Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][C:14](=O)[CH3:15].[BH4-].[Na+].C([OH:22])(C)C>CO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[CH:13]([CH2:14][CH3:15])[OH:22]
Reactant: CC(=O)Cc1c(C)nc2ccccc2c1N
Reactant: CC(C)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(O)c1c(C)nc2ccccc2c1N
Temperature: 25 °C

Procedure:
A mixture prepared from 1-(4-amino-2-methyl-3-quinolinyl)-propanone (8 g), sodium borohydride (3 g), 75 ml of isopropanol and 25 ml of methanol was stirred twenty hours at ambient temperature. The reaction mixture was concentrated and stirred with water, and the product which separated was collected and dried to 8 g of solid, mp 220°-230°. This material was recrystallized from absolute ethanol to give 4.6 g of crystals, mp 240°-241°.
Reaction SMILES: C(CC([O-])=O)#N.[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:27]([O:26][C:24](=[O:25])[C:23](=[C:17]1[CH2:18][CH2:19][N:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16]1)[C:21]#[N:22])[CH3:28]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CC#N
Agent: N#CCC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1

Procedure:
[A] Synthesis of 1-benzyl-piperidin-4-ylidene)-cyanoacetate (2; FIG. 4). A solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (9400 mL), ethyl cyanoacetate (50.6 mL, 0.48 mol) and acetic acid (918.2 mL, 0.32 mol) was refluxed for 4 hr. The mixture was quenched with ice-water and extracted with diethyl ether. The combined extracts were washed with water, brine and dried over Na2SO4 to give ethyl(1-benzyl-piperidin-4-ylidene)cyanoacetate in quantitative yield. Rf=0.53 (hexane:AcOEt=1:1).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:7][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].C(=O)(O)[O-].[Na+].[Cl:28][C:29]1[CH:40]=[CH:39][C:32]([CH:33]=[CH:34][S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH:33]=[CH:34][S:35]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:8]3[S:7][C:6]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:5][C:4]=3[CH3:3])=[O:10])[CH2:12][CH2:13]2)(=[O:37])=[O:36])=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)cc1
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)C=Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution of 1-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]piperazine dihydrochloride (200 mg) in ethyl acetate (10 ml)/sodium bicarbonate (10 ml) was added 4-chlorostyrene-β-sulfonylchloride (275 mg), and the mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, washed with brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (169 mg).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:6]=1[CH2:20][C:21]([OH:23])=O)([O-])=O>[Pd].CO>[CH3:16][CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[NH:2][C:21](=[O:23])[CH2:20][C:6]=12)[CH2:17][CH2:18][CH3:19].[ClH:1]
Reactant: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1CC(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCN(CCC)CCc1cccc2c1CC(=O)N2

Procedure:
2-Nitro-6-[2-(N,N-Di-n-propyl amino)ethyl]phenyl acetic acid hydrochloride (100 g) is dissolved methanol (2000 ml) and then hydrogenated in presence of 10% Palladium on charcoal. The reaction mixture is filtered to obtain clear solution. Methanol is distilled out under vacuum at 50° C. Isopropanol (100 ml) is added to the residue and it is cooled, filtered and washed with isopropanol to obtain light yellow crystalline Ropinirole hydrochloride. The product is dried at 60-70° C. under vacuum. Yield 65-75 g.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].Cl[O-].[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1OC
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1OC
Reaction time: 2 h
Yield: 88 %

Procedure:
3-butyryl-4-(2-methoxyphenylamino)-8-(2-methylthioethoxy)quinoline (0.35g, 0.85 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.42 ml) were added and the mixture was stirred for 2 h. Another portion of sodium hypochlorite (0.5 ml) was added and the stirring was continued for 2 h. The organic layer was dried over sodium sulfate and evaporated. The residue crystallized from a mixture of ethyl acetate and isopropyl ether and 0.32 g (88%) of the title compound was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(C)n1nc2c(c1-c1ccc(C(F)(F)F)cc1)CCNCC2
Yield: 68.4 %

Procedure:
The title compound (103 mg) was prepared as in Example 177, Steps C and D, using 199 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 265 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C17H20F3N3, 323.16. found, m/z 324.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.86 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 4.34 (m, 1H), 3.43-3.40 (m, 2H), 3.20-3.18 (m, 2H), 2.80-2.78 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[C:20]1([C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH2:28][CH2:29][C:30]#[N:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-:39].[Na+]>C(OCC)(=O)C>[C:32]1([C:26]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:31][C:30](=[O:39])[CH2:29][CH2:28][CH2:27]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C([O-])O
Reactant: N#CCCC=C(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCCC(c2ccccc2)(c2ccccc2)N1
Temperature: 0 °C
Yield: 66 %

Procedure:
A stirred mixture of 24. g (0.17 tool) of granular phosphorus pentoxide and 240.g (2.5 mol) of 98% methanesulfonic acid was maintained at 110 ° C. until all the solid dissolved (1 hour) . To this solution was added in portions over several minutes 12 g (0.05 mol) of 5,5-diphenyl-4-pentenenitrile. The resulting dark mixture was heated for 5 minutes longer and then carefully added to an ice-cooled vigorously stirred mixture of 1 liter of saturated aqueous sodium bicarbonate and 1 liter of ethyl acetate. The basic aqueous phase was extracted with 3×500 ml of fresh ethyl acetate, the organic layers were combined, washed with 2×500 ml of water, 1×500 ml brine, and dried over sodium sulfate. The resulting crude solid was recrystallized from toluene to give 8.5 g (66%) of 6,6-diphenyl-2-piperidinone as a white solid (mp 193°-196° C.) .
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:22][CH2:23][CH3:24])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH2:19][CH2:20][CH3:21])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[CH2:1]([O:3][CH:4]([O:22][CH2:23][CH3:24])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:11]([O-:33])=[CH:10][C:9]=2[N:8]=[C:7]1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCCc1nc2cnc3ccccc3c2n1CC(OCC)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CC(OCC)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-(2,2-diethoxyethyl)-2-propyl-1H-imidazo[4,5-c]quinoline (4.50 g, 13.7 mmol) by reaction with m-CPBA (6.0 g) to provide 1-(2,2-diethoxyethyl)-5-oxido-2-propyl-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (4.60 g, 24.1 mmol) and ammonium hydroxide solution (130 mL) to provide 1-(2,2-diethoxyethyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid after recrystallization from aqueous methanol, mp 148-150° C.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[CH3:10][O:11][C:12]([N:14]([C:30]1[C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]2[C:33]([CH:34]3[CH2:44][CH:35]3[CH2:36][O:37]2)=[CH:32][CH:31]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1/[CH:25]=[CH:26]\[CH2:27][CH2:28]O)(=[O:17])=[O:16])=[O:13].[CH:45]([N:48](C(C)C)[CH2:49][CH3:50])(C)[CH3:46].C(NCC)C>C(Cl)Cl.O>[CH3:10][O:11][C:12]([N:14]([C:30]1[C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]2[C:33]([CH:34]3[CH2:44][CH:35]3[CH2:36][O:37]2)=[CH:32][CH:31]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1/[CH:25]=[CH:26]\[CH2:27][CH2:28][N:48]([CH2:49][CH3:50])[CH2:45][CH3:46])(=[O:17])=[O:16])=[O:13]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CCO)ccc2c1OCC1CC21
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCNCC
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CC/C=C\c1cc(F)ccc1S(=O)(=O)N(C(=O)OC)c1ccc2c(c1C(=O)OC)OCC1CC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
Methyl sulfonic anhydride (0.062 g) was added to a stirred, cooled mixture of methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-4-hydroxybut-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 73, 0.12 g) and N,N-di-isopropyl-N-ethylamine (0.046 g) in DCM (15 mL) at 0° C. The resultant mixture was stirred at 0° C. for 20 minutes. Diethylamine (0.026 g) was added and the mixture was then stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with DCM, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 2-10% to give methyl (1aRS,7bSR)-5-{N-(methoxycarbonyl)-N-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.08 g) as alight yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccsc2)c1
Yield: 46.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(thiophen-3-ylmethyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.080 g; 0.230 mmol), thiophen-3-ylboronic acid (0.031 g; 0.241 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018 g; 0.023 mmol), sodium carbonate (0.049 g; 0.461 mmol), sodium iodide (0.069 g; 0.461 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 25% ethyl acetate in dichloromethane) furnished 0.042 g (47%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1>CN(C)C=O.O>[N+:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
A solution of tert-butyl (3-aminophenyl)carbamate (0.51 g, 2.4 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in N,N-dimethylformamide (7 mL) was treated with a solution of 1-(bromomethyl)-3-nitrobenzene (0.50 g, 2.3 mmol) in N,N-dimethylformamide (3 mL) and stirred at 25° C. for 16 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with water (3×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude residue. This material was purified by flash column chromatography to give the desired product (0.78 g, 88% [90% pure]) as a solid. LCMS for C18H22N3O4 (M+H)+: m/z=344.2.
Reaction SMILES: [CH:1]1([C:4](=[O:26])[C:5](=[CH:22]OCC)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18]([CH3:21])(=[O:20])=[O:19])=[O:7])[CH2:3][CH2:2]1.Cl.[CH2:28]([O:30][NH2:31])[CH3:29].C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4](=[O:26])[CH:5]([CH:22]=[N:31][O:30][CH2:28][CH3:29])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][C:9]=2[S:18]([CH3:21])(=[O:19])=[O:20])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCON=CC(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-cyclopropyl-2-ethoxymethylene-1-(2-methylsulphonyl-4-trifluoromethylphenyl)propan-1,3-dione (3.5 g), O-ethylhydroxylamine hydrochloride (0.97 g) and sodium acetate (0.83 g) in ethanol (15 ml) was stirred at 25° C. for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated and the residue purified by column chromatography on silica, using a mixture of ethyl acetate and hexane as eluent. The resulting solution was evaporated and 3-cyclopropyl-2-(ethoxyiminomethyl)-1-(2-methylsulphonyl-4-trifluoromethylphenyl)propan-1,3-dione (compound 1) was obtained as white crystals (2 g), m.p. 46° C.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1N
Reaction time: 8 h
Yield: 112.1 %

Procedure:
1a (7.2 g, 26.5 mmol) was dissolved in a 1:1 mixture of methanol and ethyl acetate (160 mL). Palladium on charcoal (10%, 360 mg, 0.33 mmol) was added, and the mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered over Celite® and concentrated to afford 7.2 g (100%) of 1b as a white powder. [M+H]+=243.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(F)c3)CC2)c(C)c1
Yield: 68.1 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 66 and oxazolidin-2-one (87 mg), the title compound (271.1 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Reactant: c1cscn1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Yield: 55.5 %

Procedure:
The title compound (200 mg, 86%) was prepared from thiazole (0.28 g, 3.2 mmol) and (S)-2-[4-(4-iodo-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.8 mmol) using the procedure of Example 146, step 1; 1HNMR (400 MHz, CDCl3) δ 7.87 (d, J=8.4 Hz, 2H), 7.84 (d, J=3.2 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=7.2 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.9-3.75 (br, 2H), 3.40 (br, 2H), 2.03-1.84 (br, 4H), 1.46 (s, 9H); MS (ESI+) 451 (M+1, 100).
Reaction SMILES: [O-]CC.[Na+].O1CCCC1.[C:10]([C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1)(=[O:12])[CH3:11].[F:24][C:25]([F:32])([F:31])[C:26](OCC)=[O:27]>O>[Cl:19][C:18]1[C:13]([C:10](=[O:12])[CH2:11][C:26](=[O:27])[C:25]([F:32])([F:31])[F:24])=[N:14][CH:15]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:17]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 98 %

Procedure:
608 mg of a sodium ethoxide 21% ethanol solution was added at 0° C. to a tetrahydrofuran (dehydrated) 9 mL solution of 1 g of 2-acetyl-3-chloro-5-(trifluoromethyl)pyridine and 635 mg of ethyl 2,2,2-trifluoroacetate, followed by stirring at room temperature for 13 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.4 g of 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4,4-trifluorobutan-1,3-dione (after-mentioned intermediate No. IX-25).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5](OCC)=[O:6].[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[CH2:16][CH2:17][C:18]#[N:19])[CH3:13]>O1CCCC1>[CH2:21]([O:20][CH:15]([O:14][CH2:12][CH3:13])[CH2:16][CH:17]([C:5](=[O:6])[C:4]([F:11])([F:10])[F:3])[C:18]#[N:19])[CH3:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(CCC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(CC(C#N)C(=O)C(F)(F)F)OCC

Procedure:
Preparation of (trifluoromethyl)pyrrole carbonitriles and conversion thereof to dihalo (trifluoromethyl)pyrrole carbonitriles and dihalo- alkylated N-(trifluoromethyl)pyrrole carbonitriles can be achieved by the admixture of a dispersion of sodium hydride in tetrahydrofuran with a solution of ethyl trifluoroacetate and 3-cyano propionaldehyde diethyl acetal in tetrahydrofuran. The reaction that occurs yields 3-trifluoroacetyl-3-cyanopropionaldehyde diethyl acetal which is then heated with oxalic acid dihydrate in water to give the 3-trifluoroacetyl-3-cyanopropionaidehyde. The thus prepared aldehyde is then dissolved in glacial acetic acid and the resulting solution treated with ammonium acetate to provide the 2-(tri-fluoromethyl)pyrrole-3-carbonitrile. Halogenation of the above-said (trifluoromethyl)pyrrole carbonitrile may then be accomplished by reaction of said (trifluoromethyl)pyrrole carbonitrile with N-bromosuccinimide or N-chlorosuccinimide in the presence of tetrahydrofuran to yield the dihalo (trifluoromethyl)pyrrole carbonitrile. Alkylation or aoylation of this dihalo (trifluoromethyl)pyrrole carbonitrile with an alkyl halide or acylhalide in the presence of potassium t-butoxide and tetrahydrofuran yields the N-alkylated (or N-acylated) dihalo (trifluoromethyl)pyrrole carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][O:6][C:7]2=[O:12].[Br:13]N1C(=O)CCC1=O.N(/C(C)(C)C#N)=N\C(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7](=[O:12])[O:6]1
Reactant: COc1cccc2c1COC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc2c1C(Br)OC2=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
4-methoxyisobenzofuran-1(3H)-one (121) (3.18 g, 19.37 mmol) and 1-bromopyrrolidine-2,5-dione (3.62 g, 20.34 mmol) were dissolved in carbon tetrachloride (40 mL) and heated reflux. (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.318 g, 1.94 mmol) was added and the reaction stirred overnight at 80° C. The reaction was allowed to cool and filtered. The solvent removed to afford the desired material as a orange solid (3.15 g, 66.9%), which was used without further purification; 1H NMR (400.132 MHz, DMSO) δ 3.91 (3H, s), 6.66 (1H, s), 7.35-7.40 (2H, m), 7.57-7.65 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[C:11]([CH3:22])([CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:18][C:15]1[CH:16]=[C:17]2[C:12]([C:11]([CH3:22])([CH3:21])[CH2:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(C)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A mixture of 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1 carboxylic acid tert-butyl ester (8.3 g, 0.03 mol) and Pd—C (0.5 g) in methanol (100 mL) was stirred under H2 (1 atm) at room temperature overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was washed with petroleum ether to give tert-butyl 7-amino-3,4-dihydro-4,4-dimethylquinoline-1(2H)-carboxylate (DC-3) (7.2 g, 95%). 1H NMR (CDCl3) δ 7.11-7.04 (m, 2H), 6.45-6.38 (m, 1H), 3.71-3.67 (m, 2H), 3.50-3.28 (m, 2H), 1.71-1.67 (m, 2H), 1.51 (s, 9H), 1.24 (s, 6H).