Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[NH:7][C:6]2=[O:14].[CH2:15]([NH2:17])[CH3:16]>C(#N)C>[CH3:13][C:8]1[NH:7][C:6](=[O:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][NH:17][CH2:15][CH3:16])[CH:4]=2)[N:9]=1
Reactant: CCN
Reactant: Cc1nc2ccc(CBr)cc2c(=O)[nH]1
Solvent: CC#N
Product: CCNCc1ccc2nc(C)[nH]c(=O)c2c1
Reaction time: 4 h

Procedure:
A mixture of 6-bromomethyl-3,4-dihydro-2-methylquinazolin-4-one (prepared as described in Example 3; 10 g), anhydrous ethylamine (7.9 ml) and acetonitrile (250 ml) was stirred rapidly at laboratory temperature for 4 hours. The mixture was evaporated to dryness, the residue was dissolved in water, filtered and the filtrate was evaporated. The residue was triturated in acetone to give N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-ethylamine, as its hydrobromide salt (8.5 g), m.p. >260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[C:40]([N:37]1[CH2:36][CH2:35][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:39][CH2:38]1)(=[O:42])[CH3:41]
Reactant: CC(=O)N1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(=O)N1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)ethanone. MS (ESI): mass calcd. for C22H22FN5O3S, 455.14; m/z found, 456.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=6.0, 2H), 8.11-8.08 (m, 1H), 8.00 (m, 1H), 7.75-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.37-7.29 (m, 2H), 3.43-3.34 (m, 4H), 2.96-2.81 (m, 4H), 2.02 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>ClCCl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)N1CCC(NC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-fluorobenzoylamino)piperidine (0.15 g) in dichloromethane (5 ml) were added in turn pyridine (0.14 ml) and methanesulfonyl chloride (96 μl) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. To the mixture was added N,N-dimethylaminopyridine (0.13 g) and allowed to stir for another 1 hour. The reaction mixture was taken up into a mixture of water and dichloromethane. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give 4-(4-fluorobenzoylamino)-1-methylsulfonylpiperidine (0.30 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C:7]2([O:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:6]1=O.N>CCO>[Br:14][C:10]1[CH:11]=[CH:12][C:13]2[N:5]3[CH2:4][CH2:3][CH2:2][N:1]=[C:6]3[C:7]3([O:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:8]=2[CH:9]=1
Reactant: NCCCN1C(=O)C2(OCCCO2)c2cc(Br)ccc21
Agent: N
Solvent: CCO
Product: Brc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture of 1′-(3-aminopropyl)-5′-bromospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (1.89 g, 5.54 mmol) in 2M EtOH.NH3 (150 mL) was heated in a steel pressure vessel at 135° C. for 46 hr. After cooling to room temperature the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluting with 85/15 Pet ether/acetone to give the title compound (0.84 g, 66% ). A portion was dried in vacuo at 50° C. to give the analytically pure sample. Anal: Calc'd for C14H15BrN2O2: C, 52.03; H, 4.68; N, 8.67. Found: C, 52.10; H, 4.63; N 8.46. IR: consistent, NMR (300 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 323 [M+H], 1 Br pattern observed. m.p.: 145-149° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:13].[C:14](OC(=O)C)(=O)[CH3:15]>O1CCCC1>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:14]([CH3:15])[S:13][C:3]=2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)O)cc(S)c1N
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2sc(C)nc12
Temperature: -78 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
4-Amino-3-mercapto-5-methoxybenzoic acid (500 mg) was dissolved in tetrahydrofuran (15 ml) and cooled at −78° C. Acetic anhydride (0.26 ml) was added thereto, and the mixture was warmed over 30 minutes to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (550 mg, Y.:99%) as white crystals.
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[NH:30][C:31](=O)[C:32]([CH3:36])([CH3:35])[CH2:33][Cl:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[NH:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][Cl:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(NC(=O)C(C)(C)CCl)C3)c1
Solvent: C1CCOC1
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(NCC(C)(C)CCl)C3)c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of N-(1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-yl)-3-chloro-2,2-dimethylpropanamide (51.8 mg, 0.095 mmol) in dry tetrahydrofuran (1 ml) was added 2M borane dimethyl complex (0.143 ml, 0.285 mmol) and stirred at 60° C. for 6 h and at room temperature over night. Quenched by dropwise addition of 0.5N hydrochloric acid and refluxed for an other 2 h, the solution was saponified with sodium hydroxide and extracted three times with dichloromethane, dried, filtered and evaporated to obtain the crude product (m=53 mg) as a yellow oil that was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 5% methanol in dichloromethane to afford the titled compound N-(2-(3-benzyl-2-(3-chloro-2,2-dimethylpropylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a pale yellow oil. m=17.7 mg (35%)
Reaction SMILES: COC1C=CC(C[N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=3[O:13][C:12]([CH3:28])([C:25]([OH:27])=[O:26])[CH2:11]2)=CC=1.[ClH:29]>CO.[OH-].[OH-].[Pd+2]>[ClH:29].[CH3:28][C:12]1([C:25]([OH:27])=[O:26])[CH2:11][NH:10][C:15]2[CH:16]=[C:17]([O:20][C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][C:14]=2[O:13]1
Reactant: COc1ccc(CN2CC(C)(C(=O)O)Oc3ccc(OC(F)(F)F)cc32)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC1(C(=O)O)CNc2cc(OC(F)(F)F)ccc2O1
Yield: 85 %

Procedure:
4-[(4-methoxyphenyl)methyl]-2-methyl-6-(trifluoromethoxy)-3H-1,4-benzoxazine-2-carboxylic acid (300 mg, 0.7550 mmol) was dissolved in methanol (50 mL) and 2 M HCl (2 mL), and treated with Pd(OH)2 under H2 (90 bar) at 100° C. (H-Cube, ThalesNano). The product solution was dried down to a brown residue. The residue was redissolved in acetonitrile, filtered and concentrated in vacuo to provide 2-methyl-6-(trifluoromethoxy)-3,4-dihydro-1,4-benzoxazine-2-carboxylic acid hydrochloride (200 mg, 85% yield) as a brown solid. LC/MS m/z 278.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH2:28])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:31](=[O:33])[CH3:32])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(N)c3C2=O)ccc1OC(F)F
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 77.2 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester was prepared by the procedure of example 20 from 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.8 g, 7 mmol) and acetyl chloride (0.57 ml, 8 mmol) in THF (20 ml) to afford the title compound as white solid (2.5 g, 81%). The product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH3:30])=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:31])[CH:21]=2)[C:9]1=[O:32])[CH2:6][CH3:7].O.[OH-].[Li+].C(O)(=O)C>O.O1CCOCC1>[O:32]=[C:9]1[N:10]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH3:30])=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:31])[CH:21]=2)[C:11]2[CH:18]=[CH:17][CH:16]=[N:15][C:12]=2[C:13](=[O:14])[N:8]1[C@H:5]([CH2:6][CH3:7])[CH2:4][C:3]([OH:33])=[O:2]
Reactant: CC[C@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](CC(=O)O)n1c(=O)c2ncccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Yield: 42.3 %

Procedure:
A solution of 1.0 g of (R)-3-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester and 187 mg of lithium hydroxide monohydrate in 20 mL water and 20 mL of 1,4-dioxane is stirred at room temperature for 3 h. The resulting mixture is neutralized with 0.26 mL of acetic acid and the resulting mixture is diluted with water. The product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried (sodium sulfate), filtered and concentrated. The residue is purified by flash chromatography on silica gel. The combined fractions are concentrated and the residue is triturated with ether to give 410 mg (42%) of (R)-3-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid; LCMS (ESMS): m/z 435 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([CH3:8])=[N:5][CH:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CN(C)C=O>[CH3:8][C:6]1[S:7][C:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])=[CH:4][N:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ncc(CBr)s1
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ncc(CN2C(=O)c3ccccc3C2=O)s1
Yield: 40.1 %

Procedure:
Add 5-bromomethyl-2-methylthiazole (390 mg, 2.03 mmol) in dimethylformamide (2 mL) dropwise to a suspension of potassium phthalimide (434 mg, 2.34 mmol) in dimethylformamide (8 mL). Stir the reaction under nitrogen at room temperature overnight. Concentrate the mixture in vacuo, dissolve in ethyl acetate (100 mL), and wash with water (100 mL). Dry the organic phase (sodium sulfate), filter, and concentrate. Perform flash chromatography on silica gel, eluting first with 4:1 hexane/ethyl acetate, then 100% ethyl acetate to afford 210 mg of 2-(2-methylthiazol-5-ylmethyl)isoindole-1,3-dione as a tan solid. MS: m/z=259 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][CH2:7][NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([S:16][S:17][C:18]2[CH:29]=[CH:28][C:21]([C:22]([NH:24][CH2:25][CH2:26][OH:27])=O)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1>C(OC(C)C)(=O)C>[O:30]1[CH2:6][CH2:7][N:8]=[C:9]1[C:10]1[CH:11]=[CH:12][C:13]([S:16][S:17][C:18]2[CH:29]=[CH:28][C:21]([C:22]3[O:27][CH2:26][CH2:25][N:24]=3)=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: O=C(NCCO)c1ccc(SSc2ccc(C(=O)NCCO)cc2)cc1
Solvent: CC(=O)OC(C)C
Solvent: O=S(Cl)Cl
Product: c1cc(C2=NCCO2)ccc1SSc1ccc(C2=NCCO2)cc1
Reaction time: 72 h
Yield: 85.3 %

Procedure:
Thionyl chloride (20.0 g) was added to a stirred suspension of 13.3 g of N,N'-bis(2-hydroxyethyl)-4,4'-dithiobis[benzamide] in 250 ml of isopropyl acetate. The reaction mixture was allowed to stand for 3 days and the solid product was collected and dried to give 10.3 g of bis[4-(4,5-dihydro-2-oxazolyl)phenyl]disulfide, used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[NH2:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:31][C:27]3[S:26][CH:30]=[CH:29][N:28]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1nccs1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl

Procedure:
4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (EXAMPLE 5) was prepared in the same manner as INTERMEDIATE D, step 3, starting from 4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride and using thiazol-2-amine instead of intermediate A. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (br. s., 2 H) 4.36 (t, J=4.45 Hz, 2 H) 6.32 (d, J=8.41 Hz, 1 H) 6.79 (d, J=4.50 Hz, 1 H) 7.14 (dd, J=8.61, 2.15 Hz, 1 H) 7.17-7.26 (m, 2 H) 7.73 (d, J=8.31 Hz, 1 H) 7.81-7.88 (m, 1 H) 8.06 (s, 1 H) 12.58 (br. s., 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1ccc2ccc(OCC3CO3)cc2o1

Procedure:
Five grams of 7-(2,3-epoxypropoxy)cumarin obtained by the reaction of 7-hydroxycumarin with epibromohydrin in methyl ethyl ketone in the presence of anhydrous potassium carbonate is heated at reflux for seven hours with 3.1 g of N-carbamoylpiperazine in 100 ml of methanol. After the reaction, methanol is evaporated therefrom in vacuo and the residual crystals are washed with ethyl acetate to give 7.9 g of the product. Hydrochloride recrystallized from a mixture of ethanol and dimethyl formamide melts at 198°-200° C.
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:10][C:11]=2[CH:12]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42]>>[CH:1]1([C:7]2[O:8][C:9]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)=[CH:10][C:11]=2[CH:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([N:38]([CH3:37])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:23])=[CH:25][CH:26]=2)[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)CC(Oc1ccc(C(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CC(C)CC(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Yield: 91.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-cyclohexyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methylbutoxy)benzoic acid (150 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (161 mg, 91%) as an amorphous compound.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])[C:17]1=[O:35])C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH2:24][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:36])[C:17]2=[O:35]
Reactant: COc1ccc(-c2cccc3c2CN(CCCCCC(=O)NOCc2ccccc2)C3=O)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc3c2CN(CCCCCC(=O)NO)C3=O)c(OC)c1
Reaction time: 5 h

Procedure:
N-(benzyloxy)-6-(4-(2,4-dimethoxyphenyl)-1-oxoisoindolin-2-yl)hexanamide (22 mg, 0.045 mmol) in the Step 3 of Example 39 was dissolved in a mixture solvent of MeOH and EtOAc (mixture ratio=2:1 (v/v), 10 ml). 10% of Pd/C (2.2 mg) was added thereto and the reaction proceeded at room temperature for 5 hrs in state of the connected with hydrogen balloon. The resulting mixture thus obtained was filtered with Celite, and the filtrates were distilled under a reduced pressure to remove the solvent and obtained the title compound quantitatively.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl.[BH3-]C#N.[Na+]>CCO.CO>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc2c3ccccc3nc(C)n2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1cc2n(c1)C(C)Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product of Example XXXVI (14.0 g, 0.0436 m) was dissolved in EtOH (1.5 lit) and the pH was adjusted to 4 with methanolic HCl. A solution of NaBH3CN (18.0 g, 0.272 m) in MeOH (300 ml) was added. The pH was readjusted to 4 at 5 min intervals for 20 min. After this time, the pH remained at 4. The reaction mixture was stirred at ambient temperature for 2 hr. The solvent was removed and the residue slurried in H2O (250 ml) and treated with 1N NaOH until basic. The mixture was extracted with CH2Cl2 (2 × 200 ml). The organic extract was dried over Na2SO4, filtered, and the solvent removed to give a white solid; m.p. 102°-103° C.
Reaction SMILES: OC12CC3CC(CC(C3N[C:13]3[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]4[NH:22][CH:23]=[CH:24][C:14]=34)C1)C2>Br>[NH:22]1[C:15]2=[N:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[CH:13]=[C:14]2[CH:24]=[CH:23]1
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1C2CC3CC1CC(O)(C3)C2
Agent: Br
Product: NC(=O)c1cnc2[nH]ccc2c1
Yield: 172.1 %

Procedure:
4-[(5-Hydroxyadamantan-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (100 mg) was dissolved in 45% aqueous HBr (0.5 ml), and the mixture was refluxed for 1.5 hours. The reaction solution was cooled, and the obtained solid was collected by filtration and washed with water. The obtained solid was dissolved in dichloromethane and methanol, and purified by silica gel column chromatography (chloroform:methanol) to obtain 4-[5-bromoadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](B(O)O)=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=2[CH:20]=1.Cl[C:25]1[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]2)=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([C:25]2[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]3[CH2:37][C:36]([CH3:38])([CH3:39])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]3)=[CH:27][CH:26]=2)=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=2[CH:20]=1
Reactant: COc1cc2c(cc1B(O)O)nc(C)n2COCC[Si](C)(C)C
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)nc(C)n2COCC[Si](C)(C)C
Yield: 89 %

Procedure:
The mixture of (6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)boronic acid and the pinacol ester (78 mg, 0.139 mmol), and Intermediate 1-1 (26 mg, 0.092 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 6-(6-Methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained after flash column chromatography purification (44 mg, 89% yield). MS (M+1)=539.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[C:18]3(Br)Br)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18]3)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3c(c2)C(Br)(Br)C(=O)N3)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3c(c2)CC(=O)N3)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc powder (130 mg, 2.00 mmol) was added to a solution of 3-benzyl-3-(3,3-dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (115 mg, 0.20 mmol) in acetic acid (4 mL). The reaction mixture was stirred vigorously at room temperature for 1 hour. Solids were removed by filtration, and the filtrate was concentrate under reduced pressure to give 3-benzyl-3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a foam. The same procedure was repeated using the 3-benzyl-3-(3-bromo-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester to provide additional 3-benzyl-3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl[CH2:34][CH2:35][N:36]1[CH:40]=[N:39][CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:34][CH2:35][N:36]4[CH:40]=[N:39][CH:38]=[N:37]4)[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: ClCCn1cncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1CCn1cncn1
Temperature: 140 °C

Procedure:
A mixture of [(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6; 0.064 mmol), 1-(2-chloroethyl)-1H-[1,2,4]triazole (0.096 mmol), K2CO3 (0.128 mmol) in DMF (1 mL) was heated in a microwave reactor at 140° C. for 10 min, then cooled to rt and concentrated in vacuo. The resultant residue was purified by silica gel chromatography (DCM/MeOH) to afford (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(1H-1,2,4-triazol-1-yl)ethyl]-1,3-thiazolidine-2,4-dione as a yellow solid.