Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:43][CH:44]([CH3:53])[C@@H:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)O>ClCCl>[CH3:43][CH:44]([CH3:53])[C@@H:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:2][C:1](=[O:3])[CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: CC(C)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O[C@H](c1ccccc1)C(C)C
Yield: 32 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (298 mg, 0.73 mmol), 4-N,N-dimethylaminopyridine (95 mg, 0.77 mmol, 1.2 eq), 1,3-dicyclohexylcarbodiimide (243 mg, 1.18 mmol, 1.8 eq) in dichloromethane (10 mL) was treated with (S)-2-methyl-1-phenyl-1-propanol (100 mg, 0.64 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 104 mg (32%) of L-isoleucine, N-[1-(2-(2-methyl-1-(S)-phenyl-1-propoxy)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].[CH3:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CN(C)C=O.O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[CH3:23][N:24]([CH3:25])[CH2:26][CH2:27][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: CN(C)CCCl
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 50 ml of anhydrous dimethylformamide is added under ice cooling with stirring 1.2 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at room temperature for 20 minutes. To the mixture is added dropwise 6.6 g of N,N-dimethyl-2-chloroethylamine over a period of 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture is poured into iced water and then extracted with chloroform. The extract is water washed and dried over magnesium sulfate, and the solvent is distilled off. An oily product obtained as the residue is subjected to column chromatography on alumina and eluted from the column with benzene. The eluate is concentrated to obtain a crude 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The crude product thus obtained is treated, according to usual procedure, with maleic acid and then recrystallized from an anhydrous isopropyl alcohol-acetone mixture to obtain 4.8 g of 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine maleate, m.p. 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:13](=O)[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:13]=[N+:14]([O-:32])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2cccc(Oc3cc4ccccc4[nH]c3=O)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2cccc(Oc3cc4ccccc4[n+]([O-])c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
0.2 g of 3-(1,1-dimethylindan-7-yloxy) quinolone was dissolved in 5 mL of chloroform, and 0.2 g of m-CPBA (70%) was added and stirred overnight at room temperature. After the reaction mixture was diluted with chloroform and washed with saturated sodium bicarbonate water, magnesium sulfate was added to dry the resultant. The solvent was evaporated under reduced pressure to obtain 0.2 g of 3-(1,1-dimethylindan-7-yloxy) quinoline-N-oxide.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([F:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In an argon atmosphere and while cooling at −78° C., [bis(2-methoxyethyl)amino]sulfur trifluoride (7.33 mL) was added dropwise to 4-hydroxy-1-piperidinecarboxylic acid tert-butyl ester (4.00 g) in methylene chloride (80 mL), followed by stirring for 30 minutes. The resultant mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The reaction mixture was partitioned by use of saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-ethyl acetate) to thereby give 4-fluoropiperidine-N-carboxylic acid tert-butyl ester as an oily product (1.77 g, 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:13]([CH2:20][O:21][CH2:22][CH3:23])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[CH3:24][S-:25].[Na+]>CN(C)C=O>[CH2:22]([O:21][CH2:20][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([S:25][CH3:24])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:12]=1)[CH3:23]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3cc(SC)ccc3c2n1CCCOC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinoline (U.S. Patent Application Publication No. US 2004/0147543 Examples 163-175, 1.0 g, 2.64 mmol) and sodium thiomethoxide (0.185 g, 2.64 mmol) were dissolved in N,N-dimethylformamide (25 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then heated at 55° C. for 16 hours. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and sequentially washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 2-Ethoxymethyl-1-(3-methoxypropyl)-7-methylthio-1H-imidazo[4,5-c]quinoline was isolated as 1.1 g of a pale yellow oil.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].Cl.O1CCOCC1.S(Cl)([Cl:20])=O>>[ClH:20].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@@H](O)CCN
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cl)CCN
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (498 mg; 391 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 5 ml of 4 N-HCl/dioxane, followed by further addition of 321 μL of thionyl chloride. The mixture was stirred at 50° C. for 4 hours. The solvent was distilled off under reduced pressure to give 530 mg of methyl (R)-4-amino-2-chlorobutyrate hydrochloride (yield quantitative, optical purity 98.5% ee). The analysis of the optical purity was carried out by derivatizing into (R)-3-chloro-2-pyrrolidinone with sodium hydrogen carbonate, followed by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[I:29][C:30]1[CH:35]=[CH:34][C:33]([C:16]2[CH:17]=[CH:18][C:19]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:32][CH:31]=1
Reactant: CC1(C)OB(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)OC1(C)C
Reactant: Brc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Ic1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
90 g (244 mmol) 9-Phenyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-carbazole and 69 g (244 mmol) 1-Iodo-4-Brombenzene [589-87-7] are dissolved in 500 ml toluene treated with 200 ml of a 2 M solution of sodium carbonate. The reaction mixture is carefully degassed and 200 mg tetrakistriphenylphosphine palladiume are added. The reaction is heated to reflux for 20 h. The solution is then cooled to room temperature and the layers are separated. The water phase is extracted three times with toluene, and then the organic layers is washed twice with water dried over magnesium sulphate, filtrated and the solvent is removed in the vacuum. The residue is recrystallized from DMF, to yield 100 g (225 mmol) (92%) of a with powder with a purity of 98.7%.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[Cl:11][C:6]1[C:7]2[CH2:8][CH2:9][N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:2]=2[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=1
Reactant: Nc1cccnc1
Reactant: ClCCc1c(Cl)nc(N2CCOCC2)nc1Cl
Product: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Yield: 0.1 %

Procedure:
In the same manner as Example 1-B-01, from 4-[4,6-dichloro-5-(2-chloroethyl)-pyrimidin-2-yl]-morpholine (1.25 g) and 3-aminopyridine (1.97 g), the desired compound (pale yellow powder, 1.07 mg, 88%) was obtained.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:12])=CC=1)([O-])=O.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>O1CCCC1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:11](=[O:12])[N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])[CH2:18][CH2:17]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CNCCOC
Solvent: C1CCOC1
Product: COCCN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70.9 %

Procedure:
To piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (500 mg) in tetrahydrofuran (5 mL) was added N-(2-methoxyethyl)methylamine (254 mg) and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was reduced in vacuo and purified using flash chromatography to yield 4-[(2-methoxy-ethyl)-methyl-carbamoyl]-piperazine-1-carboxylic acid tert-butyl ester (304 mg). Treatment of this compound with HCl in dichloromethane/methanol yielded the title compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:26]=2[C:28](=O)[CH2:29][CH3:30])[C:21]([CH3:36])([CH3:35])[CH2:20][CH2:19]1)[CH3:17]>>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[C:28](\[C:26]1[CH:25]=[C:24]([CH:32]([CH3:34])[CH3:33])[CH:23]=[C:22]2[C:27]=1[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][C:21]2([CH3:35])[CH3:36])/[CH2:29][CH3:30])[CH3:1]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCC(=O)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Product: CCOC(=O)/C(F)=C(/CC)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C

Procedure:
Following General Procedure E, triethyl-2-fluoro-2-phosphonoacetate (15.1 g, 62.3 mmol) and 1-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-1-propanone (Intermediate 13, 4.48 g, 15.6 mmol) were reacted to give the title compound as bright yellow oil after purification by flash chromatography (SiO2, 2:98 ethyl acetate:hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1.[Cl:19][C:20]1[S:21][C:22]2[CH:28]=[C:27](I)[CH:26]=[CH:25][C:23]=2[N:24]=1.[F-].[Cs+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:8]3[N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:10]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: Clc1nc2ccc(I)cc2s1
Reactant: COc1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2cc(-c3ccc4nc(Cl)sc4c3)n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 83 %

Procedure:
tert-butyl 6-methoxy-1H-indole-1-carboxylate, from example 1BO, (2.50 g, 8.6 mmol) is dissolved in anhydrous dimethoxyethane (21.5 mL). To the solution is added 2-chloro-6-iodobenzothiazole (2.42 g, 8.2 mmol), cesium fluoride (2.53 g, 16.7 mmol) and PdCl2(PPh3)2 (0.23 g, 0.33 mmol). The reaction mixture is heated at reflux. After 17 h the reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4×20 mL). The extract is washed with saturated aqueous NaHCO3 (20 mL), dried over MgSO4 and concentrated under vacuum to give tert-butyl 2-(2-chlorobenzothiazol-6-yl)-6-methoxy-indole-1-carboxylate (2.95 g, 83%) as a hard foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][NH:28][C:19]([C@@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH2:14]1)=[O:20]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 24 f), the condensation of the (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent yields the (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=343 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Product: Ic1n[nH]c2ccccc12

Procedure:
An additional approach to compounds such as x is outlined in Scheme 4. Treatment of an appropriate alcohol R5—OH and a base such as NaH and the like, followed by addition of xvii will provide the ether xviii. The bromide xviii can be converted into the methylated intermediate xix via palladium-mediated cross coupling with Me3B3O3 and the like. The nitro derivative xix can be treated with Pd/C in the presence of HCOONH4 to produce the amine xx. The amine xx can be acylated to provide xxi. The acylated amine xxi can be treated with iso-amyl nitrate in the presence of Ac2O/KOAc and the like to provide the N-acyl indazole xxii. Compounds such as xxii can be treated with ammonia and the like to produce indazoles xxi. The indazole xxi can be treated with iodine and KOH and the like to provide the iodo-indazole xxii. The indazole nitrogen can be protected with trityl chloride and base and the like to provide xxiii. The iodo-indazole xxiii can be converted into xxiv via cross coupling using the appropriate boronic acid and the like and an appropriate palladium catalyst. The chloro-pyridine xxiv can be converted into examples such as x using the appropriate amine (HN(R2)R3), palladium catalyst, and ligand followed by deprotection of the trityl group using standard conditions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]=[C:12]([CH3:24])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:31])([F:30])[CH2:28]I.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:26][C:27]([F:31])([F:30])[CH2:28][N:10]1[C:9](=[O:25])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:12]([CH3:24])=[N:11]1
Reactant: FC(F)(F)CI
Reactant: Cc1n[nH]c(=O)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC(F)(F)F)c(=O)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 48.7 %

Procedure:
The product of Example 63 (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (3 mL) and treated with 1,1,1-trifluoro-2-iodoethane (27.5 mL, 280 mmol) in presence of anhydrous sodium carbonate (130 mg, 1.2 mmol) at 50-60° C. for 2 hours. The reaction mixture was partitioned between water and ethyl acetate to provide the desired compound as an amorphous solid (60 mg, 48%). 1HNMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 3.10 (s, 3H), 4.85 (q, J=9 Hz, 2H), 6.90 (m, 2H), 7.10 (dd, J=6 Hz, J=9 Hz, 2H), 7.25 (m, 2H), 7.95 (d, J=9 Hz, 2H). MS (DCI/NH3) 458 (M+NH4)+Anal. calc. for C20H16N2F4SO3: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.41; H, 3.56; N, 6.35.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:29][CH:28]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and α,α,α-trifluoro-p-tolualdehyde (86 ul, 0.633 mmol) similar to Example 1 and isolated as a yellow solid (60.1 mg, 12.7%). 1H NMR (CDCl3): 7.70 (d, J=15.6 Hz, 1H), 7.67 (q, J=8.6, 14.9 Hz, 4H), 7.55 (d, J=15.6 Hz, 1H), 7.33 (d, J=3.3 Hz, 1H), 7.15 (dd, J=3.3, 9.0 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 4.46-4.34 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24]([OH:26])=O)[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].[NH3:27]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24]([NH2:27])=[O:26])[CH:18]=3)[CH2:15][CH2:16]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(Cl)n3)CC2)cc1Br
Reactant: N
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)nc(Cl)n3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-chloropyrimidine-4-carboxylic acid (Example 31) with 2 M ammonia in MeOH.
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)(=O)=O)=CC=1.[F:29][C:30]([F:38])([F:37])[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CS(C)=O.Cl>O>[F:29][C:30]([F:38])([F:37])[N:31]1[CH2:36][CH2:35][N:34]([C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)[CH2:33][CH2:32]1
Reactant: FC(F)(F)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)cc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(F)(F)F)CC4)ccc3c1=O)CCC2
Yield: 52.4 %

Procedure:
A mixture of 3.4 g of 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoromethylpiperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 150° to 160° C. for 18 hours under nitrogen gas flow at a pressure of 10 atms. After completion of the reaction, the solvent and excessive piperazine compound were removed by distillation under reduced pressure and a mixture of methanol and ethanol was added to the residue. The precipitates formed were collected by filtration and washed with ether. The crystals obtained were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and insoluble substances were removed by filtration. The filtrate was rendered neutral with saturated aqueous solution of sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.7 g of 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:34]([O:41][CH2:42][C@H:43]1[N:47]([S:48]([C:51]2[CH:60]=[CH:59][C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH:52]=2)(=[O:50])=[O:49])[CH2:46][C@H:45](O)[CH2:44]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:62]([OH:65])(=[S:64])[CH3:63]>O1CCCC1>[CH2:34]([O:41][CH2:42][C@H:43]1[N:47]([S:48]([C:51]2[CH:60]=[CH:59][C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH:52]=2)(=[O:49])=[O:50])[CH2:46][C@@H:45]([S:64][C:62](=[O:65])[CH3:63])[CH2:44]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1C[C@H](O)C[C@H]1COCc1ccccc1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (2.92 g) in tetrahydrofuran (30 ml) was added diisopropylazodicarboxylate (2.20 ml) within 5 minutes at 0° C. The solution was stirred for 0.5 h at 0° C., then a solution of (3R,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-ol (2.2 g) and thioacetic acid (0.81 ml) in tetrahydrofurane (10 ml) were added to the suspension within 0.5 h at 0° C. Stirring was continued for 1 h at 0° C. and 1 h at room temperature. The reaction mixture was concentrated, and the residue was chromatographed on silica gel using EtOAc/hexane 1:4 and 1:3 as eluents to obtain (3S,5S)-thioacetic acid S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl] ester (2.1 g) as a syrup, MS: 456 (MH+).