Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9]>C(O)C.[B-](F)(F)(F)F.[Ag+]>[C:1]([NH2:8])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: N#Cc1ccccc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: NC(=O)c1ccccc1
Temperature: 90 °C
Yield: 87407.4 %

Procedure:
(0.0045 g, 0.0097 mmol) of the catalyst of Example 3, was dissolved in a vigorously stirred mixture of benzonitrile (3.5 g, 0.034 mmol), ethanol (7 cm3) and water (2 ml, 0.06 mmol). To this was added an excess of AgBF4 (0.0045 g, 0.019 mmol) and the reaction mixture refluxed at 90° C. for five hours. After cooling, it was filtered to remove the precipitated AgCl. The solvent was then removed under reduced pressure to give benzamide (3.60 g, 87%), which was dried in vacuo.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][N:30]=1>C1COCC1.CCCCCC.O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[CH2:2])=[CH:31][N:30]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cn1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=Cc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of triphenylmethylphosphonium bromide (31.2 g, 0.0875 mol) in THF (150 mL) at −78° C. under an atmosphere of nitrogen was added 2.5 M n-BuLi (38.0 mL, 0.0948 mol) in hexane during a period of 30 min. The reaction was warmed to room temperature to give a deep red ylide solution. To the ylide solution, cooled in ice, was introduced 6-methoxynicotinaldehyde (10.0 g, 0.0729 mol) in THF (30 mL). The reaction was allowed to reach room temperature and stirred at rt for 3 h. Then the result suspension was heated to 60° C. over 30 minutes and heated at 60° C. for 1 hour. After cooling, the reaction was diluted with water (500 mL). The product was extracted into ethyl ether, washed with brine, dried (MgSO4), and concentrated. The residue was purified with silica gel column (0-40% EtOAc/hexane) to give a light yellow oil. LC-MS: 136.0 [M+1]+;
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[CH:10]1[CH2:13][O:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:10]2[CH2:13][O:12][CH2:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: IC1COC1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cn(C2COC2)cn1
Temperature: 120 °C
Yield: 33.4 %

Procedure:
A sealed tube was charged with 4-nitro-1H-imidazole (500 mg, 4.42 mmol), 3-iodooxetane (920 mg, 5.0 mmol), Cs2CO3 (2.90 g, 8.84 mmol), and dioxane (12 mL). The sealed tube was heated at 120° C. for 16 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 285a as a white solid (250 mg, 33%). MS-ESI: [M+H]+ 170.2.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[C:6]([NH2:12])=[N:7][CH:8]=[N:9][C:10]=1Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[Cl:21]>>[CH3:1][O:2][N:3]=[CH:4][C:5]1[C:6]([NH2:12])=[N:7][CH:8]=[N:9][C:10]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([Cl:21])[CH:16]=1
Reactant: CON=Cc1c(N)ncnc1Cl
Reactant: Nc1ccc(O)cc1Cl
Product: CON=Cc1c(N)ncnc1Oc1ccc(N)c(Cl)c1

Procedure:
Using the procedure for Example 9, 4-amino-6-chloro-pyrimidine-5-carbaldehyde O-methyl-oxime Compound 9a (0.20 g) and 4-amino-3-chloro-phenol Compound 10a (0.19 g) were reacted to provide 4-amino-6-(4-amino-3-chloro-phenoxy)-pyrimidine-5-carbaldehyde O-methyl-oxime Compound 10b (0.20 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.60 (s, 1H), 7.15 (s, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 5.32 (s, 2H), 3.98 (s, 3H). MS (ESI) m/z: 299 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22]N(C)C=O.[H-].[Na+].S(F)(OC)(=O)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:22])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: CN(C)C=O
Agent: COS(=O)(=O)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.6 g of approximately 55 % sodium hydride, and the solution was stirred for 30 minutes at room temperature. To this was added 2.3 g of methyl fluorosulfate, and the whole was reacted for one hour at room temperature. After the reaction was complete, the solvent was distilled off from the reaction mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. Recrystallization of this product from methanol gave 2.7 g of 1-(m-nitrophenyl)- 3-methylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 241°-242° C.
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:18][CH2:19][CH2:20][S:21](=[O:23])(=[O:22])[C:13]=3[CH:12]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Br:31])[CH:25]=3)[C:11]=2[C:10](=[O:32])[CH2:9]1)C1C=CC=CC=1.Cl[C:34]([O:36][CH:37]=[CH2:38])=[O:35]>C1COCC1>[Br:31][C:26]1[CH:25]=[C:24]([CH:12]2[C:11]3[C:10](=[O:32])[CH2:9][N:8]([C:34]([O:36][CH:37]=[CH2:38])=[O:35])[CH2:17][C:16]=3[NH:15][C:14]3[CH2:18][CH2:19][CH2:20][S:21](=[O:23])(=[O:22])[C:13]2=3)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: C=COC(=O)Cl
Reactant: O=C1CN(Cc2ccccc2)CC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCS1(=O)=O)N2
Solvent: C1CCOC1
Product: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C2c2ccc(F)c(Br)c2)S(=O)(=O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A solution of the product from Example 9A 0.48 g, 0.92 mmol) in THF (5 mL) was treated with vinyl chloroformate (0.10 mL, 0.94 mmol) and stirred at ambient temperature overnight. The solvent was evaporated and the residue was purified by flash chromatography over silica gel (ethyl acetate and then 10% ethanol/methylene chloride) to provide the title compound (0.25 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24](=[O:29])[N:25]([O:27][CH3:28])[CH3:26])[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[C:24](=[O:29])[N:25]([O:27][CH3:28])[CH3:26])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)C1CNCCN1C(=O)OCc1ccccc1
Temperature: 40 °C
Yield: 97.6 %

Procedure:
A mixture of (RS)-2-(methoxy-methyl-carbamoyl)-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (WO 01/00214) (5 g, 0.012 mol) in dichloromethane (100 ml) and trifluoroacetic acid (20 ml) was heated at 40° C. for 0.5 h, cooled and evaporated. The residual oil was dissolved in dichloromethane (150 ml) and washed with 1M sodium hydroxide (80 ml). The aqueous phase was re-extracted with dichloromethane (2×) and the combined extracts dried (Na2SO4) and the solvent removed in vacuo to give the title compound as an oil (3.6 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution ethyl (3S)-3-(4-hydroxyphenyl)hex-4-ynoate (0.1 g, 0.43 mmol) and 1,4-bis(bromomethyl)benzene (0.227 g, 0.861 mmol) in DMF (5 mL) is added Cs2CO3 (0.28 g, 0.861 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature over 2 h. The reaction mixture is diluted with water (25 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL), dried, filtered, and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (0.1 g, 55.9%). ESI/MS m/z (M+H)+ 415.4.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:26][CH3:27])=[C:12]([NH:14][CH:15]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)[CH:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:28][NH2:29].CO>CN1C(=O)CCC1>[CH3:27][O:26][C:11]1[N:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:29][CH3:28])[CH:7]=2)=[CH:13][C:12]=1[NH:14][CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1
Reactant: CN
Reactant: COc1ncc(-c2ccnc(F)c2)cc1NC1CN(C(=O)OC(C)(C)C)C1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CNc1cc(-c2cnc(OC)c(NC3CN(C(=O)OC(C)(C)C)C3)c2)ccn1
Temperature: 140 °C
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-((2′-fluoro-6-methoxy-[3,4′-bipyridin]-5-yl)amino)azetidine-1-carboxylate (530 mg, 1.42 mmol) in NMP (3 mL) was added CH3NH2/MeOH (5 mL). The reaction mixture was stirred while being heated at 140° C. in a microwave for 1 h. The mixture was cooled to rt, the solvent was removed and diluted with ethyl acetate (100 mL). The organic layer was washed with water (60 mL), brine (60 mL), dried over Na2SO4, filtered, concentrated in vacuo, and the residue was purified by flash chromatography to obtain 436 mg of tert-butyl 3-((6-methoxy-2′-(methylamino)-[3,4′-bipyridin]-5-yl)amino)azetidine-1-carboxylate as a yellow solid (80%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=5.3 Hz, 1H), 7.72 (d, J=2.1 Hz, 1H), 6.63 (dd, J=5.3, 1.5 Hz, 1H), 6.58 (s, 1H), 6.39 (d, J=1.7 Hz, 1H), 4.63 (d, J=6.7 Hz, 1H), 4.53 (d, J=6.5 Hz, 1H), 4.27 (dd, J=8.8, 7.1 Hz, 2H), 4.18 (ddt, J=9.4, 7.0, 3.4 Hz, 1H), 3.97 (s, 3H), 3.74 (dd, J=9.0, 4.6 Hz, 2H), 2.90 (d, J=4.2 Hz, 3H), 1.37 (s, 9H); MS (ES) m/z 386 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:29]I>C1COCC1>[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:13]2[CH2:14][CH:15]([CH2:17][O:18][CH3:29])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(CO)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1Cc2c(OCc3ccccc3)cc(C(=O)OC(C)(C)C)cc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28.5 %

Procedure:
NaH (134 mg, 3.35 mmol) was added to a solution of 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204a) (994 mg, 2.79 mmol) in THF (10 mL). The resulting mixture was stirred at 0° C. for 10 min and methyl iodide (210 uL, 3.37 mmol) was added. The mixture was stirred at room temperature for 2 hr, quenched with H2O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 20-30% EtOAc in hexanes to give a colorless oil (295 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 7.34-7.45 (m, 5 H) 7.19 (d, J=1.01 Hz, 1 H) 7.11 (d, J=1.01 Hz, 1 H) 5.13 (s, 2 H)) 4.99-5.09 (m, 1 H) 3.54-3.64 (m, 2 H) 3.44 (s, 3 H) 3.23-3.33 (m, 1 H) 2.98 (dd, J=16.42, 7.33 Hz, 1 H) 1.57 (s, 9 H); LCMS for C22H26O5 m/z 371.20 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([CH3:27])=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29].N12CCN(CC1)CC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:28]([C:21]1[CH:22]=[C:23]([CH3:27])[C:24]([F:26])=[CH:25][C:20]=1[F:19])(=[O:30])=[O:29]
Reactant: Cc1cc(S(=O)(=O)Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(F)cc2F)c(OC)c1
Yield: 79.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.0 g, 4.08 mmol) prepared in Example 14a, 2,4-difluoro-5-methylbenzenesulfonyl chloride (WO 2010/079443; 1.85 g, 8.15 mmol), 1,4-diazabicyclo[2.2.2]octane (0.91 g, 8.15 mmol) and THF (20 mL), to yield the title compound (1.41 g, 79%) as a colorless amorphous solid.
Reaction SMILES: CS(C)=O.C(O)(=O)C.[N+:9](/[CH:12]=[CH:13]/[C:14]1[CH:27]=[CH:26][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)([O-:11])=[O:10].[BH4-].[Na+]>C(OCC)C.C(OCC)(=O)C.O>[N+:9]([CH2:12][CH2:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a dimethylsulfoxide (150 mL) solution of acetic acid (7.4 mL) and 2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (30.8 g, 120 mmol) described in Manufacturing Example 2-2-3 was added sodium borohydride (2.45 g, 64.8 mmol) at 30° C. or less. The reaction solution was stirred at room temperature for 40 minutes. To the reaction solution were added water, ethyl acetate and diethyl ether at 30° C. or less to partition it into water and an organic layer. The water layer was extracted with ethyl acetate. This ethyl acetate layer was combined with the organic layer obtained previously, washed with water (3 times) and aqueous sodium chloride (1 time), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (15.2 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Si](C=[N+]=[N-])(C)C.CCCCCC>C1(C)C=CC=CC=1.CO>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 0.33 h
Yield: 31 %

Procedure:
66 mg (0.239 mmol) of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in toluene (0.6 mL) and methanol (0.6 mL), and, under ice cooling, 0.54 mL (0.324 mmol) of 0.6 M trimethylsilyldiazomethane-hexane solution was added, followed by stirring for 20 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=2/1) to afford 21.5 mg of the title compound as a colorless solid (yield 31%). The resulting solid was recrystallized with ethyl acetate-hexane, the generated precipitate was filtered off, the wet crystal was washed with hexane, and subsequently dried under reduced pressure at room temperature to afford the title compound as a colorless crystalline powder. Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×1.50 mm, hexane/ethanol-2/1. UV 210 nm, flow rate 1 mL/min., retention time 12.8 min.). Mp 86° C.; [α]20D+5.3° (c 1.10, CHCl3) 1H NMR (400 MHz, CDCl3, δ): 1.65-1.70 (m, 1H), 2.03-2.12 (m, 3H), 2.90 (d, J=12.0 Hz, 1H), 3.07 (m, 1H), 3.79 (s, 3H), 4.12 (dd, J=4.6, 4.4 Hz, 1H), 4.91 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.35-7.44 (m, 5H); MS m/z: 291 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:36][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: NC1CCCC1
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NC4CCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 2 mL of dimethyl sulphoxide and 60 mg of cyclopentanamine. After chromatography on a column of silica, eluting with a mixture of diethyl ether/ethyl acetate (gradient from 100/0 to 0/100 by volume), 33 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-cyclopentylurea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][C:31]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:30]([F:29])=[C:31]([C:39]([F:42])([F:40])[F:41])[CH:32]=4)[CH2:24][CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ncnc2sc(NC(=O)N3CCC(N)CC3)nc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc2sc(NC(=O)N3CCC(NC(=O)c4ccc(F)c(C(F)(F)F)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.1 %

Procedure:
A suspension of the trifluoroacetic acid salt of 4-amino-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (prepared as in Example 83, 580 mg, 1.37 mmol), 4-fluoro-3-trifluoromethyl-benzoyl chloride (261 mL, 1.64 mmol) and triethylamine (573 μL, 4.11 mmol) in methylene chloride (15 mL) was stirred at 25° C. overnight. At this time, the reaction was diluted with water and was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution and a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 3:7 ethyl acetate/hexanes to 100% ethyl acetate) afforded 4-(4-fluoro-3-trifluoromethyl-benzoylamino)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (21 mg, 30.6%) as an off-white solid; ES-HRMS m/e calcd for C20H18F4N6O3S (M+H)+ 499.1170, found 499.1170.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:8][C:9](=[O:10])[C:2]1=2)=[O:7].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Mg]Br>C1COCC1>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:6]([C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: Cc1ccccc1[Mg]Br
Reactant: O=C1OC(=O)c2sccc21
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccsc1C(=O)O

Procedure:
2,3-Thiophenedicarboxylic anhydride was allowed to react with 2-methylphenyl magnesium bromide in THF, and the reaction mixture was processed to give 3-(2-methylbenzoyl)-2-thiophenecarboxylic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:24])[CH2:13][CH:12]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:21](=O)[NH2:22])[CH:10]=2)[O:5]1.O=P(Cl)(Cl)Cl>ClCCCl>[CH3:1][O:2][CH2:3][C:4]1([CH3:24])[CH2:13][CH:12]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:21]#[N:22])[CH:10]=2)[O:5]1
Reactant: COCC1(C)CC(n2ccccc2=O)c2cc(C(N)=O)ccc2O1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COCC1(C)CC(n2ccccc2=O)c2cc(C#N)ccc2O1
Reaction time: 0.75 h

Procedure:
A mixture of 2.98 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-carbamoylchroman, 2 ml of POCl3 and 200 ml of 1,2-dichloroethane is boiled for 45 min. Cooling and customary working up gives 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyanochroman.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Cl>O1CCCC1>[CH:3]([CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[CH2:9][CH2:10]1)=[O:2]
Reactant: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1

Procedure:
Into a 1 l capacity three-necked flask were added the compound obtained in the above item (ii) (36.2 g, 0.15 mol), 2N-hydrochloric acid (142 ml) and tetrahydrofuran (560 ml), followed by refluxing these for one hour, distilling off tetrahydrofuran, adding water (100 ml) to extract with ethyl acetate, washing the extract with 1N-NaOH aqueous solution, washing with water till the washing water became neutral, drying over magnesium sulfate, removing magnesium sulfate, concentrating under reduced pressure, recrystallizing from a mixed solvent of heptane with ethyl acetate and drying to obtain white crystals (20.5 g). The NMR spectra of this product accorded with those of the captioned compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=2[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:16]([F:25])=[CH:17][C:18]([NH2:22])=[CH:19][C:20]=2[F:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc(N)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3,5-difluoronitrobenzene (2.13 g) in ethanol (40 ml) was added palladium on carbon (0.20 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (1.70 g, yield 87%) as a colorless solid.