Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C:10]([O:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][O:27][C:28](=[O:38])[CH2:29][O:30]CC1C=CC=CC=1)=[O:25])=[O:15])=[O:11])C1C=CC=CC=1>CN(C=O)C.[Pd]>[OH:8][CH2:9][C:10]([O:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][O:27][C:28](=[O:38])[CH2:29][OH:30])=[O:25])=[O:15])=[O:11]
Reactant: O=C(COC(=O)COCc1ccccc1)NCCCCCCNC(=O)COC(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(COC(=O)CO)NCCCCCCNC(=O)COC(=O)CO
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Benzyloxy-acetic acid {6-[2-(2-benzyloxy-acetoxy)-acetyl amino]-hexylcarbamoyl}-methyl ester (250 g) was dissolved in DMF (600 ml) in a pressure vessel (Autoclave), 50% wet palladium on carbon (10%, 75 g) was added and the mixture was stirred under hydrogen atmosphere (8 Kg) for 72 hours at 70° C. The catalyst was removed by filtration and 80% of the DMF was distilled off. The crude product was precipitated by adding to Methanol and filtered and dried to get pure (Hydroxy-acetic acid {6-[2-(2-hydroxy-acetoxy)-acetylamino]-hexylcarbamoyl}-methyl ester) (90 g) as a white powder with a melting point of 156-158° C. The pure product was characterized by IHNMR (CDCl3+ DMSO-d6) δ 1.22 (m, 2H, CH2), 1.38 (m, 2H, CH2), 3.06 (m, 2H, CH2), 4.15 (d, 2H, CH2), 4.48 (s, 2H, CH2), 5.42 (t, 1H, OH), 7.98 (bt, 1H, NH).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#N.[OH-:9].[K+].[OH2:11]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:11])=[O:9]
Reactant: [OH-]
Reactant: O
Reactant: N#CCc1ccco1
Agent: [K+]
Product: O=C(O)Cc1ccco1

Procedure:
A mixture of 2-furanacetonitrile (6.14 g), KOH (4.0 g), and water (25 mL) was refluxed for 1 hour and then cooled. Following extraction with ether, the aqueous layer was acidified to pH 2.0 with concentrated aqueous HCl. This solution was extracted with ether, and the organic phase was dried over MgSO4 and evaporated under vacuum to yield 2-furanacetic acid. The structure of the product was confirmed by NMR.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[CH:9][CH:10]=[O:11].[CH3:13][C:14]1[O:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:18]=1>C(#N)C>[CH3:13][C:14]1[O:15][C:16]([CH:8]=[CH:9][CH:10]=[O:11])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:18]=1
Reactant: Cc1cc(-c2ccc(F)cc2)co1
Reactant: CN(C)C=CC=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(F)cc2)c(C=CC=O)o1
Temperature: -23 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 1.1 mL (11.9 mmol) of phosphorus oxychloride in 15 mL of acetonitrile was allowed to react with 1.2 mL (11.9 mmol) of 3-dimethylaminoacrolein at -23° C. After 0.25 hour at -23° C., 1.4 g (7.9 mmol) of 2-methyl-4-(4'-fluorophenyl)furan in 10 mL of acetonitrile was added dropwise. The reaction mixture was stirred at -23° C. for 0.15 hour then at 24° C. for 2 hours. The reaction was quenched upon treatment with 20 mL of 1M NaOH and extracted three times with CHCl3. The CHCl3 layers were combined, dried (MgSO4) and concentrated under reduced pressure. Column chromatography (3:1 hexanes-diethyl ether) of the residue on silica gel produced 1.76 g (97%) of 3-(5-methyl-3-p-fluorophenyl-furan-2-yl)acrylaldehyde as a solid (m.p. 89°-90° C.), homogeneous by TLC and spectroscopic criteria; Rf 0.58 (1:1 hexanes-diethyl ether); IR (KBr) 1655, 1600, 1205, 1118, 1095 cm-1 ; 1HNMR (300 MHz, CDCl3) 9.60 (d, 1H, J=10.5 Hz), 7.41 (m, 2H), 7.27 (d, 1H, J=15 Hz), 7.18 (t, 2H, J=9.0 Hz), 6.64 (dd, 1H, J=10.5 Hz, 15 Hz), 6.32 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C-:12]#[N:13].[K+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>ClCCl.O>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]2[C:12]#[N:13])=[O:21])=[CH:18][CH:17]=1
Reactant: [C-]#N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc2ncccc2c1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1)C=CC(C#N)N2C(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 5 %

Procedure:
To a biphasic mixture of 6-methylquinoline (1.0 g) in dichloromethane (9 mL) and potassium cyanide (1.37 g) in water (4 mL) was added 4-chlorobenzoyl chloride (1.78 mL). The reaction mixture was stirred at ambient conditions overnight. The reaction mixture was then filtered and the filtrate washed successively with water, 1N hydrochloric acid, 1N sodium hydroxide solution and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by liquid chromatography (gradient elution of acetonitrile (0.02% trifluoroacetic acid)/water (0.02% trifluoroacetic acid) through a reverse phase C 18 column) to give the titled compound (118 mg product, 5% yield) as a foam. (M+H)+−309.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]C=2)[CH:3]=C1.C([Cu])#N.C[N:14]1[C:18](=O)[CH2:17][CH2:16][CH2:15]1.C[C:21](=[O:25])[O:22]CC>>[C:9]([C:4]1[CH:3]=[C:18]2[C:17]([C:16]([C:21]([OH:25])=[O:22])=[CH:15][NH:14]2)=[C:6]([CH3:7])[CH:5]=1)#[N:1]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Product: Cc1cc(C#N)cc2[nH]cc(C(=O)O)c12
Temperature: 180 °C
Yield: 45.6 %

Procedure:
A mixture of compound 1 (10.0 g, 50.0 mmol), CuCN (9.0 g, 100 mmol) and NMP (60 mL) was heated at 180° C. for 6 h. The mixture was cooled to room temperature, diluted with EA, then washed with H2O, brine, dried and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1) to give the desired product (3.30 g, 22.8 mmol, 45.6%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:15]1([CH:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:22]2[CH2:25][CH:24](S(C)(=O)=O)[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH:21]([N:22]1[CH2:25][CH:24]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:23]1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Temperature: 75 °C
Yield: 29.1 %

Procedure:
To a solution of 3.9 g (0.035 mol) of 3-fluorophenol in 250 mL of acetonitrile, was added 6.3 g (0.045 mol) of K2CO3 followed by 12.25 g (0.039 mol) of 1-(diphenylmethyl)-3-methane sulfonyl azetidine, prepared according to the procedure of Example 1a, Step 4. The reaction mixture was heated at 75° C. for 18 h. The solvent was removed under vacuo, and the residue was taken up in a mixture of ether and water. The aqueous layer was extracted with ether, the combined extracts were dried over magnesium sulfate, and the solvent was removed under vacuo. The product was filtered through 500 mL of silica gel, eluted with 50% CH2Cl2/hexane then 15% ethyl acetate/hexane to give 3.4 g of the title compound: mp 81-82° C. 1H NMR (300 MHz, CDCl3) δ 3.17 (dd, 2H), 3.72 (dd, 2H), 4.46 (s, 1H), 4.77 (m, 1H), 6.48 (dd, 1H), 6.53 (dd, 1H), 6.63 (m, 1H), 7.22 (m, 3H), 7.29 (m, 4H), 7.31 (dd, 4H); MS (ES) m/z (relative intensity): 334 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([C:10](=[O:23])[CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH3:9])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH3:25].[Br:26]N1C(=O)CCC1=O.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>ClCCl>[Br:26][CH2:25][C:3]1[C:2]([Cl:1])=[C:7]([CH:6]=[CH:5][C:4]=1[Cl:24])[N:8]([CH3:9])[C:10](=[O:23])[CH2:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17]
Reactant: Cc1c(Cl)ccc(N(C)C(=O)CN2C(=O)c3ccccc3C2=O)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CBr)c1Cl
Yield: 27.8 %

Procedure:
A mixture of 2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]toluene (303 mg), N-bromosuccinimide (150 mg), 2,2'-azobis-(2,4-dimethyl-4-methoxyvaleronitrile) (30 mg) and dichloromethane (6 ml) was heated under reflux for 5 hours. N-Bromosuccinimide (75 mg) was added therein and the mixture was heated under reflux for additional 3 hours. The reaction mixture was washed with saturated sodium bicarbonate solution twice and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-bromomethyl-2,4-dichloro-N-methyl-N-(phthalimidoacetyl)aniline (102 mg) as crystals.
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:8]=1)[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:21]
Reactant: C1CCNC1
Reactant: CCOC(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Product: CCOC(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N1CCCC1

Procedure:
Synthesized as in Example 51 from Intermediate 17 (0.54 g, 1.86 mmol) and pyrollidine (284 mg, 4.0 mmol). This gave 0.415 mg (62%) of product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[N:6]=[CH:5]2.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:33][C@H:29]4[CH2:30][CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28]4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COc1ccc(Cn2ncc3cc(Br)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ncc3cc(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)ccc32)cc1
Temperature: 80 °C
Yield: 83.3 %

Procedure:
To a solution of 5-bromo-1-(4-methoxybenzyl)-1H-indazole (870 mg, 2.75 mmol) in toluene (10 mL) was added in succession (S)-tert-butyl3-aminopiperidine-1-carboxylate (660 mg, 3.3 mmol), sodium tert-butoxide (475 mg, 5 mmol), and rac-(±)-BINAP (180 mg, 0.29 mmol). The flask was evacuated and refilled with nitrogen three times, after which Pd2 dba3 (83 mg, 1.5 mol %) was added. The flask was again purged with nitrogen three times, and was then heated to 80° C. overnight. The solution was cooled to room temperature and then filtered through a pad of celite, washing with additional toluene. The toluene solution was then loaded directly onto a silica gel column that had been packed with heptane. The column was flushed with 2 column volumes of heptane, and then eluted with 40/60-EtOAc/heptane to afford the title compound (1.00 g 82%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:17]([C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][Cl:28])=[C:22]([O:31][CH3:32])[CH:21]=1)(=[O:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C(OC(=O)C)C(C)C>[ClH:28].[C:17]([C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][N:11]2[CH2:12][CH2:13][C:8]([C:6](=[O:7])[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=3)([OH:14])[CH2:9][CH2:10]2)=[C:22]([O:31][CH3:32])[CH:21]=1)(=[O:19])[CH3:18]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: O=C(c1ccc(F)cc1)C1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OCC(C)C
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(O)(C(=O)c2ccc(F)cc2)CC1
Product: Cl

Procedure:
A stirred mixture of 11.1 g (0.05 mole) of 4-(p-fluorobenzoyl)-4-hydroxy-piperidine, 14.6 g (0.06 mole) of 3-(p-acetyl-o-methoxyphenoxy)-propyl chloride and 25 g of anhydrous sodium carbonate in 350 ml iso-butylacetate was allowed to reflux for 48 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residual oil was converted to the HCl salt. 1-[3-(p-Acetyl-o-methoxyphenoxy)propyl]-4-(p-fluorobenzoyl)-4-hydroxy-piperidine hydrochloride was recrystallised from ethanol. Melting point 160°-162° C. Yield 16.2 g. Said product contained a certain amount of ethanol which can only be removed by extreme means.
Reaction SMILES: F[C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[N:14]2[CH3:17])=[CH:9][CH:8]=1)=[O:5].CN1CCCCC1=O.[NH2:35][C@@H:36]([CH3:39])[CH2:37][OH:38]>>[OH:38][CH2:37][C@@H:36]([NH:35][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[N:14]2[CH3:17])=[CH:9][CH:8]=1)=[O:5])[CH3:39]
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3F)cc21
Reactant: C[C@H](N)CO
Agent: CN1CCCCC1=O
Product: C[C@@H](CO)Nc1cc(C(F)(F)F)ccc1C(=O)Nc1ccc2c(c1)N(C)C(=O)CC2
Temperature: 180 °C
Reaction time: 0.67 h
Yield: 65.4 %

Procedure:
2-Fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide (250 mg), N-methylpiperidone (0.5 mL) and (2S)-2-aminopropan-1-ol (800 mg) were mixed, followed by stirring at 180° C. for 40 minutes under microwave irradiation. After spontaneous cooling and subsequent purification by silica gel column chromatography (chloroform:methanol, 99:1 to 95:5), 2-{[(1S)-2-hydroxy-1-methylethyl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide (188 mg) was obtained as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]1[C:10](=[O:11])[C:9]([C:12]#[N:13])=[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[C:7]12)[CH3:2].[OH:20]S(O)(=O)=O>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]1[C:10](=[O:11])[C:9]([C:12]([NH2:13])=[O:20])=[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[C:7]12)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)Cn1c2cccccc-2c(C#N)c1=O
Product: CCOC(=O)Cn1c2cccccc-2c(C(N)=O)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Cyano-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester (2.56 g, described in example 12), was suspended in concentrated H2SO4 (10 ml). The mixture was stirred at 25° C. for 3 hr and then poured into ice water (20 ml). After 5 minutes, the resulting solid was collected on a filter, washed with water and then diethyl ether, air dried and recrystallized from ethanoldiethyl ether to give 1.75 g of 3-(aminocarbonyl)-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester; mp 215°-220° C.; nmr (DMSO-d6) δ1.20 (t,J=7.5 Hz, 3H), 3.25 (broad, 2H), 4.15 (q, J=7.5 Hz, 2H), 5.0 (s, 2H), 7.6 (m, 4H), 9.3 (d, J=10 Hz, 1H); ir (white mineral oil) 3360, 3160, 1743, 1734, 1667, 1590 cm-1 ; uvλmax (MeOH) 276 nm (ε32,100), 232 (17,200), 223 (17,100); Anal Calc for C14H14N2O4 : C, 61.36% H, 5.15% N, 10.21%; Found: C, 61.12% H, 5.26% N, 10.24%.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>CC(O)C>[I:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13])=[C:2]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:10]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(I)nc21
Temperature: 85 °C

Procedure:
A mixture of 6-chloro-2-iodo-9-isopropyl-9H-purine (a) (1.0 g, 3.1 mmol), tyramine (0.64 g, 4.65 mmol), triethylamine (0.63 g, 6.2 mmol) and 2-propanol (30 mL) was heated at 85° C. for 2 hr. The reaction mixture was concentrated and saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (25 to 75% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 424.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:31])[C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(O)c1ccncc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccncc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and isonicotinic acid (66 mg, 0.54 mmol). The title compound was obtained as off-white powder (76 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[S:14])[CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15]I>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]=[C:12]([S:14][CH3:15])[CH2:11][S:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CSCC(=S)N2)cc1
Reactant: CI
Solvent: C1CCOC1
Product: CSC1=NC(c2ccc(F)cc2)CSC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature solution of 5-(4-fluoro-phenyl)-thiomorpholine-3-thione (710 mg, 3.2 mmol) in THF (20 mL) was added methyl iodide (1.1 mL, 16.7 mmol). The mixture was stirred at room temperature in the dark 18 hours, then concentrated under reduced pressure to give crude 3-(4-fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]thiazine as a hydroiodide salt, which was used directly in without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:23])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:16]([N:4]1[C:3](=[O:23])[C:2]([N:1]([S:32]([CH3:31])(=[O:34])=[O:33])[S:32]([CH3:31])(=[O:34])=[O:33])=[CH:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:5]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2cc(N)c(=O)n(Cc3ccccc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 4-amino-2-benzyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (60 mg, 0.20 mmol) and triethylamine (80 mg, 0.79 mmol) in toluene (1 ml), methanesulfonyl chloride (70 mg, 0.61 mmol) was added, followed by heating under stirring at 40° C. for 1 hour. Chloroform was added to the reaction mixture. The organic layer was washed with water and brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was separated and purified by silica gel preparative chromatography [developer: hexane/ethyl acetate (1/1)], whereby the title compound (76 mg, 90.4%) was obtained.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:23](C(C)C)CC)(C)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl>[Cl:29][CH2:30][C:31]([NH:23][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1)=[O:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)CCl
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Solvent: ClCCl
Product: O=C(CCl)NN1CCOC(c2ccccc2)(c2ccccc2)CC1

Procedure:
To the solution of 4.5 g of 7,7-diphenyl-hexahydro-1,4-oxazepine and 2.65 g of di-isopropyl-ethylamine in 30 ml of methylene chloride, that of 2.21 g of chloroactyl chloride in 25 ml of methylene chloride is added dropwise while stirring and cooling with ice. After stirring for 30 minutes at 0°-5°, the mixture is washed twice with 10 ml of cold N hydrochloric acid and 10 ml of cold 10% aqueous sodium carbonate each, dried, filtered and evaporated. The residue is triturated with diethyl ether and recrystallized from ethanol, to yield the 4-(2-chloroacetamido)-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 150°-152°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][NH:4][C:5](=[O:7])[CH:6]=1.[Mg].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>C1COCC1.CCOCC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]3([CH3:1])[CH2:6][C:5](=[O:7])[NH:4][NH:3]3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Reactant: Cc1cc(=O)[nH][nH]1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 9.8 g of 3-methyl-pyrazolin-5-one in 100 ml of THF is added dropwise with stirring and cooling, to a Grignard solution prepared from 4.8 g of magnesium and 20.3 g of 4-bromo-4'-fluoro-biphenyl in 800 ml of absolute ether. After stirring for 2 hours at 10°-25°, the mixture is decomposed with ice and dilute hydrochloric acid and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[O:8]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:17][C:12]=2[O:11][CH:10]=[CH:9]1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCCC>[ClH:1].[ClH:1].[O:8]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][N:19]3[CH2:20][CH2:21][N:22]([C:2]4[N:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:23][CH2:24]3)=[CH:17][C:12]=2[O:11][CH:10]=[CH:9]1
Reactant: Clc1ncccn1
Reactant: C1=COc2cc(CN3CCNCC3)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: C1=COc2cc(CN3CCN(c4ncccn4)CC3)ccc2O1
Product: Cl
Yield: 156.5 %

Procedure:
A solution of 11.4 g (0.1 mole) of 2-chloropyrimidine and 23.2 g (0.1 mole) of 1-(6-benzodioxinyl methyl)piperazine (oil) in 500 ml of pentanol, as refluxed for 6 hours, in the presence of 13.8 g (0.1 mole) of potassium carbonate. After the completion of the reaction, the so-formed salt was filtered off and the solvent was evaporated under reduced pressure. The so-obtained oily residue (30 g) was dissolved in 160 ml of anhydrous ethanol. After addition of an excess of hydrochloric acid ether solution, the dihydrochloride crystallises. 30 g of 1-(benzodioxin-6-yl methyl)-4-(pyrimidin-2-yl)piperazine dihydrochloride white crystals were finally obtained, melting at 215°-220° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]([CH3:16])[CH2:14][OH:15])=[CH:7]2)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C.O.C([O-])(O)=O.[Na+]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]([CH3:16])[CH2:14][OH:15])=[CH:7]2
Reactant: CC(CO)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(CO)c1cc2cc(N)ccc2[nH]1
Temperature: 120 °C
Yield: 81.5 %

Procedure:
To a solution of 2-(5-nitro-1H-indol-2-yl)propan-1-ol (0.13 g, 0.60 mmol) in ethanol (5 mL) was added tin chloride dihydrate (0.67 g, 3.0 mmol). The mixture was heated in the microwave at 120° C. for 1 h. The mixture was diluted with ethyl acetate before water and saturated aqueous NaHCO3 were added. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2-(5-amino-1H-indol-2-yl)propan-1-ol (0.093 g, 82%).