Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([I:15])=[N:6][CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(Br)cnc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-bromopyridin-3-ol (2.75 g, 15.8 mmol) and sodium carbonate (3.35 g, 31.6 mmol) in water (45 mL) was added iodine (4.01 g, 15.8 mmol), and the mixture was stirred at room temperature for 1 hr. 6N Hydrochloric acid (7 mL) was added thereto, and the mixture was weakly acidified with 1N hydrochloric acid (about 5 mL) (pH 4). The resulting solid was collected, washed with water and dissolved in ethyl acetate. The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained solid was washed with a small amount of acetonitrile to give the title compound (3.57 g, yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH3:39])=[O:29])=[CH:25][CH:26]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CC(=O)O)cc3)C(=O)O2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc([C@H](C)N2CC[C@](CCCOCc3ccc(OC)cc3)(c3ccccc3)OC2=O)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetic acid (260 mg, 0.50 mmol) and K2CO3 in DMF (2 mL) was added CH3I (0.2 g, 1 mmol). The resulting mixture was stirred overnight. The solid was filtered, and the filtrate was concentrated to give the crude product, which was purification by TLC to afford methyl 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetate (100 mg, 37%). 1H NMR (CDCl3): δ=1.42 (d, 3H), 1.68 (m, 1H), 1.88 (m, 2H), 2.12 (m, 1H), 2.23 (m, 2H), 2.78 (m, 1H), 3.29 (m, 2H), 3.44 (s, 2H), 3.64 (s, 3H), 3.75 (s, 3H), 4.28 (s, 2H), 5.56 (q, 1H), 6.73 (m, 4H), 6.92 (m, 2H), 7.14 (m, 2H), 7.25 (m, 5H).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[NH:4][CH3:5].Br.Br[CH:14]([C:16]1[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])[CH3:15]>>[CH3:36][N:35]([CH3:37])[C:33]([C:18]1[CH:19]=[C:20]2[C:25](=[C:16]([CH:14]([N:4]([CH3:5])[C:3]3[CH:6]=[C:7]([F:11])[CH:8]=[C:9]([F:10])[C:2]=3[F:1])[CH3:15])[CH:17]=1)[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])=[O:34]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1cc(F)cc(F)c1F
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1F
Yield: 7.9 %

Procedure:
2,3,5-trifluoro-N-methylaniline (197 mg, 1.22 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.31 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-8-(1-(methyl(2,3,5-trifluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (12 mg, 8%) as a white solid. Mass Spectrum: M+H+ 490. NMR Spectrum (DMSOd6): 1.63 (d, 3H), 2.67 (s, 3H), 2.92 (bs, 3H), 3.02 (bs, 3H), 3.18-3.26 (m, 2H), 3.22-3.37 (m partially hidden by H2O, 2H), 3.49-3.56 (m, 2H), 3.56-3.63 (m, 2H), 5.38 (q, 1H), 5.53 (s, 1H), 6.68-6.75 (m, 1H), 6.88-6.96 (m, 1H), 7.78 (d, 1H), 7.86 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.[F:16][C:17]([F:51])([F:50])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]3[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=3)[CH:35]=2)[N:19]=1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:46]([C:42]2[CH:41]=[C:40]([C:36]3[CH:35]=[C:34]([C:20]4[N:19]=[C:18]([C:17]([F:16])([F:50])[F:51])[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[N:21]=4)[CH:39]=[CH:38][N:37]=3)[CH:45]=[CH:44][CH:43]=2)(=[O:47])=[O:48])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2cccc(-c3cc(-c4nc(-c5ccc(C(F)(F)F)cc5)cc(C(F)(F)F)n4)ccn3)c2)CC1
Temperature: 0 °C
Yield: 87.1 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methyl-piperazine (0.09 g, 0.9 mmol), triethylamine (0.09 ml, 0.63 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example 1.1) (0.20 g, 0.34 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.18 g, 88%). MS (ISP) 607.6 [(M+H)+]; mp 205° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=O)[N:5]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](S(NC(NC3CCC(C)CC3)=O)(=O)=O)=[CH:16][CH:15]=2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].CCC1[C:41](=[O:42])N(C(NCCC2C=CC(S(NC(N[C@@H]3CC[C@@H](C)CC3)=O)(=O)=O)=CC=2)=O)CC=1C.C1(CCN=C=O)C=CC=CC=1>>[CH2:1]([CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[C:4]1=[C:41]=[O:42])[CH3:2]
Reactant: CCC1=C(C)CN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)N[C@H]3CC[C@H](C)CC3)cc2)C1=O
Reactant: CCC1=C(C)CN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)NC3CCC(C)CC3)cc2)C1=O
Agent: O=C=NCCc1ccccc1
Product: CCC1C(=C=O)N(C(=O)NCCc2ccccc2)CC1C

Procedure:
U.S. Pat. No. 4,379,785 (hereinafter referred to as the '785 patent) discloses heterocyclic substituted sulfonylureas, particularly N-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]-benzenesulfonyl]-N′-4-methylcyclohexylurea i.e. glimepiride. The '785 patent teaches the preparation of glimepiride starting from 3-Ethyl-4-methyl-3-pyrrolidin-2-one and 2-phenylethylisocyanate to give [2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl]benzene. The [2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl]benzene is converted to the 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl]benzene sulfonamide, a compound of formula 4, by reacting with chlorosulfonic acid, followed by treatment with ammonia solution. This intermediate compound of formula 4 is further reacted with trans-4-methylyclohexyl isocyanate to form glimepiride. The '785 patent teaches a three step process for preparation of the intermediate compound of formula 4, i.e. 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl]benzene sulfonamide, which is represented in Scheme 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].Cl[CH2:19][CH:20]=[N:21][O:22][CH3:23]>C(#N)C>[CH3:23][O:22][N:21]=[CH:20][CH2:19][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: CON=CCCl
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CON=CCOc1ccccc1S(N)(=O)=O
Yield: 57.3 %

Procedure:
30 g (0.2 mol) of potassium carbonate are introduced into a stirred solution of 18 g (0.1 mol) of 2-hydroxybenzenesulphonamide in 20 ml of acetonitrile. 11 g (0.1 mol) of 1-chloro-2-methoxyiminoethane are then rapidly added dropwise, and the mixture is heated at the boiling point for a further 3 hours. The precipitate which separates out is filtered off under suction, in filtrate is evaporated down, the oily residue is triturated with water, and the product is filtered off under suction and dried on clay. 14 g (57% of theory) of 2-(2-methoxyiminoethoxy)phenylsulphonamide of melting point 103° to 105° C. are obtained.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13]C1(C)CCCB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: CB1CCCC(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)ccc1N
Temperature: 100 °C

Procedure:
A mixture of 2-iodo-4-trifluoromethyl aniline (5.0 g, 17.42 mmol), trimethylboroxane (3.64 ml, 26.1 mmol), tetrakis(triphenylphosphine)palladium (1.0 g, 0.87 mmol) and potassium carbonate (4.82 g, 34.8) in DMF (10 ml) was heated to 100° C. for 48 h. The reaction was quenched with water (50 ml) and extracted with EtOAc (3×50 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/1:9 as the eluant. 1H NMR (CDCl3, 500 MHz): δ7.13 (s, 1H), 7.30 (d, J=8 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 3.98 (br s, 2H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)C[C@@H](CBr)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a stirred mixture of N-tert-butoxycarbonyl-1-bromo-2-(S)-amino-4-methylpentane 1.76 g, 6.3 mmol) and triethylamine (0.96 ml, 6.9 mmol) in THF (50 ml) at room temperature was added morpholine (0.60 ml, 6.9 mmol). The mixture was stirred overnight and the solvent removed under reduced pressure. The residue was partitioned between saturated aqueous ammonium chloride (50 ml) and ethyl acetate (2×100 ml). The crude N-tert-butoxycarbonyl-1-morpholino-2-(S)-amino-4-methylpentane was then used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1>C1COCC1.O>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][O:15][C:19]2[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Reactant: Clc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cccnc1OCC1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.675 g, 3.019 mmol) [C.A.S. 158984-76-0] in dry THF (40 ml) cooled at 0° C., was added NaH (0.138 g, 3.622 mmol; 60% mineral oil). The resulting reaction mixture was stirred at 0° C. for 30 min. Then, a solution of 2-chloro-3-bromopyridine (0.58 g, 3.019 mmol) in dry THF (10 ml) was added and the mixture was heated in a sealed tube at 85° C. for 2 h. After cooling, additional (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.675 g, 3.019 mmol), NaH (0.138 g, 3.622 mmol; 60% mineral oil) were added to the reaction mixture, which was then heated at 85° C. overnight. Then, after cooling, the mixture was diluted with water and extracted with EtOAc. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D58 (0.55 g, 50%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].C(OCC=C)C=C>C1(C)C=C(C)C=C(C)C=1>[CH2:15]([C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[OH:12])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: CC(C)(C)c1cc(Cl)ccc1O
Agent: C=CCOCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(Cl)cc(C(C)(C)C)c1O

Procedure:
Treatment of 2-tert-butyl-4-chlorophenol (12.73 g, 0.070 mol) with allyl bromide (10.01 g, 0.083 mol) and potassium carbonate (38.11 g, 0.276 mol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-6-tert-butyl-4-chlorophenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (35.90 g, 0.146 mol, 77%) followed by potassium carbonate (28.18 g, 0.204 mol) generally according to the procedure described for Intermediate 9 provided (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of the alcohol with with p-toluenesulfonyl chloride (10.27 g, 0.054 mol) generally according to the procedure described for Intermediate 10 afforded 13.84 g (51%) (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 74-77° C.; Anal. calcd. for C20H23ClO4S C, 60.83; H, 5.87. Found C, 60.79; H, 5.80.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][S:11][CH3:12]>>[CH3:12][S:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: CSCCCl
Product: CSCCN1CCC(=O)CC1

Procedure:
1-(2-Methylthioethyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-2-methylthioethane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2.C[N:19](C)C=O>O1CCCC1>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:19])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Solvent: C1CCOC1
Product: NC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (4.4 g., 0.018 mol) and 1,1'-carboxyldiimidazole (2.9 g., 0.018 mol) in tetrahydrofuran (300 ml) and dimethylformamide (4 ml) is refluxed under nitrogen for 3.5 hours. The solution is cooled in an ice bath and anhydrous ammonia is bubbled through for 45 minutes. The precipitate is filtered off, washed with hot 0.5 M. aqueous sodium bicarbonate solution, with hot dimethylformamide with ether and dried to give a yellow powder (2.9 g.). mp 285° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[N:17][CH:18]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Br)cn1

Procedure:
The-captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-amino-5-bromopyridine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C.CCOC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2ncccn2)CC1

Procedure:
As shown in step 5-i of Scheme 5, a mixture of tert-butyl ((cis)-4-aminocyclohexyl)carbamate (compound 1009, 490 mg, 2.3 mmol), 2-chloropyrimidine (262 mg, 2.3 mmol) and TEA (463 mg, 637θL, 4.6 mmol) in DMF (10 mL) was subjected to microwave irradiation for 20 minutes at 150° C. The reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 50% EtOAc/hexanes gradient) to provide tert-butyl ((cis)-4-(pyrimidin-2-ylamino)cyclohexyl)carbamate (compound 1010) as a white solid: 1H-NMR (300 MHz, CDCl3) δ 8.28 (d, J=4.8 Hz, 2H), 6.53 (t, J=4.8 Hz, 1H), 5.12 (s, 1H), 4.56 (s, 1H), 3.99 (dq, J=7.0, 3.5 Hz, 1H), 3.65 (s, 1H), 1.83 (tq, J=10.2, 3.6 Hz, 5H), 1.66 (s, 8H), 8.13-7.91 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10](OCC)=[O:11])[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[N:20][N:21]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:18][CH:19]=[N:20][N:21]=2)=[O:11])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Nc1nncs1
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2nncs2)c(=O)n1C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 74.7 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 94 mg of 2-amino-1,3,4-thiadiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, the resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 185 mg of 1,6-dimethyl-4-hydroxy-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 16) represented by the formula:
Reaction SMILES: BrC1SC(N[C:8](=[O:10])C)=NN=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]2[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=[C:21]2[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][CH:8]=[O:10])[CH2:15][CH2:16]2)=[CH:28][CH:29]=1
Reactant: CC(=O)Nc1nnc(Br)s1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 4.4 parts of N-(5-bromo-1,3,4-thiadiazol-2-yl)acetamide, 7.3 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 3.18 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 80°-90° C. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1.7 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]formamide; mp. 153.2° C. (intermediate 156).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:25]4[S:26][CH:27]=[CH:28][C:24]=4[CH3:23])[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3sccc3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3-methylthiophene-2-boronic acid pinacol ester (125 mg, 0.557 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(3-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.52-7.71 (m, 2H), 7.42 (s, 1H), 7.4 (m, 2H), 7.35 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.42 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][C:7]([CH3:20])=[N:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[Se](=O)=[O:24]>O1CCOCC1>[CH:20]([C:7]1[CH2:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:9][N:8]=1)=[O:24]
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2C1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2C1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
9.17 g (29.0 mM) of 8-chloro-4-methyl-1-(4-nitrophenyl)-5H-2,3-benzodiazepine (prepared according to the method described in Example 39) were dissolved in 120 ml of dioxane, then 2.27 g (20.5 mM) of selenium dioxide powder were added and the mixture was stirred on a 90° C. water bath for 40 minutes. Then the solution was treated with active carbon, filtered and poured into 1500 ml of water. The precipitated crystals were filtered and washed with water. The crude product was purified on a Kieselgel column using benzene as eluant.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>CN(C1C=CN=CC=1)C.CN(C)C=O>[F:1][C:2]1[C:7]([S:8]([NH:11][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: C=C(C)C(=O)Cl
Reactant: NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 61.9 %

Procedure:
Using 24.7 g (0.1 mol) of pentafluorobenzene-sulfonamide, 1.2 g (0.01 mol) of 4-(N,N-dimethylamino)pyridine, 22.3 g (0.22 mol) of triethylamine, 13.5 g (0.12 mol) of methacryloyl chloride, and 100 ml of dimethylformamide, reaction was conducted in the same manner as in Synthesis Example 1. As a result, 19.5 g of N-(pentafluorobenzene-sulfonyl)methacrylamide was obtained (yield, 61.9%; light-yellow crystals; m.p., 133-133.5° C.).