Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[H][H]>C(O)C.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:35])=[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]4)[C:13]=3[O:12]2)=[CH:2]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OC(Cc2c[nH]c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.030 g, 0.063 mmol) obtained in Example A11, Step 1 in ethanol (2.0 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.027 g) under an argon atmosphere, and then the inside of the reaction vessel was replaced with hydrogen. The reaction mixture was stirred at room temperature for 4 hours, and then filtered through Celite, and the solvent was evaporated under reduced pressure to obtain tert-butyl 4-({2-[(1H-indol-3-yl)methyl]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.028 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=NO)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
4-Methylbenzaldehyde (20 g, 166 mmol), hydroxylamine hydrochloride (12.7 g, 183 mmol), and sodium acetate (23.1 g, 282 mmol) were dissolved in a mixed solvent of ethanol (400 ml) and water (150 ml), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (20.6 g, 152 mmol, 91.8%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[C:25](OC([O-])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(Cl)(Cl)Cl>[C:28]([O:27][C:25]([NH:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(nnc1CNC(=O)OC(C)(C)C)CN=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (20 g) was dissolved in chloroform (200 ml). tert-Butyl dicarbonate (13.4 g) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The mixture was washed with a saturated aqueous sodium hydrogen-carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 23.85 g of 9-(tert-butoxycarbonylaminomethyl)-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([CH2:13][CH3:14])[NH:7]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>O1CCOCC1.C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][CH3:14])=[N:7]2
Reactant: CCC1Nc2cccc(Cl)c2NC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2cccc(Cl)c2[nH]c1=O
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 8-chloro-3-ethyl-3,4-dihydroquinoxalin-2(1H)-one (1.30 Kg, 6.17 mol) in anhydrous 1,4-dioxane (15 L) was added DDQ (1.47 Kg, 6.48 mol). The reaction mixture was stirred for 3 h (the internal temperature went up to 45° C. after DDQ addition). After this time LC-MS analysis showed that the reaction was complete. The mixture was evaporated under reduced pressure to give a brown residue. To this residue was added 2M aqueous NaOH to adjust the pH to 7-8. The resulting yellow solid was collected by filtration, suspended in saturated aq. NaHCO3, stirred for 1 h, and filtered to give a light green solid. The light green solid was suspended in saturated aqueous NaHCO3, stirred, filtered and washed with saturated aqueous NaHCO3 and water to give an off-white solid. The off-white solid was suspended in water, mixed well, filtered, washed with water, air-dried overnight, and dried under high vacuum at 50° C. to give 8-chloro-3-ethylquinoxalin-2(1H)-one (1 Kg). 1H NMR (DMSO-d6) δ ppm 7.69-7.75 (m, 1H), 7.59-7.65 (m, 1H), 7.29 (t, J=8.0 Hz, 1H), 2.84 (q, J=7.4 Hz, 2H), 1.23 (t, J=7.4 Hz, 3H). Mass Spectrum (ESI) m/z=209.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C(=O)C2=CC=CC=C2C1=O.OO>C(OCC)(=O)C>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(O)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: OO
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1
Temperature: 75 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
A mixture of 5 mmol of 1-phenylethanol, 0.5 mmol of N-hydroxyphthalimide, and 5 ml of ethyl acetate was stirred at 75° C. in an air atmosphere (5 atm) for 24 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 35% (selectivity: 86%). Separately, a gas chromatographic analysis of the reaction mixture revealed that the conversion rate from 1-phenylethanol was 40%, and acetophenone was formed in yield of 40%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]2CC)[CH:5]=[CH:6][CH:7]=1.Cl.[F:23][C:24]([F:34])([F:33])C1C=C(NN)C=CC=1.C1C=CC=CC=1>C(N(CC)CC)C>[C:14]1([C:11]2[C:12](=[O:13])[N:8]([C:4]3[CH:3]=[C:2]([C:24]([F:34])([F:33])[F:23])[CH:7]=[CH:6][CH:5]=3)[NH:9][CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCn1cc(-c2ccccc2)c(=O)n1-c1cccc(Cl)c1
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=c1c(-c2ccccc2)c[nH]n1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 8.2 grams of the atropic acid, methyl ester, (prepared in Example 11), 8.5 grams 3-(trifluoromethyl)-phenyl-hydrazine hydrochloride, 100 ml. benzene and 4 grams triethylamine, was refluxed overnight and worked up to yield 6.5 grams of 4-phenyl-1-(α,α, α-trifluoro-3-tolyl)-3-pyrazolin-5-one having a melting point of about 210°-213° C.
Reaction SMILES: [NH2-:1].[Li+].Cl[SiH:4]1[N:8]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:6][N:5]1[C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].CCCCCC>COCCOC>[NH2:1][SiH:4]1[N:8]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:6][N:5]1[C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1Cl
Reactant: [NH2-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
In an argon atmosphere, 439 mg (purity: 95%, 18.2 mmol) of lithium amide was suspended in 20 mL of 1,2-dimethoxyethane and after adding 6.07 g (17.6 mmol) of Si(tOctNCHCHNtOct)(H)Cl, the mixture was stirred at room temperature for 4 hours. To the reaction mixture, 20 mL of hexane was added, and the mixture was stirred at room temperature for 10 minutes. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 116° C./1.3×102 Pa) to obtain 2-amino-1,3-bis(1,1,3,3-tetramethylbutyl)-1,3-diaza-2-silacyclopent-4-ene (Si(tOctNCHCHNtOct)(H)NH2) as a pale yellow liquid (yielded amount: 4.99 g, yield: 87%).
Reaction SMILES: [CH:1]1([C@@H:7]([C:11]2[C:12]([NH2:28])=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=3)[CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1C2CCCC1CCC2.[OH-:38].[Na+].OO>O1CCCC1.O>[NH2:28][C:12]1[C:11]([C@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9][CH2:10][OH:38])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:13]=1
Reactant: C=CC[C@H](c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCCCC1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2ccc(Oc3ccccc3)cc2cc1[C@@H](CCCO)C1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of 3-((S)-1-cyclohexyl-but-3-enyl)-6-phenoxy-quinolin-2-ylamine (0.82 g, 2.2 mmol) in tetrahydrofuran (5.5 mL) at −20° C. was added 9-BBN (0.5 M in THF, 17.6 mL, 8.8 mol) dropwise over 20 min. The reaction mixture was stirred overnight while it reached room temperature. To the reaction mixture at 0° C. was then added aqueous 1N NaOH solution (8.2 mL) and aqueous 30% H2O2 solution (8.2 mL) and stirring was continued for 2.0 h. Water (15.0 mL) was added to the reaction mixture which was then extracted with EtOAc. The separated organic layer was dried (MgSO4) and concentrated in vacuo to yield crude material. The crude material was purified by silica gel column chromatography using 10% MeOH in CHCl3 to yield 4-(2-amino-6-phenoxy-quinoline-3-yl)-4-(S)-cyclohexyl-butan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:13](OC)=[O:14])[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>C(OCC)C>[CH3:1][O:2][C:3]([C:5]1([CH:13]=[O:14])[CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]1)=[O:4]
Reactant: CCCCC1CC(C(=O)OC)(C(=O)OC)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: CCCCC1CC(C=O)(C(=O)OC)C1
Reaction time: 2.5 h

Procedure:
To a solution of 3-butyl-cyclobutane-1,1-dicarboxylic acid dimethyl ester (8.37 g, 36.7 mmol) in diethyl ether (300 mL) at −78° C. under a nitrogen atmosphere was added diisobutylaluminum hydride (1.5M in toluene, 49 mL, 73.4 mmol) dropwise. After 2.5 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL) then with 1N HCl solution (150 mL). The aqueous phase was extracted with diethyl ether (100 mL×5), was dried (MgSO4) and was evaporated in vacuo to yield the title compound as a clear, colorless oil (7.2 g, 100%) which was used without further purification. MH+199.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[NH:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])N>CO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[N:2][N:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CNN
Reactant: COc1ccc(C(=CN(C)C)C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)Cn1ncc(-c2ccc(OC)cc2)c1-c1ccccc1

Procedure:
Following the procedure of example 1B 11 g (0.39 mol) of 3-(dimethylamino)-2-(4-methoxyphenyl)-1-phenyl-2-propene-1-one and 6.6 g (0.43 mol) of ethyl hydrazinoacetate hydrochloride were reacted in 55 mL of absolute methanol under nitrogen. After 11/2 hours, 11.2 g of solid product was filtered off, mp 81°-84° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl.O>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 30.9 %

Procedure:
To a stirred mixture of 2-amino-5-fluoro-3-nitrobenzotrifluoride (554 mg, 2.47 mmol) in ethanol (10 mL) was added SnCl2.2 H2O (2.78 g, 12.36 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h, cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried over Mg2SO4 and evaporated to give 148 mg (30%) of 2,3-diamino-5-fluorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ 3.666 (s, 2H); 3.676 (s, 2H); 6.610 (dd, 1H, J1 =2.4 Hz, J2 =9.0 Hz), 6.703 (dd, 1H, J1 =2.4 Hz, J2 =9.0 Hz).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:38]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1)([O-:40])=[O:39].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:17]=[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[N:8]1[C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:49][CH:48]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of trans-2-(4-hydroxy-cyclohexyl)-isoindole-1,3-dione (38 g, 155 mmol), triphenylphosphine (65 g, 248 mmol), and 4-nitrobenzoic acid (41 g, 248 mmol) in 1500 mL of THF was added dropwise diisopropyl azodicarboxylate (50 g, 248 mmol) at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated, and the resulting solid was recrystallized from methanol to afford 53 g (87%) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.40-8.36 (m, 4H), 7.79 (ddd, J=0.12, 0.02, and 0.02 Hz, 4H), 5.39 (s, 1H), 4.37-4.22 (m, 1H), 2.82-2.65 (m, 2H), 2.27-2.16 (m, 2H), 1.84-1.65 (m, 4H).
Reaction SMILES: NC1C=CC=C2C=1C=NN2C1C=C(C=CC=1)C(OC)=O.[CH3:21][C:22]1[CH:23]=[C:24]([NH2:31])[C:25]2[CH:26]=[N:27][NH:28][C:29]=2[CH:30]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1I>>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[N:28]1[C:29]2[CH:30]=[C:22]([CH3:21])[CH:23]=[C:24]([NH2:31])[C:25]=2[CH:26]=[N:27]1
Reactant: Cc1cc(N)c2cn[nH]c2c1
Reactant: Fc1ccc(I)c(F)c1
Agent: COC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Product: Cc1cc(N)c2cnn(-c3ccc(F)cc3F)c2c1

Procedure:
Similarly prepared to Intermediate 9 from 6-methyl-1H-indazol-4-amine and 2,4-difluoroiodobenzene.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CC1(C)[O:18][C:17](=O)[CH2:16][C:15](=[O:20])[O:14]1>CN(C)C=O>[OH:11][C:9]1[CH:8]=[C:3]2[N:2]([C:17](=[O:18])[C:16]=1[C:15]([OH:20])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4]2
Reactant: O=C(O)Cc1ccccn1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1c(O)cc2ccccn2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of pyridin-2-ylacetic acid hydrochloride (1 g) in N,N-dimethylformamide (10 ml) was added N,N'-carbonyldiimidazole (934 mg) at room temperature and the mixture was heated at 60° C. for 20 minutes. To the mixture was added 2,2-dimethyl-1,3-dioxane-4,6-dione (830 mg) at 60° C. and the mixture was stirred for 1 hour at the same temperature. The solvent was distilled off and the residue was diluted with chloroform and washed with water. The chloroform layer was extracted with aqueous sodium hydrogen carbonate and the aqueous layer was washed with chloroform and acidified to pH 2 with 6N hydrochloric acid at 0° C. and extracted with chloroform. The chloroform layer was washed with brine, dried over magnesium sulfate, and evaporated to give 2-hydroxy-4H-quinolizin-4-one-3carboxylic acid (220 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[C:6]([OH:8])=[O:7].[CH3:17]C1C(B2OC(C)(C)C(C)(C)O2)=CNN=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[C:16]([CH3:17])=[N:15][NH:14][CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1-c1cn[nH]c1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(C(=O)O)ccc1-c1c[nH]nc1C

Procedure:
Intermediate 3 was synthesized by following a similar route to Intermediate 1 using 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 1A. LCMS (ESI) m/z: 233.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([NH2:13])=[O:12])[NH:6]2.[C:14]1([CH:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:21]2[CH2:24][CH:23]([O:25][CH2:26][CH:27]3[O:29][CH2:28]3)[CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[OH-].[Na+].O1CCOCC1>[C:30]1([CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]2[CH2:24][CH:23]([O:25][CH2:26][CH:27]([OH:29])[CH2:28][O:1][C:2]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:3]=3[CH:4]=[C:5]([C:11]([NH2:13])=[O:12])[NH:6]4)[CH2:22]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)c1cc2c(O)cccc2[nH]1
Reactant: c1ccc(C(c2ccccc2)N2CC(OCC3CO3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1cc2c(OCC(O)COC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2[nH]1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
8.8 g of 4-hydroxy-1H-indole-2-carboxamide are dissolved in 250 ml of 0.8 percent strength sodium hydroxide solution and a solution of 16.3 g of 1-(diphenylmethyl)-3-(2,3-epoxypropoxy)azetidine in 250 ml of dioxane is added. The mixture is allowed to stand for 4 hours at room temperature and then warmed to 60° C. for a further 20 hours. The reaction mixture is then stirred into 1 l of ice water and extracted twice with 500 ml of methylene chloride each time. The organic phase is dried using potassium carbonate and the solvent is removed by distillation in vacuo. The residue is triturated twice with 100 ml of diisopropyl ether each time and filtered off with suction.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([OH:21])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]CCl>CN(C)C=O>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([Cl:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a suspension of 3-(3-phenylsultamoylphenyl)acrylic acid (5a) (0.173 g, 0.57 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17 ml, 1.95 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.185 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[C:24]([NH2:27])(=[O:26])[CH3:25].[H-].[Na+]>CN(C)C=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:24](=[O:26])[CH3:25])[N:7]=3)=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CCCC3)cc1
Reactant: CC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (i.e. the product of Step B) (0.10 g, 0.27 mmol), acetamide (0.08 g, 1.3 mmol), molecular sieves (4 Å, 3.0 g) in 4 mL of N,N-dimethylformamide was stirred at room temperature for 15 minutes. Sodium hydride (55% dispersion, 0.06 g, 1.3 mmol) was added, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was then filtered though a pad of Celite® diatomaceous filter aid, and then concentrated under reduced pressure. The crude oil was purified by medium-pressure liquid chromatography on silica gel using 0-100% of ethyl acetate in hexanes as eluant to give 55 mg of the title compound, a compound of the present invention, as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[NH:3]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24]Cl)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][N:3]2[C:4](=[O:7])[CH2:5][CH2:6][C:2]2=[O:1])[CH2:20][CH2:21]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: O=C1CCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CCCN2C(=O)CCC2=O)CC1
Temperature: 80 °C

Procedure:
Scheme-I: A mixture of 2,5-dioxopyrrolidine (3.68 g, 37.24 mmol), 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-chloropropane (10.0 g, 37.24 mmol), potassium carbonate (7.70 g, 55.8 mmol) and tetrabutylammonium bromide (2.38 g, 7.4 mmol) in acetone (100 ml) was refluxed for 12 hours at 80° C. with stirring. The solvent was evaporated off in vacuo and the residue was taken up in water (80 ml). The aqueous solution was extracted with chloroform (3×50 ml) and the organic layers combined, washed with water (2×50 ml), dried over Na2SO4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel using chloroform-methanol (99:1) as eluent; yield 8.00 g (65%) in oil. The hydrochloride salt was prepared by the method described above; mp 199-202° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][C:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:34][CH:33]=2)([OH:32])[CH2:27][CH2:28]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: BrCCCOc1ccccc1OCc1ccccc1
Product: Cc1ccc(CC2(O)CCN(CCCOc3ccccc3OCc3ccccc3)CC2)cc1

Procedure:
The title compound, MS: m/e=446.5(M+H+), was prepared from 1-(3-bromopropoxy)-2-(benzyloxy)-benzene and 4-(4-methyl-benzyl)-piperidin-4-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(Cl)c1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccnc(Cl)c1
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A solution of 1-(2-chloropyridin-4-yl)ethanone (7.18 g) in tetrahydrofuran (10 mL) was added dropwise to a solution of (+)-DIP-chloride (19.2 g) in tetrahydrofuran (340 mL) at −20° C., and the reaction solution was stirred at the same temperature overnight. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with an ether, diethanolamine (12.1 g) was added to the diluent, and the reaction solution was stirred at room temperature for four hours. The insoluble matter was separated by filtration through celite, and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex, elution solvent: heptane-ethyl acetate) to obtain the title compound (3.84 g). The property values of the compound are as follows.