC1C=CCCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-4) (1.88 g, 8.27 mmol) in dichloromethane (30.0 mL) was added 2-cyclohexen-1-ol (0.812 g, 8.27 mmol, Aldrich), EDC (2.38 g, 12.4 mmol), and DMAP (0.100 g). The mixture was stirred at room temperature overnight and quenched with EtOAc (200 mL). The organic solution was washed with a 5% aqueous HCl solution (100 mL), saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL), and dried over anhydrous MgSO4, and concentrated. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (1-5) as colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:24]1[CH:25]=[C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:29]=[CH:30][CH:31]=1)[CH:21]=[CH2:22]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: C=CCOc1cccc(C=O)c1
Product: C=CCOc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-prop-2-enoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-prop-2-enoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl.N1([C:7]([CH:9]2[CH2:17][CH2:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10]2)=[O:8])CCCC1.P(Cl)(Cl)(Cl)=O.[CH3:23][C:24]1[N:32]2[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)=[CH:26][CH:25]=1>ClC(Cl)C>[CH3:23][C:24]1[N:32]2[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)=[C:26]([C:7]([CH:9]2[CH2:17][CH2:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10]2)=[O:8])[CH:25]=1
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Reactant: Cc1ccc2ccccn12
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)C2CCc3nc[nH]c3C2)c2ccccn12
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To 10 ml of dichloroethane were added 1.08 g of 5-pyrrolidinocarbonyl-4,5,6,7-tetrahydrobenzimidazole hydrochloride and 1.18 ml of phosphorus oxychloride, and the mixture was stirred at 80° C. for 1 hour. At the same temperature 0.69 g of 3-methylindolizine in 2 ml of dichloroethane was added dropwise thereto during 15 minutes. The mixture was refluxed while stirring for 3 hours after that the mixture was poured into 20 ml of ice-water, and then the mixture was stirred at room temperature for 30 minutes. After liquid-liquid separation, the aqueous layer was washed with 10 ml of dichloromethane. Further, the aqueous layer was adjusted to a pH of about 9 with an aqueous 20% sodium hydroxide solution and then extracted with 20 ml of chloroform-methanol (4:1) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed off under reduced pressure. The residue was washed with 20 ml of dichloromethane-ethylacetate (3:1) to obtain 1.00 g of 5-[(3-methylindolizin-1-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:10][C:11]1[CH:26]=[CH:25][C:14]([CH2:15][CH:16]([C:22]([CH3:24])=O)[C:17](OCC)=[O:18])=[CH:13][CH:12]=1.Cl>C(O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[C:17](=[O:18])[O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[C:3]=3[C:22]=2[CH3:24])=[CH:25][CH:26]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1c(Cc2ccc(Cl)cc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (1.57 g) and ethyl 2-(4-chlorobenzyl)-acetoacetate (3.18 g) in ethanol (25 ml) was treated with dry HCl at 0° C. for 1.5 hours and the solution was kept at that temperature overnight. Solvent was evaporated and the precipitate triturated with water. Yield 3.87 g (98%). Melting point 270-278° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])C>O1CCOCC1>[N:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][CH:8]([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]1
Reactant: CCOC(=O)C1CCN(c2ccccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.3 %

Procedure:
Sodium hydroxide solution (5M, 24.8 ml, 0.12 mol) was added drop wise to a solution of 3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-carboxylic acid ethyl ester (5.8 g, 24 mmol)(see reference Farmaco, 1993, 48(10), 1439) in 1,4-dioxane (100 ml). The mixture was stirred at room temperature for 72 hours and then evaporated under reduced pressure. The residue was purified by ion exchange chromatography on Dowex® 50 WX8 resin using methanol and ammonium hydroxide solution in water as eluant (gradient from 0:0:100 to 0:5:95 to 5:5:90). The material obtained was triturated with diethyl ether to give the title compound (4.42 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:42]=[N:41]C=2C=1.O.NN>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([NH:41][NH2:42])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)O)c2ccccc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NN)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.9 %

Procedure:
A mixture of 4-(1-phenyl-1-carboxy-methylene)piperidine-1-carboxylic acid tert-butyl ester (0.153 g, 0.048 mol), EDCI (0.113 g, 0.059 mol), and HOBt (0.081 g, 0.060 mol) in DMF (3 mL) was stirred for 30 min at room temperature and then hydrazine hydrate (1.0 mL) was added. Stirring was continued for 12 h and then the mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed, (H2O ×5, brine) and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (0.147 g, 92%) as a colorless oil:
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[CH:11]=[N:12]/O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.CO>CC(O)=O.[Zn]>[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:15])([CH3:14])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(/C=N/O)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)OB(O)c2cc(CN)ccc21
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]-oxaborole-6-carbaldehyde oxime (2.7 g, 13.15 mmol) in AcOH (30 mL) at rt was added zinc dust (2.56 g, 39.45 mmol). The reaction mixture was stirred at 40° C. for 4 h under argon. Methanol was added and the mixture was filtered over Celite. The filtrate was concentrated and dissolved in ethyl acetate. The organic layer was washed with water. The water layer was lyophilized to give the crude compound 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:22])[C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)([OH:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH:23]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH:23]1([CH2:30][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:22])[C:9]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)([OH:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:5][CH2:6]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(NC1CCNCC1)C(O)(c1ccccc1)C1CCCC1
Reactant: O=CC1CCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccccc1)C1CCCC1
Reaction time: 17 h

Procedure:
34 mg of N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide obtained in Step 2 of Example 27, 50 mg of cycloheptanecarbaldehyde and 10 mg of acetic acid were dissolved in tetrahydrofuran. 70 mg of sodium triacetoxyborohydride was added thereto and the resulting mixture was stirred for 17 hours. After the addition of a saturated aqueous solution of sodium bicarbonate, the reaction mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by preparative thin layer chromatography (Kieselgel™, 60F254, Art 5744 (manufactured by E. Merck; developing solvent: chloroform/methanol=10/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:32][NH2:33].C1COCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[F:20][C:17]1[CH:18]=[CH:19][C:14](/[C:12](/[CH3:13])=[CH:11]/[N:7]2[C:8]3[CH:9]=[CH:10][C:2]([NH:33][CH3:32])=[CH:3][C:4]=3[C:5]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:6]2=3)=[CH:15][CH:16]=1
Reactant: CN
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)c1c(n2/C=C(\C)c2ccc(F)cc2)CCN(C)C1
Temperature: 100 °C

Procedure:
Palladium (II)acetate (314 mg, 1.4 mmol) and 2-(di-t-butylphosphino)biphenyl (418 mg, 1.4 mmol) were charged in a reaction bottle which was evacuated and backfilled with nitrogen. Toluene (10 mL) was added dropwise under nitrogen and stirred at RT overnight. The reaction mass was passed through basic alumina using 0-30% ether:hexane and triturated with pentane to yield 300 mg of brownish solid. 8-Chloro-5-(2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (50 mg, 0.282 mmol), sodium tert-butoxide (81.2 mg, 0.846 mmol), and palladacycle [palladium (II)acetate+2-(di-t-butylphosphino)biphenyl) (10.7 mg, 0.0282 mmol)] was charged in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Dry toluene (1 mL) was added under nitrogen atmosphere. Finally, 2M methyl amine in THF (0.39 mL, 0.198 mmol) was added and the contents heated at 100° C. overnight. The reaction mixture was filtered and washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and purified by reverse phase chromatography to yield 10 mg of free base. 1H NMR (DMSO, oxalate salt) δ (ppm): 7.62 (d, 2H), 7.20 (d, 2H), 6.96 (d, 2H), 6.58 (d, 1H), 6.50 (s, 1H), 4.24 (m, 2H), 3.40 (m, 2H0, 2.95 (m, 2H), 2.88 (s, 3H), 2.64 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[S:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[N:18][C:17]=3[CH3:31])=[CH:10][C:7]=2[S:8][CH:9]=1.CC1N=C(C2C=CC(C(F)(F)F)=CC=2)SC=1CSC1C=CC2OC(C(O)=O)=CC=2C=1>>[CH3:31][C:17]1[N:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[S:20][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:6]2[C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:9][S:8][C:7]=2[CH:10]=1
Reactant: COC(=O)Cc1csc2cc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2oc(C(=O)O)cc2c1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(CC(=O)O)csc2c1

Procedure:
The title compound was prepared from compound 23D in a manner analogous to compound 6. MS m/z 464 (M+1).