Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[N:19]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[N:19]1([CH:24]2[CH2:29][CH2:28][N:27]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([B:4]4[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]4)=[CH:17][CH:16]=3)=[O:15])[CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: C1CCN(C2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reaction time: 0.33 h
Yield: 32.9 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid (9.80 mmol, 2.43 g), 4-(1-pyrrolidinyl)piperidine (10.77 mol, 1.66 g), 1-hydroxybenzotriazole (16.67 mmol, 2.25 g), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19.57 mmol, 3.75 g) in DMF (30 mL) was stirred overnight at 60° C. Upon removal of DMF on rotavap, the residue was taken into mixture of EtOAc and H2O. The combined organic layers from extraction were stirred with aq. 2N HCl for 20 min and the aqueous layer was purified by reverse phase prep-HPLC to furnish the desired boronic acid (1.24 g. 42%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:13]1(OB(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1.CO.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: Cc1cc(Br)c2nccnc2c1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2ccccc2)c2nccnc2c1

Procedure:
A mixture of 400 mg of 5-bromo-7-methyl-quinoxaline, 244 mg of phenylboric acid and 100 mg of tetrakis(triphenylphosphine)palladium in 12 ml dioxane, 4 ml of methanol and 3.6 ml 1 M aqueous sodium carbonate solution is refluxed for three hours under an argon atmosphere. Then the reaction mixture is evaporated down and the residue is distributed between ethyl acetate and water. The ethyl acetate phase is separated off, dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography over a silica gel column with cyclohexane/ethyl acetate (85:15 to 70:30) as eluant.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[Cl:8][C:5]1[N:4]=[N:3][C:2]([N:1]=[CH:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ccc(Cl)nn1
Yield: 81.2 %

Procedure:
A mixture of 3-amino-6-chloropyridazine (1.3 g, 10 mmol) and dimethylformamide dimethylacetal (1.35 mL, 10.2 mmol) was heated at reflux for 2 h and concentrated in vacuo to afford a brown solid. After recrystallization with EtOAc, 1.5 g of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine was obtained in 81% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][CH2:26][CH2:27]P(OCC)(OCC)=O)(=[O:24])[CH3:23].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[CH:23]/[C:22]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.7 %

Procedure:
To a mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (3.00 g), diethylphosphonoethyl acetate (2.67 g) and N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 0.52 g) at 0° C. and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration to give ethyl (E)-3-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)propenoate (3.18 g, yield 85%), which was then recrystallized from ethyl acetate-hexane. melting point: 105–106° C.
Reaction SMILES: Cl[C:2]([CH3:8])([CH3:7])[CH:3]([N:5]=[O:6])[CH3:4].Cl.Cl.[NH2:11][CH2:12][CH:13]([O:23][NH2:24])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N+:20]([O-:22])=[O:21]>>[CH3:7][C:2]([CH3:8])([NH:24][O:23][CH:13]([CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N+:20]([O-:22])=[O:21])[CH2:12][NH:11][C:2]([CH3:8])([CH3:7])[C:3](=[N:5][OH:6])[CH3:4])[C:3](=[N:5][OH:6])[CH3:4]
Reactant: CC(N=O)C(C)(C)Cl
Reactant: NCC(Cn1ccnc1[N+](=O)[O-])ON
Agent: Cl
Product: CC(=NO)C(C)(C)NCC(Cn1ccnc1[N+](=O)[O-])ONC(C)(C)C(C)=NO

Procedure:
According to the General Reaction Scheme, N-(2,3-epoxypropyl)phthalimide (1) is reacted with 2-nitro-imidazole (2) to obtain 2-[2-Hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3). This product is then reacted with N -hydroxyphthalimide, preferably in the presence of a tertiary amine such as triphenylphosphine, to obtain the intermediate of Formula II, 2-{2-(1,3-dioxoisoindolin -2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline-1,3-dione (4). This intermediate is then reacted with hydrazine to obtain 1-[3-amino-2-(aminooxy)propyl]-2-nitro-1H -imidazole dihydrochloride (5), which is then reacted with the compound of Formula III to yield the compound of Formula I. A preferred compound of Formula III is 3-chloro-3-methyl-2-nitrosobutane, which, when used contacted with 1-[3-amino-2-(aminooxy)propyl]-2-nitro -1H-imidazole dihydrochloride (5), yields 3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl)methyl]-5-oxa-4,8-diazaundecane-2,10-dione dioxime (7).
Reaction SMILES: CSC.B(F)(F)F.[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([N:18]2[C:22]3[CH:23]=[C:24]([O:29]C)[C:25]([O:27]C)=[CH:26][C:21]=3[N:20]=[CH:19]2)=[N:15][C:14]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:12])[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([N:18]2[C:22]3[CH:23]=[C:24]([OH:29])[C:25]([OH:27])=[CH:26][C:21]=3[N:20]=[CH:19]2)=[N:15][C:14]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CCOC(=O)c1sc(-n2cnc3cc(O)c(O)cc32)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 90.4 %

Procedure:
Boron trifluoride dimethylsulfide (4.1 ml, 39 mmol) was added in multiportions over 5 hrs. to a suspension of 2-(5,6-Dimethoxybenzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (2.04 g, 4.99 mmol) in methylene chloride at RT. The mixture was stirred for an additional 40 mins. Ice water was added. Methylene chloride was removed, the residue was filtered, the solid was washed with water and a small amount of methanol, and then dried in air to give the product (1.72 g, yield 90%). 1H-NMR (DMSO-D6) 8.72 (s, 1H); 8.78-8.88 (m, 2H); 7.64 (s, 1H); 7.42-7.51 (m, 3H); 7.08 (s, 1H); 4.22 (q, 2H), 1.22 (t, 3H). MS M/z 382 (M+1)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:29][CH3:30])=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1>[CH2:27]([O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:29][CH3:30])[N:19]=[CH:18][N:17]=[C:16]2[S:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH3:28]
Reactant: CCOc1cc2c(Cl)ncnc2cc1OC
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOc1cc2c(Sc3cccc(N)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a stirred suspension of cesium carbonate (3.60 g, 11.06 mmol) in THF (60 mL) was added 3-aminobenzenethiol (1.00 g, 7.99 mmol). After stirring for 30 minutes at rt, 4-chloro-6-ethoxy-7-methoxyquinazoline described in Example 11A (1.91 g, 7.99 mmol) was added and the reaction mixture was heated at rt for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to give a solid. Purification by silica gel column chromatography (eluting with 2% methanol in dichloromethane) afforded 3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)aniline (1.20 g, 46%) as a cream solid, which did not require further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 7.12 (dd, J=8, 8 Hz, 1H), 6.79 (s, 1H), 6.66-6.73 (m, 2H), 5.33 (brs, 2H), 4.21 (q, J=7 Hz, 2H), 3.98 (s, 3H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 328 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].I[CH2:6][CH2:7][O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10]>CN(C)C=O.O>[N:1]([CH2:6][CH2:7][O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10])=[N+:2]=[N-:3]
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCCI
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Temperature: 60 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
6 mg of sodium azide was added to 18 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-iodoethyl)ester dissolved in a mixture of 0.2 mL of N,N-dimethylformamide and 0.02 mL of water at room temperature, and the mixture was stirred for 12 hours at 60° C. After standing to cool, the solvent was distilled under reduced pressure, and the residue was purified by reverse phase column chromatography (Wako gel 50C18, eluent: water to a 70% aqueous solution of acetonitrile), thereby yielding 7 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-azidoethyl)ester
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]1[S:32][C:21]2[N:22]([CH:29]([CH3:31])[CH3:30])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=2[CH:19]=1.O>CN(C)C=O>[N:1]1([CH2:17][C:18]2[S:32][C:21]3[N:22]([CH:29]([CH3:30])[CH3:31])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=3[CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)n1c(=O)n(C)c(=O)c2cc(CCl)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(=O)n(C)c(=O)c2cc(Cn3cnc4ccccc43)sc21
Reaction time: 48 h
Yield: 55.1 %

Procedure:
Benzimidazole (0.395 g) and potassium carbonate (1 g) were added to a stirred solution of 6-(chloromethyl)-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.55 g) in anhydrous dimethylformamide (5 ml) at room temperature. After 2 days, water (50 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic extracts were dried over anhydrous magnesium sulfate and filtered through a silica pad which was washed with ethyl acetate. The filtrate was evaporated and the residue was purified twice by normal-phase preparative HPLC with gradient dichloromethane/ethanol elution to give the title compound (0.394 g) as a foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:17][C:18]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:19]=1[CH:20]=[O:21].Cl>CN(C=O)C.CCOC(C)=O>[Br:17][C:18]1[CH:25]=[C:24]([CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])[O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)c(Br)c2)c(F)c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
To a solution of 3-fluoro-4-hydroxy-benzonitrile (5 g, 36 mmol) in DMF (anhydrous, 100 mL) was slowly added K2CO3 (5.54 g, 40.1 mmol). After stirring for 5 minutes, to the solution was added 2-bromo-4-fluoro-benzaldehyde (8.89 g, 43.8 mmol). The reaction was heated at 70° C. and monitored by T.L.C. After 4 hours, the heating was stopped and after cooling to the room temperature, 100 mL of EtOAc was added. With stirring, 1 M HCl (˜50 mL) was slowly added until the pH was 7. The organic layer was then washed with H2O (3×50 mL), dried over MgSO4 and filtered. The filtrate was evaporated under vacuum. The residue was purified over silica gel, eluting with 12.5% EtOAc/hexanes to afford 4-(3-bromo-4-formyl-phenoxy)-3-fluoro-benzonitrile (3) 7.1 g in 61% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.28 (s, 1 H), 7.96 (d, J=8.60 Hz, 1 H), 7.51-7.59 (m, 2 H), 7.21-7.29 (m, 3 H), 7.03 (dd, 1 H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][C:34](N)=[CH:35][C:28]=4[O:27][C:26]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16]1)(C)(C)C>ClCCl>[NH2:14][C:15]1([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[O:27][C:26]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:23][CH:24]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)ccc4c3=O)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.1 %

Procedure:
TFA: To a solution of {1-[4-(7-amino-4-oxo-2-phenyl-4H-1-benzopyran-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (12.2 mg, 0.03 mmol) in dichloromethane (1 mL) was added TFA (1 mL) and the mixture was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo to give a white solid (16.0 mg, 100%). 1H-NMR (400 MHz, D2O) δ 8.02 (d, 1H), 7.76 (dd, 2H), 7.55 (d, 2H), 7.42 (dd, 2H), 7.28-7.34 (m, 3H), 7.17-7.22 (m, 3H) 2.60-2.67 (m, 2H), 2.44-2.52 (m, 2H), 2.04-2.08 (m, 1H), 1.80-1.83 (m, 1H). LCMS (Method I): RT=4.50 min, [M+H]+=368
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[NH:12][CH:13]=[CH:14][CH:15]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[NH:12][CH:13]=[CH:14][CH:15]=4)[C:5]3=[CH:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Clc1ccc2c(-c3ccc[nH]3)n[nH]c2n1
Product: CN1CCN(c2ccc3c(-c4ccc[nH]4)n[nH]c3n2)CC1

Procedure:
6-chloro-3-(1H-pyrrol-2-yl)-1H-pyrazolo-[3,4,b]-pyridine (Example 9) and N-methyl piperazine using the same metho in Example 36.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:41])[N:8]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH2:19][CH2:18]4)[N:14]=[C:13]([CH3:33])[N:12]=3)[C:5]=2[NH:4][N:3]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[NH2:1][C:2]1[C:6]2[C:7](=[O:41])[N:8]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)[N:14]=[C:13]([CH3:33])[N:12]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cc1nc(-c2cn(-c3ccccc3C)c(=O)c3c(N)n[nH]c23)cc(N2CCN(CCO[Si](C)(C)C(C)(C)C)CC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn(-c3ccccc3C)c(=O)c3c(N)n[nH]c23)cc(N2CCN(CCO)CC2)n1
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 3-amino-7-(6-(4-(2-((tert-butyl(dimethyl)silyl)oxy)ethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)-5-(2-methylphenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step C (195 mg) in tetrahydrofuran (2.0 mL) was added tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.679 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol/dichloromethane), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). To the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (50.0 mg).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:15])[CH2:7][NH:8][C:9]2[CH2:13][S:12][C:11](=[O:14])[N:10]=2)[CH2:2]1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[C:13]2/[C:9]([NH:8][CH2:7][C:6]([NH:5][CH:3]3[CH2:4][O:1][CH2:2]3)=[O:15])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:23][CH2:22]1
Reactant: O=C(CNC1=NC(=O)SC1)NC1COC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C(CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)NC1COC1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 52.4 %

Procedure:
To a solution of N-oxetan-3-yl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (2 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.47 g) in 2-propanol (20 mL) was added piperidinium acetate (1.06 g). The reaction mixture was stirred at 80° C. for 3.5 hr and concentrated under reduced pressure. Water and THF were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane/water to give the title compound (2.1 g).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:7][CH2:6][CH2:5][C:4](Cl)([Cl:8])[C:3]1=[O:10].CN(P(N(C)C)(N(C)C)=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:10]
Reactant: O=C1C(Cl)(Cl)CCCC1(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Oc1c(Cl)cccc1Cl
Yield: 63.8 %

Procedure:
118 g (0.5 mol) of 2,2,6,6-tetrachlorocyclohexanone and 1 g (0.006 mol) of hexamethylphosphorotriamide were introduced into the reactor used in Example 1. The reaction mixture was heated at 150°-180° C., under stirring; the reaction was terminated when the evolution of hydrogen chloride from the reaction mixture ceased. The reaction mixture was then distilled under reduced pressure (boiling point (20 mm Hg)=100° C.) to yield 52 g of 2,6-dichlorophenol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)#[N:2].[SH2:17]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)(=[S:17])[NH2:2]
Reactant: CCOC(=O)c1cc2cc(C#N)cnc2o1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(C(N)=S)cnc2o1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 5-cyanofuro[2,3-b]pyridine-2-carboxylate (773 mg, 4.14 mmol) was dissolved in a mixed solvent of pyridine (40 ml) and triethylamine (8 ml), and a hydrogen sulfide gas was blown in for 10 minutes. The mixture was stirred at room temperature for 14 hours. The solvent was distilled away from the reaction mixture under reduced pressure to give ethyl 5-thiocarbamoylfuro[2,3-b]pyridine-2-carboxylate as a yellow solid. Acetone (80 ml) and methyl iodide (8.0 ml) were added and the mixture was refluxed under heating for one hour. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give ethyl 5-[(1-methylthio)-iminomethyl]furo[2,3-b]pyridine-2-carboxylate. Methanol (80 ml) and ammonium acetate (694 mg, 9.00 mmol) were added and the mixture was refluxed under heating for 3.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=97/3-4/1) to give 2.05 g of ethyl 5-amidinofuro[2,3-b]pyridine-2-carboxylate hydrochloride as a yellow solid (69% in 3 steps).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:31])[CH2:18][CH:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:16]2[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:15]=2[O:14]1>ClCCl>[C:29]([C:26]1[CH:27]=[CH:28][C:15]2[O:14][C:13]([CH3:31])([CH3:12])[CH2:18][CH:17]([C:19]3[CH:20]=[N+:21]([O-:9])[CH:22]=[CH:23][CH:24]=3)[C:16]=2[CH:25]=1)#[N:30]
Reactant: CC1(C)CC(c2cccnc2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2ccc[n+]([O-])c2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
The 3-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide used as the starting material was prepared as follows: (A) 10.25 g of 3-iodopyridine were added at room temperature to a solution of 44 mg of palladium(II) chloride, 131 mg of triphenylphosphine and 95 mg of copper(I) iodide in 200 mg of diethylamine. 9.25 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were then added and the mixture was stirred for 3 days. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (11:9) for the elution to give 11.8 g of 4-[1,1-dimethyl-3-(3-pyridyl)-2-propynyloxy]benzonitrile in the form of an oil. (B) 11.8 g of 4-[1,1-dimethyl-3-(3-pyridyl)-2-propynyloxy]benzonitrile were heated at reflux in 75 ml of 1,2-dichlorobenzene for 3.5 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution. After recrystallization from cyclohexane there were obtained 6.7 g of 2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 98°-99° C. (C) 2.1 g of 2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 50 ml of ethyl acetate and shaken at room temperature under a hydrogen atmosphere with 50 mg of 10% palladium-on-charcoal for a total of 30 hours with several changes of catalyst. The mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution. 910 mg of 3,4-dihydro-2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile were obtained in the form of an oil. (D) 610 mg of m-chloroperbenzoic acid were added to a solution of 792 mg of 3,4-dihydro-2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane. After stirring at room temperature for one hour the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was crystallized from t-butyl methyl ether to give 710 mg of 3-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in the form of a solid of melting point 134°-137° C.