Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([C:26]2[C:27]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][C:59]([F:65])=[CH:60][CH:61]=2)[N:56]=1)(=O)=O.N1CCC1>O.CS(C)=O>[F:42][C:34]1[CH:33]=[C:32]([C:27]2[C:26]([CH:24]3[CH2:23][N:22]([C:55]4[CH:64]=[CH:63][C:62]5[C:57](=[CH:58][C:59]([F:65])=[CH:60][CH:61]=5)[N:56]=4)[CH2:25]3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH:41]=[CH:40][C:35]=1[C:36]([NH:38][CH3:39])=[O:37]
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CNC2)cc1F
Reactant: O=S(=O)(Oc1ccc2ccc(F)cc2n1)C(F)(F)F
Agent: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(c3ccc4ccc(F)cc4n3)C2)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of 4-(3-(azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate) (0.953 g, 1.517 mmol), potassium carbonate (0.839 g, 6.070 mmol), 7-fluoroquinolin-2-yl trifluoromethanesulfonate (0.537 g, 1.821 mmol, prepared according to Step 3 of Example 2), and DMSO (10 mL) was stirred at 50° C. for 1 h. LCMS showed the product and no more azetidine starting material. The mixture was diluted with water and extracted with CH2Cl2 three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 40 g, 5-100% EtOAc-hexane. The impurity 2-hydroxyquinoline was further removed by trituration with CH2Cl2 and hexane twice. The product was obtained as a white solid (510 mg, 78%). 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.09 (d, J=4.50 Hz, 3 H) 4.33-4.50 (m, 5 H) 6.56 (d, J=9.00 Hz, 1 H) 6.81 (d, J=7.04 Hz, 1 H) 6.98 (td, J=8.61, 2.54 Hz, 1 H) 7.31-7.45 (m, 3 H) 7.56 (dd, J=8.71, 6.36 Hz, 1 H) 7.84 (d, J=9.00 Hz, 1 H) 8.28 (t, J=8.02 Hz, 1 H) 8.57 (d, J=2.15 Hz, 1 H) 8.64 (d, J=2.35 Hz, 1 H). m/z=432 (M+1 ).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1([F:25])[CH2:22][CH:21]1[CH2:23]Br.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH2:23][CH:21]2[CH2:22][C:20]2([F:25])[F:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: FC1(F)CC1CBr
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCC2CC2(F)F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.6 g 2-Chloro-4-fluoro-5-nitrophenol was dissolved in dimethylformamide and treated with potassium carbonate. The mixture was stirred at room temperature for one hour and then 3.3 g 2,2-difluorocyclopropylmethyl bromide added. It was the heated at 80° C. for 2 hours and added to water. The mixture was extracted with methylene chloride and the organic phase washed with saturated brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using a mixture of 3 parts hexane and 1 part ethyl acetate. There was obtained 5 g (=93% of theory) of yellow crystals whose nmr spectrum is as follows: δ=1.1-2.4 ppm (m) 3H, δ=4.15 ppm (d 7 Hz,tr 1.5 Hz) 2H, δ=7.35 ppm (d 10 Hz) 1H, δ=7.5 ppm (d 7 Hz) 1H.
Reaction SMILES: [OH:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:23][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34]([O:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1)=[O:35])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(O)cc1C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(OC(=O)Nc2c(C(C)C)cccc2C(C)C)cc1C

Procedure:
A mixture of 5-(4-hydroxy-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester, 1.5 g and 1.0 g (5 mmol) of 2,6-diisopropylphenylisocyanate in 75 mL of tetrahydrofuran containing 0.1 g of 4-dimethylaminopyridine is stirred at reflux for 18 hours overnight. The solvent is removed leaving 3.1 g of the title carbamate which crystallizes on standing. The crude precipitate is chromatographed on a 4.5 cm column containing 125 g of silica gel prepared in 1:1 hexane:dichloromethane. Elution with dichloromethane affords 1.8 g of the title compound. Recrystallization from 75 mL of hexane affords the title compound as a colorless solid; mp 111°-112° C.
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[C:6]([C:12]([O:14]C)=O)=[N:7][C:8]([Br:11])=[CH:9][N:10]=1.NN>CCO>[NH2:4][C:5]1[C:6]([C:12]([NH:2][NH2:3])=[O:14])=[N:7][C:8]([Br:11])=[CH:9][N:10]=1
Reactant: NN
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 50 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
Hydrazine hydrate (23.59 mL, 480.75 mmol) was added dropwise to a stirred mixture of methyl 3-amino-6-bromopyrazine-2-carboxylate (100 g, 418.04 mmol) in EtOH (2 L). The mixture was heated at 50° C. under nitrogen. The resulting thick suspension was stirred at 50° C. for 16 hours. Further hydrazine (2.5 mL) was added in one portion and the suspension was stirred at 50° C. for a further 24 hours. Ethanol (500 mL) was charged to the thick reaction mixture and the mixture was allowed to cool to room temperature. The resulting suspension was filtered and the solid washed with ethanol (1 L) and dried in vacuo to give 3-amino-6-bromopyrazine-2-carbohydrazide (98 g, quantitative) as a cream solid: 1H NMR Spectrum; (DMSO-d6) 4.52 (2H, s), 7.59 (2H, s), 8.30 (1H, s), 9.74 (1H, s); Mass Spectrum [M+H]+=232.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:55][C:56]1[CH:61]=[C:60]([Cl:62])[CH:59]=[CH:58][C:57]=1[C:63](=[O:66])[CH2:64][CH3:65]>C(Cl)Cl.CO>[Br:1][CH:64]([CH3:65])[C:63]([C:57]1[CH:58]=[CH:59][C:60]([Cl:62])=[CH:61][C:56]=1[Cl:55])=[O:66]
Reactant: [Br-]
Reactant: CCC(=O)c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reaction time: 24 h

Procedure:
17.4 g of tetra-butylammonium tribromide are added, at room temperature, to 7 g of 1-(2,4-dichlorophenyl)-1-propanone dissolved in a mixture of 420 ml of methylene chloride and 140 ml of methanol. After 24 hours, the reaction medium is evaporated to dryness under vacuum. The residue is taken up in water and extracted with ethyl acetate, and the organic phase is dried over sodium sulphate. The solvent is evaporated off under vacuum and the product is then purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:3]=1.[H-].[Na+].[CH3:18]I>C1COCC1>[I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH3:18])[CH:3]=1
Reactant: CC(C)(CO)n1cc(I)c2cncnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(C)(C)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
An anhydrous THF (100 mL) solution of 2-(5-Iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-propan-1-ol (Preparation 22) (32 g, 100.91 mmol) was added slowly to a suspension of NaH (60% in paraffin oil, 2.98 g, 121.13 mmol) in anhydrous THF (200 mL) at 00° C. under nitrogen. The mixture was warmed to room temperature and stirred for another 30 minutes and again cooled to 00° C. and methyl iodide (19 mL, 302.82 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 2 hours, quenched with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified by column chromatography on silica (100-200 mesh, gradient of hexane:EtOAc 100:0 to 70:30) to afford the title compound as a yellow sticky solid in 22% yield, 7.5 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]([NH2:31])[C@@H:23]1[OH:32]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:31][C@H:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][C@H:23]2[OH:32])[CH:6]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([N:27]([CH3:36])[CH3:26])=[CH:29][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(c1ccccc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccccc1)N1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Temperature: 70 °C
Reaction time: 0.02 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-(1-phenylethyl)piperazin-1-yl)pyridin-2-amine (0.038 g, 0.10 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.023 g, 0.15 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 6 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column, which was eluted with 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The obtained yellow solid was suspended in dichloromethane (2 ml), and then a solution of HCl in methanol (1.25 M; 0.8 ml) was added. The mixture was stirred for approximately 1 min, and then diethyl ether was added. The yellow precipitate was collected by filtration, washed with ether to afford the title compound as a hydrochloride salt. (0.013 g); 1H-NMR (500 Mz, CD3OD) 1.90 (d, J=5.43 Hz, 3H, CHCH3), 3.43 (m), 3.96 (m), 4.12 (m) (8H, piperazine N(CH2)2), 3.21 (s, 6H, N(CH3)2), 4.65 (m, 1H, NCHCH3), 7.14 (d, J=7.30 Hz, 2H) and 8.14 (d, J=7.32 Hz, 2H) (3,5-C6H4—NMe2 and 2,6-C6H4—NMe2) 7.55 (m, 3H) and 7.66 (m, 2H) (ArH), 8.41 (s, 1H, imidazo[4,5-b]pyridine 5-H);
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:31]([N:12]1[CH:13]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:14]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=1[O:34][CH2:35][CH3:36])=[O:32]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)CCN
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)NCCN(C)C

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N,N-dimethyl-1,2-ethanediamine (Aldrich) to give the title compound. LC-MS: 595.2 [(M+H)+]
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:21])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[ClH:22].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:22].[CH3:21][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(=O)NC(C)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-[3-(acetylamino)butyl]piperidine-1-carboxylate (2.65 g) in ethyl acetate (30 mL) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 3 hr. The resulting precipitate was collected by filtration to give the title compound (2.06 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH2:35][O:36][CH3:37])[NH:29][C:28](=[O:39])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH2:35][O:36][CH3:37])[NH:29][C:28](=[O:39])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CCC3)C(=O)N2
Yield: 75 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a obtained from step 1 of Example 7 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 37 (59 mg, yield 75%) as a yellow solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.C([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O.[CH3:24][O:25][CH3:26].C([Li])CCC.CCCCCC>CC(C)=O.C1COCC1.CN(C=O)C>[CH3:24][O:25][C:26]1[C:4]([CH:5]=[O:10])=[C:3]2[O:2][CH2:1][O:9][C:8]2=[CH:7][CH:6]=1
Reactant: COC
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: COc1ccc2c(c1C=O)OCO2
Temperature: 25 °C

Procedure:
Compound 1 (47 g) in dry acetone (500 ml), K2CO3 (100 g) and dimethylsulphate (70 ml) were refluxed overnight. The white solid was filtered off, the filtrate concentrated, diluted with water and extracted with EtOAc. The EtOAc layer was washed with NaHCO3 solution and water, dried over anhydrous MgSO4. Removal of solvent afforded a straw coloured liquid, one spot by TLC, IR νmaxliq.film cm-1 : 1624; UV νmaxMeOH nm (ε): 296 (2875), 236 (2937), 217 (3027): 1H-NMR δ (CDCl3): 3.74 (3H, s, OCH3), 5.91 (2H, s, OCH2O), 6.31 (1H, dd, J=2.5, 8.5 Hz, H-5), 6.49 (1H, d, J=2.5, Hz, H-1), 6.70 (1H, d, J=8.5 Hz, H-4); HRMS m/z: 152.0473 (M+, 100, C8H8O3), 137.0238 (M+ --CH3, 88.42, C7H5O3). This methyl ether (40 g) in absolute THF (300 ml) at -10 C under argon gas was stirred with butyl lithium in hexane (100 ml, 1.1 mole) for 21/2 hrs. After the addition of BuLi the temperature of the reaction mixture was slowly raised to room temperature. Formation of the anion was confirmed by quenching an aliquot of the reaction mixture with D2O and observing the 1H=NMR (disappearance of the doublet signal at 6.49 ppm). The anion thus formed was stirred with dry DMF (20 ml) in THF (100 ml), at 0° C. (10 min) followed by refluxing (2 hrs). The reaction mixture was then acidified with HCL (6N) and extracted with ether (11/2 L). Drying over anhydrous MgSO4 and evaporation of the solvent afforded a pale yellow crystalline compound mp 124° C., IR νmaxKBr cm-1 : 1620, 1695, UV νmaxMeOH nm (ε): 211 (7811), 217.9 (7788), 268 (4536), 294.6 (2177): 1H-NMR δ (CDCl3): 3.81 (3H, s, OCH3), 6.07 (2H, s, OCH2O), 6.33 (1H, d, J=7 Hz, H-5), 6.88 (1H, d, J=Hz, H-4), 10.31 (1H, s, aldehyde); HRMS m/z: 180.0401 (M+, 100, C9H8O4), 165.0189 (M+ --CH3, 35, C8H5O4), 137.0238 (M+ --CH3CO, 45, C7H5O3).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH:2]([CH3:4])[CH3:3].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15]>C(N(CC)CC)C>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:13](=[O:17])[C:14](=[O:15])[O:12][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(O)c(O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc2oc(=O)c(=O)oc2c1

Procedure:
The same procedures as described in Example 8 were carried out by using 4.16 g (25 mM) of 4-isobutylcatechol, 5.06 g (50 mM) of triethylamine and 3.50 g (28 mM) of oxalyl chloride. 6-iso-Butyl-1,4-benzodioxine- 2,3-dione 2/5 hydrate was obtained in the yield of 5.11 g (22.5 mM) as colorless crystals having a melting point of 92°-97° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)=O.C(O)(=O)C>C1(C)C=CC=CC=1>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)Nc2ccccc2N)C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc3ccccc3[nH]2)C1

Procedure:
(R)-tert-Butyl 3-(2-aminophenylcarbamoyl)piperidine-1-carboxylate (7A) (2.80 g, 8.77 mmol) was added to a 100 mL round-bottomed flask equipped for stirring under nitrogen. Glacial acetic acid (20 mL) was then added and the resultant solution was stirred at 65° C. under nitrogen for 2 hr. Analysis of the reaction mixture at this time by LC/MS indicated that the reaction was complete. The reaction solution was then concentrated in-vacuo to give a brownish oil. Toluene (30 mL) was added and the subsequent solution was concentrated in vacuo. This was repeated three times to remove any trace quantities of acetic acid affording (R)-tert-Butyl 3-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (7B) as a tannish-white solid. (13.94 mmol, 4.2 g, 80% over 2-steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.52 (m, 10H) 1.73-1.83 (m, 2H) 2.10-2.17 (br. s. 1H) 2.79-2.96 (m, 2H) 3.89-3.96 (br. s., 1H) 4.08-4.33 (br.s., 1H) 4.33-4.43 (br.s, 1H) 7.09-7.18 (dd, 2H, 8.97 Hz, 6.19 Hz) 7.39-7.48 (d, 1H, 6.82 Hz) 7.49-7.57 (d, 1H, 7.07 Hz) 12.27 (s, 1H) ESI-MS: adz 302.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]=[CH:19]OC)=[C:16]([S:22]([C:24]([F:27])([F:26])[F:25])=[O:23])[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)=[N:14]1.Cl.[NH2:34][OH:35].O1CCOCC1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]=[CH:19][NH:34][OH:35])=[C:16]([S:22]([C:24]([F:25])([F:26])[F:27])=[O:23])[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)=[N:14]1
Reactant: COC=Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=S(c1c(-c2ncon2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N=CNO)C(F)(F)F
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methoxymethylideneamino-3-(1,2,4-oxadiazol-3-yl)-4-trifluoromethylsulfinylpyrazole (720 mg, 1.38 mmol) were added hydroxylamine hydrochloride (240 mg, 3.45 mmol), dioxane (2.0 ml) and triethylamine (0.40 ml, 2.90 mmol), and then the mixture was stirred at room temperature. Five hours after stirring, triethylamine (0.4 ml, 2.90 mmol) and dioxane (1.0 ml) were further added, followed by stirring at room temperature for 66 hours. After 40 ml of ethyl acetate was added, the organic layer was washed three times with 30 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a pale yellow oil. The oil was purified by subjecting to silica gel preparative TLC [developing solvent: mixed solvent of chloroform and ethyl acetate (volume ratio=10:1)] to obtain 284 mg (0.54 mmol) of the title compound as a colorless crystal. Yield 55%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[CH:28]=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:34])[C:30]=1[C:31]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[CH:15][N:14]=[C:13]2[NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[F:1])=[O:32]
Reactant: Nc1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12)c1c(F)cccc1Cl
Yield: 52.2 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-14, 60 mg, 0.18 mmol), 6-chloro-2-fluorobenzoic acid (48 mg, 0.27 mmol), oxalyl chloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) in CH2Cl2 (2 mL) to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.69 (s, 1H), 10.16 (s, 1H), 8.80 (d, J=7.5 Hz, 1H), 8.57 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.02 (d, J=5.7 Hz, 1H), 7.74-7.68 (m, 2H), 7.63-7.51 (m, 2H), 7.44-7.36 (m, 2H); MS (m/z): 479.30 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1cccs1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cccs1
Temperature: 4 °C
Yield: 48.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-thiophenecarboxylic acid (9 g), N,N'-carbonyldiimidazole (11.3 g) and 2-amino-7-chloro-1,8-naphthyridine (9.5 g). The product produced by precipitation in water (9.6 g; m.p. 242° C.) is dissolved in boiling ethanol (700 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-2-thiophenecarboxamide (7.5 g) is produced, m.p. 244° C.