Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1.[F:21][C:22]1[C:27](O)=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=1[F:32].Cl.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20][C:27]2[C:26]([F:29])=[C:25]([F:30])[C:24]([F:31])=[C:23]([F:32])[C:22]=2[F:21])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1
Reactant: CNc1nccc(-c2cc3cc(C(=O)O)ccc3[nH]2)n1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cc3cc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc3[nH]2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.5 %

Procedure:
6.38 g (23.78 mmol) of the acid 20 were suspended in 100 ml of THF. 5.25 g (28.54 mmol) of pentafluorophenol and 5.47 g (28.54 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC*HCl) were then added. The mixture was stirred at RT for 15 h, after which the solvent was removed i.v. and the residue was partitioned between 300 ml of a sat. solution of NaHCO3 and 300 ml of ethyl acetate. The solids were filtered off through kieselguhr and the residue was washed twice with in each 100 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with in each case 100 ml of ethyl acetate. The combined organic phases were washed with 200 ml of a sat. solution of NaCl and then dried with MgSO4. After the solvents had been removed i.v., the residue was chromatographed on silica gel using heptane/ethyl acetate 1:1. 4.7 g (46%) of the pentafluorophenyl ester 55 were obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([CH:23]=1)[C:14]([O:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[O:15]>C1COCC1>[Cl:5][C:6]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([CH:23]=1)[C:14]([O:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][O:20][C:1](=[O:3])[CH3:2])=[O:15]
Reactant: CC(C)(CO)COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 765.6 %

Procedure:
Acetyl chloride (0.79 g, 0.01 mole) was added to a solution of 3-hydroxy-2,2-dimethyl-propyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (0.25 g, 0.00056 mole) and THF (10 ml). The solution was held at reflux for 3 hrs., cooled and concentrated. The residue was taken into 250 ml of ether, washed two times with water and dried over MgSO4. After the solvent was stripped off, 2.1 g of 3-Acetoxy-2,2-dimethylpropyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate was obtained as a yellowish gum, nmr (CDCl3) δ 1.0 (s, 6H), 2.03 (s, 3H), 3.87 (s, 2H), 4.12 (s, 2H), 6.96-8.22 (m, 6H); ir (CHCl3) 1743 Cm-1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:40]I>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][I:40])[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: O=C1CC(CO)CN1Cc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1CC(CI)CN1Cc1ccccc1
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
To alcohol lactam 74 (11.18 g, 0.056 mol) in 210 mL toluene was added in turn, triphenylphosphine (20.0 g, 0.076 mol), imidazole (10.8 g, 0.159 mol), and iodine (19.0 g, 0.075 mol). After stirring the suspension for 1.5 hours, the supernatant was poured into another flask. The sticky yellow residue was washed twice with ether and the solutions were combined. The solvent was evaporated and the residue was chromatographed on silica, eluting with 1:1 acetone/hexane to give 7.92 g, 46% of the iodolactam 75 as yellow oil. 1H NMR (CDCl3) δ 7.25 (m, 5H), 4.38 (d, 1H, J=14.6), 4.46 (d, 1H, J=14.6), 3.38 (dd, 1H, J=7.8 and 2.2), 3.20 (dd, 1H, J=5.6 and 4.4), 3.12 (dd, 1H, J=7.3 and 2.4), 2.96 (dd, 1H, J=5.8 and 4.4), 2.60 (m, 2H), 2.22 (dd, 1H, J=10.5 and 9.7). MS, m/z (relative intensity): 224 [M−H-Bn, 94%], 317 [M+2H, 64%]. IR 3027, 2917, 1688, 1438, 1267, and 701 cm−1.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[N:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F.CCOCC>CCOCC.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[Si:1]([O:8][CH2:9][CH2:10][C:11]1([NH2:12])[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC#N
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCC1(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)propanenitrile (11.1 g, 60 mmol) in Et2O (400 mL) was added titanium tetraisopropanolate (28.9 g, 102 mmol) under N2 atmosphere. Ethylmagnesium bromide (3M in Et2O, 50 mL) was slowly added drop-wise at 0° C. The mixture was stirred at rt for 1 hr. Boron trifluoride etherate (17.0 g, 120 mmol) was slowly added at 0° C. The mixture was stirred at rt for 1 hr. The mixture was quenched with 10% aq. NaOH (300 mL) and then extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 5˜50% EtOAc/petroleum ether) to afford 1-(2-(tert-butyldim ethylsilyloxy)ethyl)cyclopropanamine (3.9 g, 30%) as a colorless oil. ESI-MS (EI+, m/z): 216.2 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:34])[CH2:10][N:11]1[C:16]([CH3:17])=[C:15](Cl)[N:14]=[C:13]([NH:19][CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]1=[O:33])C1C=CC=CC=1>[OH-].[Pd+2].[OH-]>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@@H:21]1[CH2:20][NH:19][C:13]1[C:12](=[O:33])[N:11]([CH2:10][C:9]([OH:34])=[O:8])[C:16]([CH3:17])=[CH:15][N:14]=1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: Cc1c(Cl)nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: Cc1cnc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)O

Procedure:
The title compound was prepared by a similar method to preparation 44 from tert-butyl (2R)-2-[({4-[2-(benzyloxy)-2-oxoethyl]-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl}amino)methyl]-1-pyrrolidinecarboxylate [see preparation 53] and palladium hydroxide to afford the product as a white foam, (68%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32]>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[N+:31]([O-:33])=[O:32])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a solution of 4-(benzyloxy)phenol (2.00 g, 10 mmol) in N,n-dimethylformamide (20 ml) was added potassium tert-butoxide (1.12 g, 10 mmol), followed by stirring for 10 minutes. To the reaction solution was added 4-chloro-3-nitroanisole (1.88 g, 10 mmol), followed by stirring at 150° C. for 6 hours. After allowing to stand overnight, the reaction solution was poured into water and extracted with ethyl acetate. After drying subsequent to washing with water and a saturated aqueous sodium chloride solution, the solvent was evaporated under reduced pressure. The resulting crude crystals were recrystallized from ethanol to give 4-[4-(benzyloxy)phenoxy]-3-nitroanisole (2.13 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:21]C(C)(C)[N:19]([C:24](=[O:28])[CH:25]([F:27])[F:26])[C@@H:18]3[CH2:29][F:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-]>[CH2:1]([NH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:28])[CH:25]([F:26])[F:27])[CH2:29][F:30])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCc1ccc(-c2ccc([C@@H](O)[C@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
To a solution of 1-{(4S,5R)-5-[4-(6-Ethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl}-2,2-difluoro-ethanone (0.062 g, 0.147 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (1.0 mL) at room temperature. The resulting reaction mixture is stirred at room temperature for 5 hours. Solvent is evaporated in vacuo to get the crude residue and diluted with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography using 15% methanol in CH2Cl2 as an eluent. Obtained solid is washed with n-pentane and diethyl ether to afford the title compound (0.035 g) after drying in lypholizer. 1H NMR (400 MHz, DMSO-d6) δ: 1.16 (t, J=7.2 Hz, 3H), 2.83-2.88 (q, 2H), 4.14 (s, 2H), 4.30-4.33 (m, 1.5H), 4.41-4.45 (m, 0.5H), 4.55-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (t, J=4.08 Hz, 1H), 5.93 (d, J=4.55 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.24 Hz, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.24 Hz, 2H), 8.12-8.15 (dd, J1=2.32 Hz, J2=8.16 Hz, 1H), 8.85 (d, J=8.8 Hz, 1H), 8.90 (d, J=2.12 Hz, 1H). LC-MS (m/z): [M+H]=382.1.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][CH2:15][CH2:16]Br.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:13][CH2:14][CH2:15][CH2:16][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: ClCCCBr
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: ClCCCN1CCC(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
24 Grams of 4-phenylpiperidine, 24 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed with 100 ml of dimethylformamide and stirred at 50°-60° C. for 1 hour. The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous-solution and the organic layer was extracted with chloroform. Then the chloroform layers was washed with water, dried and the chloroform was removed by distillation. The residue thus obtained was purified by a silica-gel column chromatography (to obtain only the main product at the upper-most portion in the column). 15.3 Grams of 1-chloro-3-(4-phenylpiperidinyl)propane was obtained as in the form of colorless oily substance. Then this oily substance was distilled under a reduced pressure to obtain 11 g of a fraction of distillate having the boiling point of 112°-115° C. (0.1 mmHg). A part of this distillate was made as in the form of hydrochloride and recrystallized from ethanol to obtain 1-chloro-3-(4-phenyl-1-piperidyl)propane monohydrochloride having the melting point of 167°-169° C. as in the form of colorless needle-like crystals.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[C:16](F)[CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([O:19][CH3:20])[CH:13]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: CN1CCC(O)CC1
Reactant: COc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc(OC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL) at 65° C. was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 30 minutes, a solution of 3-bromo-5-fluoroanisole (2.05 g, 10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature then was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were loaded onto a SCX-2 cartridge, which was then washed with acetonitrile then eluted with 2N ammonia in methanol. Concentration of the basic methanolic fractions in vacuo gave the title compound (1.5 g, 50%). 1H NMR (CDCl3, 400 MHz): 6.65 (dd, J=2.2, 1.6 Hz, 1H), 6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd, J=2.3, 2.1 Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.1 min, M+H+=300.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:26])=O>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ncc2ccc(OCCCC)cc2c1O
Reactant: O=P(Br)(Br)Br
Product: CCCCOC(=O)c1nc(Br)c2ccc(OCCCC)cc2c1O

Procedure:
0.175 g of 6-butoxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester, 1were allowed to react with phosphorous oxybromide analogously to Example D-46 b) to give 0.073 g of a white solid: Proton NMR (200 MHZ, chloroform-d): δ 11.84 (s, 1H), 8.13 (d, 1H), 7.60 (m, 1H), 7.42-7.35 (m, 1H), 4.48 (t, J=7 Hz, 2H), 4.15 (t, J=7 Hz, 2H), 1.95-1.75 (m, 4H), 1.65-1.40 (m, 4H), 1.05-0.95 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22]1([CH2:28]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:28]([N:18]1[N:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[O:20][C:19]1=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1oc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1Cc1ccccc1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a 1.16 g, 4 mmol) on reacting with C6H5CH2Br (0.82 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-benzyl-5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6c, 1.42 g, 94%). Nitro compound (6c, 1.52 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7d, 1.23 g, 88%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7d, 0.35 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8d, 405 mg, 83%).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[Cl:22][C:23]1[S:27][C:26]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:12]([CH3:13])[N:4]([CH:1]5[CH2:2][CH2:3]5)[N:5]=4)[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: OCc1ccc(Cl)s1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)ccc2nn1C1CC1
Reaction time: 3 h
Yield: 20.5 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (70 mg) in tetrahydrofuran (5 ml) were added (5-chlorothiophen-2-yl)methanol (74 mg), 1,1′-(azodicarbonyl)dipiperidine (188 mg) and tributylphosphine (151 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (21 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[C:24]([F:38])[CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30](=[CH:16][C:13]2[NH:12][C:9]4[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=4[C:14]=2[CH3:15])[C:31](=[O:37])[NH:32]3)=[C:24]([F:38])[CH:23]=1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2F)N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(-c5ccc(Cl)cc5F)c43)c(C)c2C1=O
Yield: 38.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(4-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(4-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 38.9%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[C:8]3[NH:31][CH:30]=[N:29][C:9]3=[CH:10][C:11]=2[C:12]=1[N:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)C=O)#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO>[O:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:13][C:12]2[C:11]3[CH:10]=[C:9]4[N:29]=[CH:30][N:31]=[C:8]4[CH2:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:1]#[N:2])=[CH:17][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1cnc2cc3[nH]cnc3cc2c1N(C=O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1cnc2c(c1Nc1ccc(Oc3ccccc3)cc1)C=C1N=CN=C1C2
Yield: 70 %

Procedure:
A suspension of 211.8 mg (0.52 mmol) of 7-cyano-3H-imidazo[4,5-g]quinolin-8-yl(4-phenoxyphenyl)formamide and 288.9 mg (2.09 mmol) of potassium carbonate in 15 mL of methanol is refluxed for 2.5 hours. The solution is concentrated and the residue is diluted with water followed by neutralization to pH 7-8 with acetic acid. The precipitate is collected by filtration and washed with water and dried in vacuo, giving a deep yellow solid. The solid is purified by flash chromatography (elution with a gradient of 98:2 to 90:10 methylene chloride/methanol) yields 137.4 mg (70.0%) of the final product as a yellow solid, mp>270° C.
Reaction SMILES: CO.C(O[C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.[CH2:26]([NH2:28])[CH3:27]>O>[CH2:26]([NH:28][C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])[CH3:27]
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Reactant: CCN
Solvent: CO
Solvent: O
Product: CCNC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Yield: 80 %

Procedure:
To the solution of methanol (20 ml) was added 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (1 g) prepared from preparation example 1, added70% aq. ethylamine (25ml) at room temperatute, and reacted at 30-35° C. for 3 hr. The reaction mixture was cooled and slowly added H2O (30 ml) and stirred for 0.5 hr. The reaction mixture was filtered, washed with 30% aqueous methanol solution (10 ml) obtained the desired compound (0.8 g, 80%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][C:19]#[CH:20])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:20]#[C:19][CH2:18][NH:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:21])=[CH:8][CH:9]=1)=[O:4]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Br)o1
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)o1

Procedure:
The title compound of Step A was prepared from 5-bromo-furan-2-carboxylic acid methyl ester and prop-2-ynyl-carbamic acid tert-butyl ester as described in Step A of Preparation 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[C:15]=[O:16])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)cc(OC)c1OC

Procedure:
600 ml of a solution of 18.3 g of 3,4,5-trimethoxyaniline in toluene was added to 140 ml of a solution of 48 ml of trichloromethyl chloroformate in toluene and the mixture was refluxed for 3 h. After cooling, the solvent was distilled off and the residue was distilled under reduced pressure (115° C./1 mmHg) to obtain 15.53 g of 3,4,5-trimethoxyphenyl isocyanate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1)#[N:2].S(C1C=CC(C)=CC=1)(O[CH:14]1[CH2:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:20][C:16]1([CH3:21])[CH2:17][CH2:18][CH2:19][CH:14]([S:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1
Reactant: N#Cc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC(C)(C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CCCC(Sc2ccc(C#N)cc2)C1
Temperature: 60 °C

Procedure:
To a solution of 4-cyanothiophenol (1 g, 7.4 mmol) in DMF (15 mL) add 3,3-dimethylcyclohexyl tosylate (2.06 g, 7.4 mmol) and potassium carbonate (3.06 g, 22.2 mmol), and warm to 60° C. for 18 h. Dilute the mixture with EtOAc (50 mL) and wash sequentially with water (3×50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a clear oil that solidifies on standing (0.35 g, 20%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].Br[C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:9][C:8]1[CH:7]=[CH:6][C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)=[CH:4][C:3]=1[C:1]#[N:2])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cnn(-c2ccc(O)c(C#N)c2)c1
Reactant: CC(C)(C)Br
Product: CCOC(=O)c1cnn(-c2ccc(OC(C)(C)C)c(C#N)c2)c1

Procedure:
The same reaction and treatment as in Example 5 using ethyl 1-(3cyano-4-hydroxyphenyl)pyrazole-4-carboxylate and 1-bromo-1,1-dimethylethane gives ethyl 1-(4-tert-butoxy-3-cyanophenyl)pyrazole-4-carboxylate.