Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(I)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(Cl)c(-c2ccccc2)c1
Yield: 55.7 %

Procedure:
In a schlenck tube, a mixture of 2-chloro-3-iodo-5-nitropyridine (1.76 mmol, 0.5 g), phenylboronic acid (1.94 mmol, 0.24 g), PdCl2dppf.DCM (0.18 mmol, 0.1 g), Cs2CO3 (5.28 mmol, 1.7 g) in a dioxane/water 4:1 mixture (6.5 ml) was heated at 120° C. for 4 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/dichloromethane mixtures affording 2-chloro-5-nitro-3-phenylpyridine (0.23 g, yield 55%) of the expected product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[N:21]#[C:22]Br>C1COCC1.CCOC(C)=O>[CH2:13]([N:6]([CH2:5][C@@H:2]1[CH2:3][O:4][C:22]([NH2:21])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CCN(C[C@@H](N)CO)c1ccccc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(C[C@@H]1COC(N)=N1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
To a stirred solution of (R)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (235 mg) at r.t. in THF (10 ml) under an argon atmosphere were added potassium carbonate (334 mg) and a solution of cyanogen bromide (256 mg) in THF (5 ml). Stirring at r.t. was continued for 18 h. The mixture (off-white suspension) was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient:CH2Cl2->CH2Cl2/MeOH 9:1) to provide (R)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (142 mg, 54%) as off-white solid. MS (ISP): 220.1 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](CO)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[CH2:34]NS(C1C=NC=CC=1)(=O)=O.S1C=CN=C1C1C=CC([CH2:54][NH:55][S:56]([C:59]2[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=2)(=[O:58])=[O:57])=CC=1>>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:54]([CH2:34][C:26]2[O:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)[NH:55][S:56]([C:59]2[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=2)(=[O:58])=[O:57])[N:10]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Reactant: O=S(=O)(NCc1cc2ccccc2o1)c1cccnc1
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2cc3ccccc3o2)NS(=O)(=O)c2cccnc2)n1
Yield: 88 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate (252 mg, 0.745 mmol) obtained in Reference Example 3-(b), and using N-(benzofuran-2-ylmethyl)pyridin-3-ylsulfonamide (215 mg, 0.747 mmol) obtained in Reference Example 10-(c) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide to afford the title compound (397 mg) as a white foam. (Yield: 88%) Mass spectrum (FAB, m/z): 609 (M++1).
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].[CH2:5]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1)=[O:9])[CH3:6]>>[CH2:5]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:3]([CH2:1][CH3:2])[CH3:4])[N:11]=1)=[O:9])[CH3:6]
Reactant: CCNC
Reactant: CCNC(=O)c1cccc(Br)n1
Product: CCNC(=O)c1cccc(N(C)CC)n1

Procedure:
prepared by reaction of ethyl-methyl-amine with 6-bromo-pyridine-2-carboxylic acid ethylamide
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.Cl[Si:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:8][Si:7]([CH3:10])([CH3:9])[N:2]1[N:3]=[CH:4][CH:5]=[N:1]1
Reactant: c1cn[nH]n1
Reactant: C[Si](C)(C)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)n1nccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
A 1000-mL 4-necked round-bottomed flask was charged with a solution of 2H-1,2,3-triazole (30 g, 434.78 mmol, 1.00 equiv) in benzene (500 mL). To this solution was added chlorotrimethylsilane (49.3 g, 456.48 mmol, 1.05 equiv) drop wise 0° C. followed by addition of triethylamine (48.3 g, 478.22 mmol, 1.10 equiv). The resulting solution was stirred for 16 hours at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation and the fraction was collected at 140-150° C. affording 2-(trimethylsilyl)-2H-1,2,3-triazole as colorless oil (11 g, 18%). To a solution of 2-(trimethylsilyl)-2H-1,2,3-triazole (6.2 g, 43.97 mmol, 2.74 equiv) in DMF (100 mL) was added tert-butyl 3-(4-nitrophenylsulfonyloxy)piperidine-1-carboxylate (6.2 g, 16.06 mmol, 1.00 equiv). The resulting solution was refluxed for 3 hours. Upon completion, the mixture was cooled down to room temperature and concentrated on a rotary evaporator affording tert-butyl 3-(1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate as brown solid (2.3 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21](O)[CH3:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:4])=[O:3].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O>C1COCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]([N:28]2[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]2=[O:29])[CH3:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:3])=[O:4]
Reactant: CC(O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h

Procedure:
To a mixture of crude of 1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanol (700 mg, 2.13 mmol) and phthalimide (627 mg, 4.26 mmol) in THF (21 mL) was added triphenylphosphene (1.12 g, 4.26 mmol) at 0° C. The reaction mixture was stirred for 10 min at same temperature. Diisopropyl azodicarboxylate (0.9 mL, 4.26 mmol) was added to mixture at 0° C. The reaction mixture was stirred for overnight at 0° C. Water was added to reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 2-(1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethyl)isoindoline-1,3-dione: LC-MS (ESI) m/z 458.1 [M+H]+. It was carried on crude for next step.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21]([Cu])#[N:22]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([C:21]#[N:22])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc3cc(OC)cc(C#N)c3o2)cc1
Temperature: 150 °C
Yield: 50.7 %

Procedure:
To 7-bromo-5-methoxy-2-(4-methoxy-phenyl)-benzooxazole (200 mg) in DMF (5 mL) was added CuCN (80 mg). The mixture was placed in an oil bath and heated to 150° C. for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with 1N HCl, brine (3×), dried (Na2SO4), and concentrated. Flash chromatography on silica gel eluting with 20% ethyl acetate-hexane afforded 85 mg (50%) of the title compound as a solid. MS: 281 (MH+), HPLC tR: 2.71 min.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[F:6][CH:7]([F:31])[C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH:22]=[O:23])[O:21][C:17]=3[CH:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=2)=[CH:10][CH:9]=1>CC#N.C(OCC)(=O)C.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](F)([O-])(=O)=O>[F:31][CH:7]([F:6])[C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([C:22]([OH:2])=[O:23])[O:21][C:17]=3[CH:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C=O)oc2c1
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=[Cr](=O)([O-])F
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C(=O)O)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
To acetonitrile (10 mL) was added periodic acid (209 mg, 0.916 mmol) and stirred vigorously at room temperature for 15 min. Ethyl 4-[4-(difluoromethyl)phenoxy]-2-formyl-1-benzofuran-6-carboxylate (300 mg, 0.833 mmol) was then added (in ice-bath) followed by addition of pyridium fluorochromate (3.32.mg, 0.02 mmol) in CH3CN (5 mL). The reaction was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with brine/water (1:1), dried over MgSO4 and concentrated to give the title compound (300 mg, 96%) as an orange solid, which was usedin the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.33 (t, J=7.16 Hz, 3 H) 4.33 (q, J=7.16 Hz, 2 H) 6.61 (t, J=56.52 Hz, 1 H) 7.06 (d, J=8.48 Hz, 2 H) 7.37 (s, 1 H) 7.43-7.54 (m, 3 H) 8.02 (s, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH:24]([NH:28][CH:29]([CH2:31][CH3:32])[CH3:30])([CH2:26][CH3:27])[CH3:25]>CN(C)C=O>[CH:24]([N:28]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH:29]([CH2:31][CH3:32])[CH3:30])([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)NC(C)CC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CCC(C)N(Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1)C(C)CC
Yield: 58.2 %

Procedure:
1.65 g (5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 75° for 24 hours in 3 ml (17.5 mmol) of di-sec.-butylamine and 25 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 and crystallization from ethyl acetate there were obtained 1.23 g (58%) of 3-(5-di-sec.-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of m.p. 155°-157°, which was converted into the hydrochloride of m.p. 133°-140°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7]SC1C=CC=CC=1.Cl[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](C(OO)=O)[CH:17]=1.[S:26]([O-:29])(O)=[O:27].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7][S:26]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:29])=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nnsc1CSc1ccccc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnsc1CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
In 5.0 ml of methylene chloride was dissolved 0.20 g (0.99 mmol) of 4-methyl-5-phenylthiomethyl-1,2,3-thiadiazole. Then, 0.40 g (2.3 mmol) of m-chloroperbenzoic acid was added to the solution obtained above, and was stirred for 20 hours at room temperature. Then, an aqueous solution of sodium hydrogen sulfite was added to the reaction mixture to stop the reaction, the objective product was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 2:1 mixture of n-hexane and ethyl acetate. Thus, 0.23 g of the objective compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])([O-:10])=[O:9]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1
Yield: 78.2 %

Procedure:
Using aniline (1.50 ml, 16.5 mmol) and 3-nitrobenzoic acid (2.64 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.84 g (78.2%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]N(C)C=O.C(Cl)(=O)C(Cl)=O.CO>ClCCl>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A slurry of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mL dichloromethane was cooled in an ice bath. Dimethylformamide (0.40 mL) was added to the reaction followed by drop wise addition of 13.85 g (109 mmol) of oxalyl chloride. The reaction was allowed to warm to room temperature and was stirred for 6 h. Methanol (200 mL) was added drop wise and the reaction was stirred overnight. The reaction was concentrated to a residue, dissolved in dichloromethane and passed through a plug of silica eluting with a 50% ethyl acetate/hexane mixture. The filtrate was concentrated in vacuo to give 21.5 g (100%) of the title compound.
Reaction SMILES: [Na].C(O)C.[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[CH2:6][CH3:7].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1>C(O)C.O1CCCC1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:5](=[O:8])[CH:6]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH3:7])[CH3:14]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrCc1ccc2ccccc2c1
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)Cc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
Sodium (1.25 g) was added to 60 mL of absolute ethanol under nitrogen atmosphere at room temperature. When all of the metal had reacted the mixture was cooled in ice and ethyl propionylacetate was added in one portion. The reaction mixture was brought to reflux temperature for 0.25 hours, an ethanol-tetrahydrofuran solution (10:1, 120 mL) of 2-bromomethylnaphthalene (10 g) added, and the resulting mixture heated at reflux temperature 15 hours. The reaction mixture was cooled to room temperature and the volatile materials removed in vacuo on the rotary evaporator. The residue was partitioned between saturated, aqueous NaCl solution and ethyl acetate. The organic phase was dried over MgSO4 and concentrated to an oily mixture which was purified by HPLC (hexane, ethyl acetate gradient elution) to give 5.2 g of ethyl-α-(2-naphthalenylmethyl)propionylacetate as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[ClH:24].[CH:33]1([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]3[CH:12]=[C:13]4[C:18]5=[C:19]([CH2:21][CH2:22][N:17]5[C:16](=[O:23])[CH2:15][CH2:14]4)[CH:20]=3)=[O:10])[CH2:5][CH2:6]2)[C:34]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][CH2:32]1
Reactant: ClC1CCCc2ccccc21
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Product: Cl
Product: O=C(CCC1CCN(C2CCCc3ccccc32)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Yield: 5.6 %

Procedure:
Using 8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (500 mg) and (±)-1-chloro-1,2,3,4-tetrahydronaphthalene (280 mg) according to the same method as that of Example 330, the title compound (43 mg) was obtained as pale yellow amorphous powders.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:44])[CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:44])[CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)[CH3:22]
Reactant: C=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: C=CCCC(C)Nc1c(C)noc1-c1ccc(-c2ccc(C3(CC(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-pent-4-enyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[C:6]([O:5][C:1]([NH:2]/[N:3]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=N/NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 80 %

Procedure:
To a solution of t-butyl carbazate (25.5 g, 193 mmol) in THF (60 ml) was added 47% ethyl glyoxylate in toluene (polymer type) (46.1 g, 212 mmol), and stirred at 60° C. for minutes. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The resulting solid was washed with a mixed solvent of hexane:ethyl acetate=5:1 to give 33.9 g of Compound (X-1) (yield: 80%) as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:20][N:19]([CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([NH:22][C:23](=[O:25])[CH3:24])[N:5]=1)[CH3:21]
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-[(dimethylamino) methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (1.0 g), acetic anhydride (0.35 g) and pyridine (50 ml) was stirred at 25° for 12 h. The pyridine was removed and the residue was dissolved in ethyl acetate. The organic solution was washed with aqueous sodium carbonate and evaporated to give the title compound as a pale yellow oil (1.1 g). TLC silica, methanol/0.88 ammonia 80:1, Rf 0.49. NMR (CDCl3) 1.42 brs (1H); 2.81 m (1H); 3-3.4 m (3H); 5.34 t (1H); 5.98 t (2H); 6.52 s (3H); 6.65 s (2H); 6.5 m (2H); 7.8 s (6H); 7.5-8.1 m (2H); 7.9 s (3H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].[H-].[Na+].Cl[C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9](=[C:18]([O:19][C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:26])([F:25])[F:14])[C:10]#[N:11])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: CCCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC(=O)OC(=C(C#N)c1ccc(C(C)(C)C)cc1)c1ccccc1C(F)(F)F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A mixture comprising 2.0 g of 4-tert-butylbenzyl cyanide, 2.35 g of 2-trifluoromethylbenzoyl chloride and 8 ml of dimethylformamide, was dropwise added to a mixture comprising 0.84 g of 68% sodium hydride and 13 ml of dimethylformamide while maintaining the temperature at a level of from 40 to 50° C. After completion of the dropwise addition, the reaction was carried out for 30 minutes at room temperature. The reaction mixture was cooled with ice, and a mixture comprising 1.5 g of n-propyl chloroformate and 1.2 ml of dimethylformamide, was dropwise added. After completion of the dropwise addition, the reaction was carried out for 30 minutes under cooling with ice. The reaction mixture was poured into ice water and extracted with methylene chloride and then washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=1/9) to obtain 3.4 g of the desired product (isomer ratio 7:93) having a melting point of 44 to 45° C. The HPLC conditions for the analysis of this product were the same as in Preparation Example 1. Further, the NMR spectrum data of this product are as follows.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:5][C:4]=1[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[CH3:29])[C:15](=O)[CH3:16])#[N:2].B1([O-])O[O:31]1.O.O.O.O.[Na+].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CO.O>[CH3:16][C:15]1[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:20]=2[CH3:29])[C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[S:7][C:3]=2[C:1](=[O:31])[N:2]=1
Reactant: [O-]B1OO1
Reactant: CC(=O)N(Cc1cccc(C(F)(F)F)c1C)c1nc(N2CCOCC2)sc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 55 °C
Reaction time: 8 h

Procedure:
In a 2 L round bottom flask equipped with a magnetic stir bar, N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]-N-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}acetamide (42.5 g, 100 mmol), sodium perborate tetrahydrate (46.2 g, 300 mmol), and potassium carbonate (27.64 g, 200 mmol) were taken up in Methanol (233 mL), Tetrahydrofuran (THF) (233 mL), and Water (233 mL) and the resulting reaction mixture was heated to 55° C. and stirred overnight at 55° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[NH:13][C:14]1[N:15]=[CH:16][C:17]2[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[O:24])[CH2:20][C:18]=2[N:19]=1>CN(C)C=O.ClCCl.O.[Cl-].[Li+]>[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[NH:13][C:14]1[N:15]=[CH:16][C:17]2[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][C:1]#[N:2])=[O:24])[CH2:20][C:18]=2[N:19]=1
Reactant: O=C(OCCCCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCCCOC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
Add sodium cyanide (0.230 g; 1.5 equiv; 4.69 mmoles) to a solution containing 3-chloropropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (1.15 g; 1.0 equiv; 3.08 mmoles) in dimethylformamide (10 mL). Heat the reaction mixture to 100° C. for 3 hours, then cool to ambient temperature, dilute with dichloromethane, water, and 5% lithium chloride solution. Separate the layers and further extract the aqueous layer with dichloromethane and ethyl acetate. Dry the combined organic extracts over sodium sulfate, filter, and concentrate to provide 3-cyanopropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (0.98 g; 87%) as a brown solid: MS (m/z): 364(M+1).