Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][CH:27]=4)=[O:24])[NH:12][C@H:11]3[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:5]2=[CH:4][CH:3]=1.C([N:46](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:34]([CH2:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:42])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[CH:27][CH:28]=1)(=[O:35])[NH2:46]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(CCC(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
A mixture of rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-propionic acid prepared in Example 209 (31 mg, 0.051 mmol), N,N-diisopropylethylamine (45 mg, 0.344 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (Chem-Impex, 32 mg, 0.084 mmol) in DMF (4 mL) was stirred for 20 min before NH4Cl (9.5 mg, 0.176 mmol) was added. The mixture was stirred for 0.5 h and diluted with EtOAc (70 mL), washed with water (10 mL), brine (15 mL) and concentrated. The crude product was purified by flash chromatography (EtOAc/hexane, 25/75 to 100/0) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-carbamoyl-ethyl)-phenyl]-amide as a white solid (9 mg, 40%). MS (ES+) m/z [(M+H)+]: 611
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>O1CCCC1>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylate (158.0 mg, 0.39 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (47.0 mg, 1.18 mmol) and water (2 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylic acid as a light yellow solid (89 mg, 58%). LC/MS (ES, m/z): [M+H]+ 390.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[C:12]([CH2:17][CH3:18])=[N:13][O:14][C:15]=2[CH3:16])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:9]([C:11]2[C:12]([CH2:17][CH3:18])=[N:13][O:14][C:15]=2[CH3:16])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1noc(C)c1C(=O)Nc1cccc(F)c1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1noc(C)c1C(=O)N(CCN(C)C)c1cccc(F)c1
Temperature: 60 °C

Procedure:
A mixture of 22.0 grams (0.0887 mole) of N-m-fluorophenyl-3-ethyl-5-methyl-4-isoxazole carboxamide and 4.4 grams (0.0921 mole) of 50% sodium hydride in oil in 500 ml. of dimethylformamide is stirred at room temperature for five hours. The resulting mixture is treated by dropwise addition with 9.68 grams (0.09 mole) of 2-dimethylaminoethyl chloride). The resulting mixture is heated at 60° C. for 20 hours. The mixture is cooled, poured onto ice water and extracted with ether. The ether is washed with 2N hydrochloric acid and the aqueous acidic layer made basic with sodium hydroxide and extracted with methylene chloride. The methylene chloride extract is dried with magnesium sulfate and evaporated to give N-(m-fluorophenyl)-N-(2-dimethylaminoethyl)-3-ethyl-5-methyl-4-isoxazole carboxamide as an oil.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]([Li])[CH2:30][CH2:31]C.C(=O)CC.CCCCCC>C1COCC1>[Br:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:5]([CH:6]=[CH:29][CH2:30][CH3:31])[CH:4]=1
Reactant: [Li]CCCC
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCC=O
Solvent: CCCCCC
Product: CCC=Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a suspension of (3-bromo-benzyl)-triphenyl-phosphonium chloride (10 g, 23.2 mmol) in THF (100 mL) at 0° C. was added n-butyl lithium (10.2 mL, 2.5 N in hexane, 25.5 mmol) dropwise. The resulting orange suspension was stirred for 30 minutes. Propanal (1.61 g, 28 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0° C. and cold hexane (500 mL) was added. The white precipitate was filtered, and the filtrate was concentrated. The residue was purified with flash chromatography using hexane to afford 1-bromo-3-but-1-enyl-benzene (4.4 g, 90%) as a mixture of 3:1 (E):(Z) isomers. MS: m/z 211 (M+H+). The mixture was distillled under vacuum to afford the (E) isomer (1 g, >95% E) and the (Z) isomer (200 mg, 75% Z).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.II.Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](/[C:7]#[N:8])=[C:6](\[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)/[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: N#C/C(=C(\C#N)c1ccc(Br)cc1)c1ccc(Br)cc1
Yield: 40 %

Procedure:
More specifically, 4-bromobenzyl cyanide was oxidized with iodine and hydrolyzed with 3% HCl (aq)/THF to form bis(4-bromophenyl)maleonitrile (40˜50%). See Cook & Linstead (1937) J. Chem. Soc. 929. Bis(4-bromophenyl)maleonitrile thus obtained was alkylated with KotBu/CH3I to afford N-methyl-bis(4-bromophenyl)maleimide (86%). NPAMLI was prepared by palladium catalyzed amination of N-methyl-bis(4-bromophenyl)maleimide (71%), followed by column chromatography and sublimation purification. The synthetic data of the synthesized compounds are listed below:
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:12])[CH2:8][CH2:9][Mg]Cl.[CH:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].Cl>O1CCCC1>[CH:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]([OH:23])[CH2:9][CH2:8][CH:7]([CH3:12])[CH2:6][CH2:5][CH2:4][C:3]([CH3:14])([O:2][CH3:1])[CH3:13])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: COC(C)(C)CCCC(C)CC[Mg]Cl
Reactant: CC(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(C)(C)CCCC(C)CCC(O)c1ccc(C(C)C)cc1
Temperature: 25 °C

Procedure:
To the 7-methoxy-3,7-dimethyloctylmagnesium chloride (0.155 mol) in tetrahydrofuran (200 ml) under nitrogen was added p-isopropylbenzaldehyde (37 g, 86.94% pure) in tetrahydrofuran (50 ml) over 20 min. The reaction was exothermic, causing solvent to boil during the course of addition. After stirring at room temperature continued thereafter for a total of 23 h, the reaction mixture was poured into dilute hydrochloric acid, and extracted with pentane. The extracts were washed with bicarbonate, brine, and dried. Upon solvent evaporation, an oil weighing 65.1 g was obtained which was shown to contain 18.31% of the alcohol product.
Reaction SMILES: C(S[C:4](=[S:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])C.[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>C1(C)C=CC=CC=1>[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:4](=[S:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCC(=S)SCC
Reactant: NCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=S)NCCCN
Temperature: 10 °C

Procedure:
10.4 g of ethyl-dodecanedithioate is dissolved in 100 ml of toluene and the solution obtained is mixed with a solution of 30 g of 1,3-diaminopropane in 200 ml of toluene. The mixture is maintained at about 10° C. for 1 hour, with stirring.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=3)[N:11]=2)[N:8]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C.O.C([O-])(O)=O.[Na+]>[Br:22][C:9]1[N:7]2[N:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]2=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Br)n2n1
Temperature: 60 °C
Yield: 94 %

Procedure:
To a stirred solution of 6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.250 g, 0.879 mmol) in acetonitrile (20 mL) is added N-bromosuccinimide (0.879 mmol) and the mixture is heated at 60° C. for 8 hours. The reaction mixture is diluted with water (50 mL) and sat. aqueous NaHCO3 (50 mL). The precipitate that forms is collected by filtration, washed with water (3×25 mL) and dried under vacuum to give the title product (0.300 g, 94% yield) as a yellow solid: Rf 0.51 (1:1 EtOAc:hexanes); LCMS (m/z)=363.2, 365.2 [M+H]+, tR=3.02 min.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)[N:5]=2.C[O-].[Na+].[C:26](OCC)(=[O:28])C.O>CO>[CH:13]1([O:12][C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([O:28][CH3:26])[N:3]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:8]([NH2:11])[N:7]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(C)=O
Reactant: Nc1nc(OC2CCC2)nc2c1nc(Br)n2C1CCCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Temperature: 67 °C

Procedure:
8-Bromo-2-(cyclobutyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.79 g, 4.86 mmol) was dissolved in anhydrous methanol (25 ml) and 25% sodium methoxide in methanol (2.274 ml, 9.72 mmol) was added under nitrogen. The mixture was heated at 67° C. for 24 hours and then cooled to room temperature. Ethyl acetate and water were added and the layers separated. The aqueous layer was extracted twice more with ethyl acetate, and the organic extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give the title compound as a cream foam (1.27 g).
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Ca+2].[Cl-].[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][C@H:20]2[O:25][CH:24](O)[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([CH:24]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:28][CH:27]=3)[O:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O)c1ccccc1
Reactant: OC1CCC[C@@H](COc2ccc(F)cc2)O1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC[C@@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
25% HCl was added dropwise to benzenesulfinic acid sodium salt (0.6 g), until the solid dissolved. This mixture was extracted with ethyl acetate (15 ml) dried (Na2SO4) and concentrated to give benzenesulfinic acid (0.4 g). To an ice-cooled mixture of benzenesulfinic acid (0.32 g, 2.23 mmol) and calcium chloride (0.25 g, 2.23 mmol) in dry CH2Cl2 a solution of (2RS,6S)-6-(4-fluorophenoxymethyl)-2-hydroxy-tetrahydropyran (0.42 g, 1.86 mmol) in dry CH2Cl2 (5 ml) was added. The reaction mixture was stirred for 4 h, filtered through celite and washed with CH2Cl2. The combined organic layers were washed with saturated aqueous Na2CO3, water, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue was purified on a silica gel column using light petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS,6S)-2-benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g, 70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): δ 1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H), 4.85-5.0 (m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:27]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccco1
Product: CCOC(=NC(=O)c1ccco1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-furoyl chloride, there is obtained ethyl N-(2-furoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6carboximidate, m.p. 87°-92° C.;
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH2:6][NH:7][CH2:8][CH2:9][O:10][CH3:11].[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22]>C1(C)C=CC=CC=1.C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=1)[CH2:6][N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:21]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22]
Reactant: COCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)n1ccnc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
In a mixed solution of 37 ml of toluene and 4 ml of methylene chloride was dissolved 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine, added thereto was 1.78 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 3 hours. To the reaction mixture was added distilled water, and extracted with chloroform. The organic layer was dried over magnesium sulfate, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone=9:1→2:1), to give 3.45 g of imidazole-1-carboxylic acid 3,5-bistrifluoromethylbenzyl-2-methoxyethylamide as shown in Table 133 below.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([OH:14])=[CH:9][CH:10]=2)[O:5]1)[CH3:2].S(OC)(O[CH3:19])(=O)=O.[OH-].[Na+].O>CO>[CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:19])=[CH:9][CH:10]=2)[O:5]1)[CH3:2]
Reactant: CCOC1CCc2ccc(O)cc2O1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC1CCc2ccc(OC)cc2O1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
The above-obtained 2-ethoxy-7-hydroxychroman (10.9 g) was dissolved in 60 ml of methanol, and 10.6 g of dimethyl sulfate and 13.5 g of a 25% sodium hydroxide aqueous solution were added thereto at room temperature. The mixture was stirred at this temperature for 1 hour. After 30 ml of water was added thereto, the methanol was removed by distillation in vacuo, and the residue was extracted twice with 50 ml of toluene. The toluene layer was washed with water, and the toluene was removed by distillation in vacuo. The resulting residue was purified by distillation to obtain 11.0 g of a desired colorless liquid (yield 94%).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Pr+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S(O)(=O)=O.[C:34]1([O:40][CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:42]1([CH3:51])[CH:47]=[CH:46][C:45]([C:48](O)=[O:49])=[CH:44][CH:43]=1>C1(C)C=CC=CC=1.O>[CH3:41][O:40][C:34]1[CH:39]=[CH:38][C:37]([C:48]([C:45]2[CH:46]=[CH:47][C:42]([CH3:51])=[CH:43][CH:44]=2)=[O:49])=[CH:36][CH:35]=1
Reactant: COc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Pr+3]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Reaction time: 22 h
Yield: 59.7 %

Procedure:
Praseodymium (III) trifluoromethanesulfonate (1.18 g as a wet solid), trifluoromethanesulfonic acid (0.30 g), anisole (2.38 g) and para-toluic acid (2.72 g) were refluxed together in 175 mL toluene with azeotropic removal of the lower water layer (Dean-Stark apparatus). After 22 hours, the mixture was cooled and extracted with 3×25 mL water, then by 2×25 mL saturated sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate, filtered, then concentrated down in vacuo to give crude 4-methoxy-4′-methylbenzophenone (2.7 g, 60% yield) as a cream-colored crystalline solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:11][N:12]1[CH2:16][CH2:15][C@H:14]([NH2:17])[C:13]1=[O:18].[Cl:19][C:20]1[N:25]=[C:24]2[CH:26]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[S:28][C:23]2=[CH:22][CH:21]=1>>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[C:4]([CH:5]=1)[CH2:11][N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][S:29]([C:27]2[S:28][C:23]3[C:24](=[N:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:26]=2)(=[O:30])=[O:31])[C:13]1=[O:18])#[N:8]
Reactant: N#Cc1ccc(O)c(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Agent: Cl
Product: N#Cc1ccc(O)c(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)c1

Procedure:
The title compound is prepared from 4-hydroxy-3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 17, Part F using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The product is obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N+:4]=1[O-:32].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:33]([N:35]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N+:4]=1[O-:32])[CH2:36][CH3:37])[CH3:34]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1CCl
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1CN(CC)CC

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate 1-oxide was reacted with diethylamine to give ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate 1-oxide. This compound was recrystallized from ethanol. Colorless prisms, mp. 143°-144° C.
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]2[N:7]=[C:8]([C:10]([NH:33]S(C(C)(C)C)=O)([C:12]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH3:11])[NH:9][C:5]=2[CH:4]=1)#[N:2].Cl>>[NH2:33][C:10]([C:8]1[NH:7][C:6]2[CH:40]=[CH:41][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([C:12]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=1)(=[O:25])=[O:24])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(NS(=O)C(C)(C)C)c4nc5ccc(C#N)cc5[nH]4)c(C)cc(C)c32)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(N)c4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (±)-N-(1-(5-cyanobenzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (97 mg, 0.165 mmol) and HCl (1.25 M in MeOH) (792 μL, 0.990 mmol) was allowed to stir at rt for 17 h. The mixture was concentrated and then diluted with 1 M aq. NaOH, brine and CH2Cl2. The organic layer was separated and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH=100:0 to 10:1) to give the title compound. MS (ESI+) m/z 484.44 (M+H).
Reaction SMILES: C[N:2]1C(=O)CCC1.N.Br[C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:15]=2)[CH:11]=1.C(OCC)(=O)C>[Cu](I)I.O.CCCCCC>[C:20]([N:14]1[CH:13]=[C:12]2[C:16]([C:17]([CH3:19])=[CH:18][C:10]([NH2:2])=[CH:11]2)=[N:15]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(Br)cc2cn(C(C)(C)C)nc12
Reactant: CN1CCCC1=O
Agent: I[Cu]I
Agent: N
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc2cn(C(C)(C)C)nc12
Temperature: 95 °C
Reaction time: 10 h

Procedure:
Copper oxide (I) (2.7 g), NMP (150 mL), and concentrated aqueous ammonia (150 mL) were added to 5-bromo-2-(tert-butyl)-7-methyl-2H-indazole obtained in the above-described Step 1 (40.3 g). The reaction solution was stirred in a portable reactor at 95° C. for 10 hours. The reaction solution was cooled to room temperature, and ethyl acetate (500 mL), hexane (200 mL), and water (300 mL) were added. After separation, the organic layer was washed successively with water four times and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum to obtain 2-(tert-butyl)-7-methyl-2H-indazol-5-amine as a purple solid.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([CH:5]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[Li+].[Li+].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:25]([C:9]1[N:8]2[C:12](=[CH:11][CH:10]=1)[CH:5]([C:3]([N:2]([CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])[CH2:6][CH2:7]2)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C(=O)C1CCn2cccc21)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CN(C(=O)C1CCn2c(C(=O)c3ccccc3)ccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
N-Methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (52 g, 216 mmol), lithium carbonate (24 g, 325 mmol, 1.5 equivalents), and toluene (155 mL) were heated to a reflux temperature of 100° C. to 105° C. Benzoyl chloride (37.5 g, 267 mmol, 1.25 equivalents) was added, and the entire reaction mixture was allowed to reflux for an additional 6 hours to 8 hours. Once the reaction was complete, the mixture was cooled to 70° C. to 80° C., lithium carbonate was filtered off and the filter cake washed with 100 mL warm toluene, and the combined filtrate and washings were seeded with a few crystals of 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide. Hexane (100 mL) was added to the warm toluene solution to effect crystallization, and the mixture was stirred for 30 minutes; then another 80 mL of hexane was added. The mixture was stirred for 1 hour to 2 hours at room temperature, cooled to 0° C. to 5° C., filtered, washed with hexane (150 mL) and dried under vacuum at 60° C. to 70° C. to yield 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (61.7 g, 82.8% yield).