Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[C:26]([CH3:27])[CH:25]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (360 mg) in DMF (5 mL) was added potassium carbonate powder (555 mg) and 3-methylbenzyl bromide (774 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.ClCCl.C(N(CC)CC)C.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>O>[C:18]([O:1][CH:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1)(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1CC(O)CO1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1COC(=O)C1
Temperature: -65 °C
Reaction time: 3 h
Yield: 117.5 %

Procedure:
In a glass flask equipped with a stirrer, two dropping funnels, a thermometer and a Dimroth condenser, β-hydroxy-γ-butyrolactone (91.1 g, 0.875 mol) having a purity of 98% obtained by repeating the process of Example 1 and 500 ml of dry dichloromethane were charged, and then triethylamine (117.5 g, 1.16 mol) was charged in one dropping funnel and methacrylic acid chloride (112 g, 1.071 mol) was charged in another dropping funnel. The atmosphere in the glass flask was replaced by nitrogen and then cooled to −60 to −70° C. in a dry ice-acetone bath. While stirring in the glass flask, triethylamine and methacrylic acid chloride were added dropwise with adjusting so that the amount of triethylamine becomes small excess to that of methacrylic acid chloride. After the completion of the dropwise addition, stirring was continued for 3 hours. To the reaction solution, 300 ml of water was added and a small amount of Celite was added, followed by filtration. The filtrate was washed three times with 300 ml of water using a separatory funnel and dried by adding 80 g of magnesium sulfate and, after filtering, the filtrate was concentrated to obtain 175 g of crude β-methacryloyloxy-γ-butyrolactone. This β-methacryloyloxy-γ-butyrolactone was purified by silica gel column chromatography to obtain β-methacryloyloxy-γ-butyrolactone (106.3 g, 0.625 mol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:14][C:12]1[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=[C:10]([C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 6′-(3-bromo-phenyl)-2′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl (example B.12) (0.098 g, 0.25 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.61 g, 0.275 mmol) according to the general procedure III. Obtained as an off-white solid (0.031 g, 31%). MS (ISP) 407.3 [(M+H)+]; mp 124-125° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:13][CH3:14])([CH3:12])[CH3:11])[CH:5]=1)[CH3:2].[I:15]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([O:13][CH3:14])([CH3:11])[CH3:12])[CH:7]=[CH:8][C:9]=1[I:15])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOc1cccc(C(C)(C)OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOc1cc(C(C)(C)OC)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
To a solution of 1-ethoxy-3-(1-methoxy-1-methyl-ethyl)-benzene (5.15 g, 26.51 mmol) in acetonitrile (60 mL) were added N-iodosuccinimide (8.349 g, 37.11 mmol) and trifluoroacetic acid (1.02 mL, 13.26 mmol). The mixture was stirred at room temperature overnight. It was then concentrated in vacuo and the residue was taken in ethyl acetate. After washing with saturated solution of sodium bicarbonate, water and brine, the organic layer was dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 9.39 g of 2-ethoxy-1-iodo-4-(1-methoxy-1-methyl-ethyl)-benzene as light brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CCCC)CCCC)CCC.[C:25](Cl)(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CN(C)C=O>[C:25]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1C
Yield: 27 %

Procedure:
A stirred solution of 4-amino-3-methylbenzoic acid (30.2 g), in dry dimethylformamide (300 ml), containing tributylamine (55 ml) was treated with n-hexadecanoyl chloride (61.0 g) in a similar manner to that described in Example 1(i) to give 4-(n-hexadecanamido)-3-methylbenzoic acid (21 g), in the form of white needles, m.p. 194°-196° C.
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:27][CH2:28][CH3:29])=[C:7]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([O-])=[O:23])=[CH:20][CH:19]=3)[CH:10]=2)[CH:8]=1.[Al].[Li].CO.Cl>O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:27][CH2:28][CH3:29])=[C:7]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=3)[CH:10]=2)[CH:8]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(C(=O)[O-])cc2)nc(NC)n1
Agent: Cl
Agent: [Al]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(NC)n1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a mixture of 4-[6-(5-chloro-2-ethoxy-phenyl)-2-methylamino-pyrimidin-4-ylamino]-benzoic acid sodium salt (100 mg, 0.25 mmol) in tetrahydofuran (20 ml) was added lithium aluminum hydide (100 mg, 2.63 mmol) in 10 portions at room temperature. After stirring for 1 hour, methanol (5 ml) was carefully added followed by hydrochloric acid (1 M, 10 ml). After stirring for 10 minutes, the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was treated with methanol (5 ml) and a solution of sodium carbonate (5.0 g) in water (15 ml). The mixture was concentrated under reduced pressure to remove methanol. Filtration and drying of the solid under reduced pressure for 12 hours yielded the title compound (80 mg, 83% yield). 1H NMR (DMSO-d6) δ 1.39 (t, 3H, J=6.93 Hz, CH3), 2.86 (d, 3H, J=4.7 Hz, OH), 4.13 (q, 2H, J=7.0 Hz, CH2), 4.45 (d, 2H, J=5.7 Hz, CH2), 5.07 (t, 1H, J=5.7 Hz, CH2), 6.75 (br s, 2H, Ar), 7.14 (d, 1H, J=8.9 Hz, Ar), 7.24 (d, 2H, J=8.5 Hz, Ar), 7.40 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.67 (d, 2H, J=8.3 Hz, Ar), 7.93 (s, 1H, NH), 9.17 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:33])(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:33])=[O:26])=[O:29])[CH3:32]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: OCCCNc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(NCCCO)n2)cc1
Yield: 29 %

Procedure:
In the reaction of 3-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propanol (154 mg, 0.57 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl-sulfoximide (127 mg, 0.53 mmol) according to procedure 5b, the desired product is obtained in 29% yield (80 mg) after chromatographic purification (silica gel, hexane/ethyl acetate (50%-100% ethyl acetate)) and subsequent purification by HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2([CH3:10])[CH:7]([OH:9])[CH2:8][CH:3]1[CH2:4][CH2:5]2.[O-]Cl.[Na+]>C(O)(=O)C>[C:6]12([CH3:10])[C:2]([CH3:11])([CH3:1])[CH:3]([CH2:4][CH2:5]1)[CH2:8][C:7]2=[O:9]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: CC12CCC(CC1=O)C2(C)C
Yield: 96.3 %

Procedure:
To a vigorously stirred solution of 600 g (3.89 mol) of (-)-borneol in 1.5 L of glacial acetic acid at 0° C. was added 7.5 L of household bleach (Chlorox™) over a period of 1 h. After 30 min the solid (800 g) was collected by filtration and dissolved in 2 L of hexane. The solution was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated to give 570 g (96%) of camphor.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:50])[NH:29][CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:50])[NH:29][CH2:30][CH2:31][OH:32])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OCCNC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCCO)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[2-(t-butyldiphenylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.68 g, 2.33 mmol) (obtained as described in Reference Example 33(2)) in anhydrous tetrahydrofuran (75 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (5.6 ml, 5.6 mmol) in an ice bath, and the mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-hydroxy-1-(4-hydroxyethylcarbamoyl-1,3-thiazol-2-yl)azetidine (481.2 mg, yield 85%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([N+:13]([O-])=O)=[C:5]2[NH:16][C:17]1([CH3:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([NH2:13])=[C:5]2[NH:16][C:17]1([CH3:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CC1(Nc2c([N+](=O)[O-])cnc3cc(F)c(Br)cc23)CCOCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1(Nc2c(N)cnc3cc(F)c(Br)cc23)CCOCC1
Temperature: 60 °C
Yield: 98.3 %

Procedure:
6-Bromo-7-fluoro-N-(4-methyloxan-4-yl)-3-nitroquinolin-4 amine (1.215 g, 3.16 mmol) was added to iron powder (1.8 g) in acetic acid (15 mL). The mixture was stirred and heated gently with a hot air gun (approximately 60° C.) to initiate reaction. The heat source was removed and the resulting mixture was stirred for 1 h. The reaction mixture was diluted with water and the solids removed by filtration and discarded. The filtrate was concentrated in vacuo, diluted with water and extracted with EtOAc. The organics were dried over Na2SO4 and concentrated in vacuo to afford the desired material (1.10 g, 98%) as a brown solid which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:16][S:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]Br)=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Reactant: CS(=O)(=O)c1ccc(CCBr)cc1
Product: CS(=O)(=O)c1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 47.3 %

Procedure:
1-(Piperidin-4-yl)indoline (200 mg) and 4-methane-sulfonylphenethyl bromide (290 mg) were treated as in Example 2 to give the title compound (180 mg) as a white powder (yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28]>C(=O)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:28][CH2:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])([C:26]([O:30][CH2:31][CH3:32])=[O:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)CCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Temperature: 25 °C

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (10 g) is dissolved in diethyl carbonate (150 ml) in a nitrogen stream, and 60% sodium hydride (2.0 g) is added with stirring at room temperature. The mixture is refluxed under heating for 2 hours and cooled to 50° C. with ice water. Ethyl acrylate (5.4 ml) is added. After stirring at 50° C. for 3 hours, the reaction mixture is poured into ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) to give 3.2 g of (±)-ethyl 3-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)propionate as an oil. (±)-Ethyl 3-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)propionate (3.2 g) is dissolved in a mixture of ethanol (90 ml) and water (30 ml), and barium hydroxide 8 hydrate (7.8 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 6N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The organic layer is washed with a saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate and isopropyl ether to give 0.1 g of (±)-3-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)propionic acid as brown crystals, melting point 210°-212° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC(N(C)C)=O>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccc3c(c2)CCCC3=O)cc1
Reaction time: 4 h
Yield: 82 %

Procedure:
Combine 6-Hydroxytetralone (4.42 g, 27.24 mmol), 4-Fluorobenzonitrile (3.0 g, 24.76 mmol), K2CO3 (5.1 g, 37.14 mmol) and toluene/DMA (30 ml/90 ml), then reflux under nitrogen using a Dean Stark Trap. After 4 hours, cool the reaction to room temperature and add to a separatory funnel. Add Ethyl acetate and wash the organic layer several times with water, then a brine solution, and dry the organic layer over Na2SO4. Flash chromatograph using 4/1 hexanes/ethyl acetate eluant to afford 5.34 g, 20.3 mmol (82% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.1-2.2 (2H, m), 2.6-2.7 (2H, m), 2.9-3.0 (2H, m), 6.85 (1H, s), 6.9-7.0 (1H, m), 7.05-7.15 (2H, m), 7.6-7.7 (2H, m), 8.05-8.10 (1H, m); MS m/z 264 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>>[C:45]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:47])[CH3:46]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C(C)=O)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.251 g, 0.611 mmol) in dry N,N-Dimethylformamide (3.00 mL, 38.7 mmol) was added N,N-Diisopropylethylamine (0.310 mL, 1.78 mmol) followed by Acetyl chloride (0.0650 mL, 0.913 mmol). The reaction mixture was stirred for overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.17 (d, J=7.6, 2H), 7.48 (d, J=7.9, 2H), 6.22 (d, J=6.1, 1H), 4.78-4.63 (m, 1H), 4.44 (dd, J=82.7, 18.2, 1H), 3.97 (s, 1H), 3.85 (d, J=11.1, 1H), 3.78 (d, J=11.6, 1H), 3.67 (d, J=7.4, 2H), 3.45 (dd, J=38.1, 25.8, 3H), 3.29 (m, 1H), 3.16-3.07 (m, 2H), 2.68 (dd, J=47.0, 37.1, 2H), 2.12 (s, 3H), 1.78 (ddd, J=27.5, 13.8, 7.0, 2H), 1.06 (t, J=7.2, 3H), 0.83 (dd, J=12.0, 7.4, 3H). LC/MS-m/z+453.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH:7]2[C:11](=[O:12])[C:10]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[C:9]([O:22]C)[CH2:8]2)=[CH:4][CH:3]=1>CC(C)=O.Cl>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH:7]2[CH2:8][C:9](=[O:22])[CH:10]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:11]2=[O:12])=[CH:4][CH:3]=1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Temperature: 40 °C
Yield: 95.6 %

Procedure:
To a solution of 5-(4-fluoro-benzyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (136 mg, 0.40 mmol) in acetone (2 ml) is added a 2N solution of hydrochloric acid (2 ml) and the resulting solution is heated to 40° C. by microwave irradiation for 30 minutes. The reaction mixture is diluted with 2N hydrochloric acid (25 ml), and extracted with ethyl acetate (2×25 ml). The combined organics are washed with brine (25 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to give 4-(4-fluoro-benzyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (124 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].ClC1C=CC=C(C(OO)=[O:32])C=1>CO>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11])=[O:32]
Reactant: CSc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1S(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 138.8 %

Procedure:
A mixture of 3-methylthio-4-[3-(2-methylphenyl)ureido]phenylacetic acid (0.2 g, Reference Example 15), meta-chloroperbenzoic acid (61 mg) and methanol (25 ml) was stirred at ambient temperature for 1 hour and then evaporated. The residue was triturated with ethyl acetate to give the title compound (0.17 g) as a white solid.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.Cl>CN(C)C=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([S:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Sc1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2nc[nH]n2)cc1
Reaction time: 1 h
Yield: 66 %

Procedure:
5 g of 3-mercapto-1,2,4-triazole was dissolved in 40 ml of N,N-dimethylformamide, and 2.17 g of sodium hydride (60% in mineral oil) was added at 0° C.. The solution was stirred at the same temperature for one hour, and then 7.78 g of 1-chloro-4-nitrobenzene was added. The solution was stirred at room temperature for one hour, and refluxed for 2 hours. Then, 10% hydrochloric acid was added to the reactant solution, it was extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate, and the solvent was evaporated, so that coarse crystals were obtained. The coarse crystals were recrystallized from n-hexane/ethyl acetate, so that 7.72 g of the titled compound was obtained (at a yield of 66%).
Reaction SMILES: N1C2C=C(C#N)N=CC=2C=C1.[CH3:12][C:13]([NH:20][C:21]1[CH:26]=[C:25]([NH2:27])[C:24]([C:28]#[C:29][Si](C)(C)C)=[CH:23][N:22]=1)([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14]>>[CH3:12][C:13]([NH:20][C:21]1[N:22]=[CH:23][C:24]2[CH:28]=[CH:29][NH:27][C:25]=2[CH:26]=1)([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14]
Reactant: CC(C)(C)CC(C)(C)Nc1cc(N)c(C#C[Si](C)(C)C)cn1
Agent: N#Cc1cc2[nH]ccc2cn1
Product: CC(C)(C)CC(C)(C)Nc1cc2[nH]ccc2cn1

Procedure:
The compound was prepared following the procedure same as that of 1H-pyrrolo[3,2-c]pyridine-6-carbonitrile starting from N2-(2,4,4-trimethylpentan-2-yl)-5-[(trimethylsilyl)ethynyl]pyridine-2,4-diamine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1
Reactant: O=C1Nc2ccccc2SC1CCCCO
Reactant: O=S(Cl)Cl
Product: O=C1Nc2ccccc2SC1CCCCCl
Yield: 59 %

Procedure:
By a process similar to that in Reference Example 13-(2), 2-(4-hydroxybutyl)-2H-1,4-benzothiazin-3(4H)-one was allowed to react with thionyl chloride to obtain 2-(4-chlorobutyl)-2H-1,4-benzothiazin-3(4H)-one. The yield was 59.0%. m.p. 111°-112° C. (recrystallized from ethyl acetate-hexane).