Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.I[CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CC(C)(C)CCI
Reactant: COc1cc(O)cc(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCCC(C)(C)C)cc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
1-(3-Hydroxy-5-methoxyphenyl)ethanone (O3.033; 1.12 g) and 1-iodo-3,3-dimethylbutane (1.57 g) were dissolved in DMF, and sodium hydride (194 mg) was added. After stirring at RT for 2 h, the DMF was drawn off. The residue was taken up in EA, washed with water, dried, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA 0-50% within 30 min). 850 mg of the title compound were obtained.
Reaction SMILES: ClC1C=CC(C2C3CCC(C(OC)=O)CCCC=3ON=2)=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:34]3[CH2:35][CH2:36][CH2:37][CH:38]([C:41]([O:43]C)=[O:42])[CH2:39][CH2:40][C:33]=3[O:32][N:31]=2)=[CH:26][CH:25]=1.[OH-].[K+].O>CO>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:34]3[CH2:35][CH2:36][CH2:37][CH:38]([C:41]([OH:43])=[O:42])[CH2:39][CH2:40][C:33]=3[O:32][N:31]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)C1CCCc2c(-c3ccc(Cl)cc3)noc2CC1
Agent: COC(=O)C1CCCc2onc(-c3ccc(Cl)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCCc2c(-c3ccc(Cl)cc3)noc2CC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
3 g (0.0094 mol) of a mixture of methyl 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-6-carboxylate and methyl 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-7-carboxylate were dissolved in 75 ml of methanol. 1.5 g of potassium hydroxide and 7 ml of water were added and the mixture was stirred at 20° C. for 18 hours. The methanol was removed by evaporation and an excess of water was added. The mixture was extracted twice with ethyl acetate and the aqueous phase was acidified with 2N hydrochloric acid. The aqueous-acidic layer was extracted three times with ethyl acetate and the combined ethyl acetate extracts were washed with sodium chloride solution and dried over magnesium sulfate. After evaporation and several crystallizations of the residue from ethyl acetate/hexane, there was obtained 0.78 g of 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-7-carboxylic acid of melting point 147°-150° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([C:24]4[O:25][C:26]([C:29]5[N:34]=[C:33]([C:35]([O:37]C)=[O:36])[CH:32]=[CH:31][CH:30]=5)=[CH:27][N:28]=4)=[O:23])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([C:24]4[O:25][C:26]([C:29]5[N:34]=[C:33]([C:35]([OH:37])=[O:36])[CH:32]=[CH:31][CH:30]=5)=[CH:27][N:28]=4)=[O:23])=[CH:18][CH:19]=3)=[CH:12][CH:13]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCOCC5)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCOCC5)cc4)cc3)o2)n1
Yield: 69.3 %

Procedure:
Methyl 6-(2-(3-(4′-(morpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (15 mg, 0.029 mmol) was dissolved in THF/H2O (3:2, 2 mL) and LiOH (2 mg, 0.09 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 25 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4′-(morpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a white solid (10 mg, 69%): 1H NMR (CDCl3, 600 MHz) δ 8.20 (d, 1H, J=7.1 Hz), 8.06 (s, 1H), 8.03-7.99 (m, 2H), 7.54 (d, 2H, J=7.7 Hz), 7.49-7.47 (m, 4H), 7.32 (d, 2H, J=7.9 Hz), 3.89 (s, 6H), 3.50 (t, 2H, J=7.4 Hz), 3.15 (t, 2H, J=7.5 Hz), 2.84 (s, 4H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 166.0, 157.4, 152.2, 149.4, 145.5, 141.1, 139.7, 138.9, 138.5, 130.7, 128.9, 128.0, 127.2, 127.2, 124.4, 123.2, 65.5, 61.9, 52.5, 40.6, 29.3; HR ESI-TOF m/z 498.2020 (M+H+, C29H27N3O5, requires 498.2023).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CN(C=O)C.O[N:18]=[C:19]([NH2:30])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1>O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][N:18]=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=2)[NH2:30])=[O:8])=[CH:10][CH:11]=1
Reactant: CC(C)Cc1ccc(C(N)=NO)cc1
Reactant: O=C(O)c1ccc(CO)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ccc(C(N)=NOC(=O)c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
1,1′-Carbonydiimidazole (2.37 g, 14.6 mmol) was added to a solution of 4-hydroxymethylbenzoic acid (2.00 g, 13.1 mmol) and DMF (50 mL) and stirred at room temperature for 1 hour. N′-Hydroxy-4-isobutylbenzamidine (2.54 g, 13.2 mmol) was added and stirred for 16 hours. The reaction mixture was diluted with water, causing a white solid to precipitate, filtered, washed with water, and dried to give the title compound (3.08 g, 72% yield) as a crude white solid.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:18][CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:9]([C:8]3[C:7]([CH2:18][CH3:19])=[CH:6][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:10])[CH2:22][CH2:23]2)=[CH:28][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a round-bottom flask were added a solution of 4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4, 1.15 g, 4.38 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.10 equiv), HBTU (2.50 g, 6.59 mmol, 1.50 equiv), and DIEA (1.07 g, 8.28 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred for 1 h at 25° C. The reaction was then quenched by the addition of 20 mL of water. The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:3) to yield 1.80 g (95%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate as a yellow solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CC=C(c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)C1CCC(c2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(4-t-butylcyclohex-1-enyl)-2-nitrobenzene (4.89 g, 18.86 mmol) prepared in Example (2b), 10% palladium on carbon (1.5 g, wet) and ethyl acetate (25 mL) was stirred for 4 hours under a hydrogen atmosphere at atmospheric pressure and room temperature.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:2].Br[CH2:13][C:14]#[N:15]>>[CH2:10]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:5][CH2:6][N:7]([CH2:13][C:14]#[N:15])[CH2:8][CH2:9]1)[CH3:11]
Reactant: N#CCBr
Reactant: CCN(CC)C1CCNCC1
Product: CCN(CC)C1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of Diethyl-piperidin-4-yl-amine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=196.2: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.80-2.75 (m, 2H), 2.45-2.30 (m, 5H), 2.15-2.05 (m, 2H), 1.70-1.60 (m, 2H), 1.45-1.35 (m, 2H), 0.95 (t, 6H).
Reaction SMILES: [2H-].[Al+3].[Li+].[2H-].[2H-].[2H-].[C:7]12([CH3:17])[C:14]([CH3:16])([CH3:15])[CH:11]([CH2:12][CH2:13]1)[CH2:10][C:8]2=[O:9].[H-]>CCOCC>[CH3:15][C:14]1([CH3:16])[C:7]2([CH3:17])[CH:8]([OH:9])[CH2:10][CH:11]1[CH2:12][CH2:13]2
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: [2H-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC1(C)C2CCC1(C)C(O)C2
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a slurry of lithium aluminum deuteride (LiAlD4) (0.012 g) in anhydrous ether (1 mL) was added, with stirring, camphor (0.1 g) in ether (2 mL), followed by heating at reflux for 3 hours. After cooling to room temperature, the excess hydride was decomposed by addition of moist ether, then the organic layer was washed with brine, dried (Na2CO4) and evaporated to give a quantitative yield of deuteriated isoborneol (0.1 g). 2H NMR (hexanes): δ 3.75. See B. Belleau, J. Am. Chem. Soc., 82, p. 5751 (1960).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1[C:34]2[CH:35]=[CH:36][CH:37]=C[C:33]=2[N:32]=[N:31]1.NN1CCCCC1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([NH:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 86.4 %

Procedure:
2,4-bis-benzyloxy-5-isopropylbenzoic acid (F67-01: 188 mg, 0.5 mmol), dimethylformamide (2 mL) and 1-hydroxy-1,2,3-benzotriazole (72 mg, 0.55 mmol) were placed in a test tube and then 1-amino-piperidine (0.059 mL, 0.55 mmol) was added. A mixed solution of dimethylformamide (1 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and triethylamine (0.15 mL, 1.1 mmol) was slowly added to the reaction mixture at 0° C. while stirring. Further, the reaction mixture was allowed to come to room temperature and stirred for 24 hours. After completing the reaction, the reaction mixture was extracted with ethyl acetate, and the extract was washed 4 times with saturated sodium chloride, dried with sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol) followed by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (F67-02: 198 mg, 86.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.[H-].[Na+].O>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1cnc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2nccc(Nc3cnc4ccccc4c3)c2cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (88 mg) and 3-aminoquinoline (72 mg) were dissolved in dimethylacetamide (1 ml) to prepare a solution. 60% sodium hydride (46 mg) was added to the solution under ice cooling. The mixture was stirred at 80° C. for 2 hr. Water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (37 mg, yield 28%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1[NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12]>CN=C=O.C1(CC#N)C=CC=CC=1.C(N(CC)CC)C>[CH3:7][NH:8][C:9](=[O:13])[O:15][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])=[C:6]([CH3:14])[CH:5]=1
Reactant: COCC(=O)Nc1c(C)cc(O)cc1C
Agent: CN=C=O
Solvent: CCN(CC)CC
Solvent: N#CCc1ccccc1
Product: CNC(=O)Oc1cc(C)c(NC(=O)COC)c(C)c1
Reaction time: 48 h

Procedure:
3,5-Dimethyl-4-methoxyacetamidophenol (0.8g., 0.0038 mole, m.p. 169°-73° C., prepared by reaction of methoxyacetyl chloride with 3,5-dimethyl-4-aminophenol) was reacted with methyl isocyanate (0.245g., 0.004 mole) in benzeneacetonitrile using a few drops of triethylamine as a catalyst. After stirring the initially clear reaction solution for about two days, the precipitated product was filtered (0.6g., m.p. 179.5°-82° C.).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([Cl:14])[C:9]([F:13])=[CH:10][CH:11]=2)[C:6](=[O:15])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:22])(=O)=O>C(=O)(O)[O-].[Na+]>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([Cl:14])[C:9]([F:13])=[CH:10][CH:11]=2)[C:6]([O:15][CH3:22])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)N1CC(=O)c2c1ccc(F)c2Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: COc1cn(C(C)=O)c2ccc(F)c(Cl)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 2 g of 1-acetyl-4-chloro-5-fluoroindolin-3-one, 2 g of powdered sodium hydroxide and 30 ml of dimethyl sulfate was stirred at room temperature for 5 hours. After the addition of 250 ml of saturated sodium bicarbonate solution the mixture was stirred overnight and subsequently filtered. The residue was filtered in 150 ml of ether and 100 ml of ethyl acetate. The solution was dried over sodium sulfate, filtered and evaporated. There were obtained 2 g (95%) of 1-acetyl-4-chloro-5-fluoro-3-methoxyindole as greenish crystals with m.p. 114°-115°.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1>>[OH:1][CH:2]([CH2:6][CH3:7])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1)=[O:4]
Reactant: Cc1ccc(N)nc1
Reactant: CCC(O)C(=O)O
Product: CCC(O)C(=O)Nc1ccc(C)cn1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A8, starting from 2-hydroxy-butyric acid and 2-amino-5-picoline,
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[C:20]4[C:15](=[CH:16][C:17]([N:21]([CH3:29])[C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=5)=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:30](N)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[C:20]4[C:15](=[CH:16][C:17]([N:21]([CH3:29])[C:22]5[CH:23]=[C:24]([NH:28][C:30](=[O:37])[C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)c1ccccc1
Reactant: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)n[nH]c2c1
Product: CN(c1cccc(NC(=O)c2ccccc2)c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)n[nH]c2c1

Procedure:
N-[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-N-methyl-benzene-1,3-diamine (prepared as described in Example 15) was converted to N-(3-{[32-benzo[1,3]dioxol-5-yl-vinyl)1H-indazol-6-yl]-methyl-amino}-phenyl)-benzamide in the manner described in Example 12(a). LCMS (ESI) [M+H]/z Calc'd 489, Found 489. Anal. Calc'd: C, 73.76; H, 4.95; N, 11.47. Found: C, 73.19; H, 5.09; N, 11.20.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:10]1([C:13]([C:32]2[CH:33]=[CH:34][C:29]([NH:28]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:30][CH:31]=2)=[O:14])[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]1
Reactant: Nc1ccccc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C(=O)C2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4cyclohexyl-carbonyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C30H28N2O4
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([NH:35][C:19]([C:8]2[C:9]3[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=3[S:18][C:7]=2[NH:6][C:4](=[O:5])[C:3]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:2]=2[F:1])=[O:21])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCC1
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NC1CCCC1

Procedure:
The title compound was prepared from the product of Example 45A and commercially available cyclopentylamine by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.43 (s, 6H), 1.47 (s, 6H), 1.43-1.50 (m, 4H), 1.55-1.66 (m, 2H), 1.74-1.82 (m, 2H), 4.02-4.14 (m, 1H), 7.67-7.77 (m, 3H), 8.04 (d, J=7.5 Hz, 1H), 11.53 (br s, 1H). MS (ESI+) m/z 499 (M+H)+. Anal. calcd. for C24H26F4N2O3S: C, 57.82; H, 5.26; N, 5.62. Found: C, 57.77; H, 5.32; N, 5.53.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.Br[CH:12]([CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].O1CCC(C=CC(OCC)=O)CC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]([CH2:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Brc1cccc2[nH]ncc12
Reactant: CCOC(=O)C(Br)CC1CCOCC1
Agent: CCOC(=O)C=CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC1CCOCC1)n1ncc2c(Br)cccc21
Yield: 53.4 %

Procedure:
A mixture of 4-bromo-1H-indazole (3.00 g), a 1:1 mixture (6.73 g) of ethyl 2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate and ethyl 3-(tetrahydro-2H-pyran-4-yl)-2-propenoate, potassium carbonate (2.1 g) and N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. To the reaction mixture was added 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 to give the title compound (3.10 g) as a yellow oil from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). MS: 383 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[O:14])[C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1.Br.C(S[C:31](=[NH:33])[NH2:32])C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:31]([N:11]1[CH2:10][CH2:9][CH:8]([N:6]2[CH2:7][C:3]([O:2][CH3:1])=[C:4]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[C:5]2=[O:14])[CH2:13][CH2:12]1)(=[NH:32])[NH2:33]
Reactant: COC(=O)CCc1ccc(C2=C(OC)CN(C3CCNCC3)C2=O)cc1
Reactant: CCSC(=N)N
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C2=C(OC)CN(C3CCN(C(=N)N)CC3)C2=O)cc1

Procedure:
Prepared from 4-methoxy-3-[4-(2-methoxycarbonyl-ethyl)phenyl]-1-(piperid-4-yl)-3-pyrrolin-2-one and S-ethylisothiourea-hydrobromide by heating to 100° C. for 4 hours in dimethylformamide in the presence of sodium carbonate.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([C:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:24])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccnc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1cccnc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {(R)-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-pyridin-3-ylmethyl-ethyl}-carbamic acid tert-butyl ester (0.149 g, 0.34 mmol) in dichloromethane (2 ml) is added trifluoroacetic acid (0.5 ml) and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture is evaporated and the residue takeup in hydrochloric acid (1M), the solution basified with sodium hydroxide solution (4M) and the precipitate extracted into dichloromethane. The dichloromethane was dried over magnesium sulphate and evaporated to afford [1-((R)-2-amino-3-pyridin-3-yl-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 1.63-1.85 (m 4H), 1.88-2.00 (m 1H), 2.08-2.32 (m 5H), 2.50 (dd J 13.5 7.9 1H), 2.67 (dd J 13.5 4.9 1H), 2.78-2.98 (m, 2H), 3.04-3.20 (m, 2H), 7.04 (t J 8.8 2H), 7.17 (dd J 6.9 4.9 1H) 7.48 (d J 7.9 1H), 7.88 (dd, J 8.8 5.4 2H), 8.33-8.45 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1.[S:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(OCC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:6]=1[C:7]([N:36]1[CH2:37][CH2:38][S:34][CH2:35]1)=[O:9]
Reactant: C1CSCN1
Reactant: CCCc1c(OC)ccc(C(=O)O)c1OCOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCc1c(OC)ccc(C(=O)N2CCSC2)c1OCOC
Reaction time: 0.25 h

Procedure:
Under argon atmosphere, a solution of 2-methoxymethoxy-3-n-propyl-4-methoxybenzoic acid (8 g) and 4-dimethylaminopyridine (0.38 g) in methylene chloride (150 ml) was cooled to 0° C., and to the solution was added N,N'-dicyclohexylcarbodiimide (7.8 g). The mixture was agitated for 15 minutes. Thiazolidine (3.0 ml) was added to the mixture, and the mixture was agitated at room temperature for another 15 hours. To the reaction mixture was added diethyl ether, and the mixture was filtered. Water and 1N aqueous hydrochloric acid were added to the filtrate, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel. There was obtained N-(2-methoxymethoxy-3-n-propyl-4-methoxybenzoyl)thiazolidine (9.0 g) from fractions eluted with n-hexane-ethyl acetate (2:1).