Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH2:17]Br)=[N:9][C:8]=2[CH:19]=1)([O-:3])=[O:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH2:17][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[CH:19]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc2oc(-c3sccc3CBr)nc2c1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3sccc3CN3CCOCC3)nc2c1
Yield: 78.8 %

Procedure:
A mixture of 5-nitro-2-(3-bromomethyl-2-thienyl)-benzoxazole (5.0 g, 0.0147 mole) and morpholine (2.6 g, 0.03 mole) in 200 ml of benzene is refluxed for 24 hours. The precipitated morpholine hydrobromide is removed by filtration and the benzene evaporated under vacuum yielding 4.0 g of solid. Crystallization from ethanol yields 3.4 g of product, melting point 143°-145° C.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:25][C:26]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:26]=2[F:25])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Reactant: CC(C)(C)c1cc(N)n(C[C@H]2CCCO2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)c2cccc(C(F)(F)F)c2F)n(C[C@H]2CCCO2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To the mixture of Example 6B (293 mg, 1.129 mmol) and triethylamine (0.472 mL, 3.39 mmol) in CH2Cl2 (5 mL) cooled with an ice-bath was added 2-fluoro-3-(trifluoromethyl)benzoyl chloride (307 mg, 1.355 mmol) in one portion. The mixture was stirred at ambient temperature for 2 h, the solvent removed under reduced pressure and the residue purified by flash chromatography (silica gel, 10-60% EtOAc/hexane) to yield 420 mg (90%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 9H), 1.58-1.97 (m, 4H), 3.55-3.78 (m, 2H), 4.06-4.20 (m, 3H), 6.30 (s, 1H), 7.57 (t, J=7.80 Hz, 1H), 8.01 (q, J=8.02 Hz, 2H), 10.42 (s, 1H); MS (ESI) m/z 414 (M+H)+, 412 (M−H)−.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:11]>>[CH2:8]([O:7][C:5]([C:4]1[N:11]([CH2:10][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=[N:2][N:1]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CCOC(=O)C#N
Product: CCOC(=O)Cn1nnnc1C(=O)OCC

Procedure:
A mixture of ethyl azidoacetate (6.4 grams, 50 millimoles) and ethyl cyanoformate (distilled, 15.0 grams, 150 millimoles) was heated on a steam bath for 40 hours. The yellow reaction mixture was concentrated under vacuum to give 9.4 grams (83 percent of theoretical yield) of an oil. Distillation of a sample at 115°-117°C. (.015 mm.) gave a viscous oil. On standing the title product, as a crystalline solid, was obtained, m.p. 26°-29.5°C. The analysis was as follows:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:26](=[O:28])[CH3:27])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CC(=O)Cl
Product: CC(=O)NCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 87.9 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-acetamide (88 mg, 88%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and acetyl chloride (0.02 mL, 0.25 mmol) following the general procedure T.
Reaction SMILES: [C:1]([NH2:8])(=[S:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[CH2:2]([C:1]1[S:7][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([OH:12])[N:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: CCCCCC(N)=S
Product: CCCCCc1nc(O)c(-c2ccccc2)s1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except thiohexanamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[C:15]#[N:16])[C:4](=[O:17])[C:3]=1[C:18]#[N:19].[Br:20]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:20][C:7]1[C:2]([Cl:1])=[C:3]([C:18]#[N:19])[C:4](=[O:17])[N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[C:15]#[N:16])[CH:6]=1
Reactant: N#Cc1cccc(F)c1-n1ccc(Cl)c(C#N)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(F)c1-n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 21.3 %

Procedure:
To a solution of 4-chloro-1-(2-cyano-6-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (4.0 g) in N,N-dimethylformamide (40 mL) was added N-bromosuccinimide (3.90 g) at room temperature. The reaction mixture was heated at 50° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.10 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1
Yield: 90 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate (commercially available), (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (90%).
Reaction SMILES: Cl.Cl.[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:17]=[C:18]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)[NH:19][C:20](=[O:25])[C:21]=1[C:22]([NH2:24])=[O:23])(=[O:8])=[O:7])([CH3:5])[CH3:4].N1C=CC=CC=1.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(O)C>[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:17]=[C:18]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:28]2)[NH:19][C:20](=[O:25])[C:21]=1[C:22]([NH2:24])=[O:23])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC2CCCNC2)[nH]c(=O)c1C(N)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC2CCCN(S(C)(=O)=O)C2)[nH]c(=O)c1C(N)=O
Reaction time: 1 h

Procedure:
To a mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide dihydrochloride (Example 29) (67 mg) and pyridine (1.3 mL), mesyl chloride (0.10 mL) was added under ice cooling and stirred for 1 hour. After ethanol was added to the reaction system, the reaction system was concentrated. The resulting residue was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate, and the organic layer was dried. The organic layer was concentrated, followed by an azeotropic process with toluene. The resulting residue was solidified with ethyl acetate-hexane. The resulting solid was recrystallized from ethanol to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-{[1-(methylsulfonyl)piperidin-3-yl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (43 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:15])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2ccc(Br)cc12
Solvent: ClC(Cl)Cl
Product: Clc1nccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A solution of 7-bromoisoquinolin-1-ol (2.5 g, 11.1 mmol) and POCl3 (10.4 mL, 111 mmol) was stirred at 70° C. for 2.5 h. The reaction mixture was cooled to room temperature, poured into ice water, and the solution was stirred overnight. The aqueous mixture was diluted with chloroform, washed with a saturated solution of NaHCO3, saturated NaCl, dried (MgSO4), filtered, and concentrated under reduced pressure to afford 7-bromo-1-chloroisoquinoline (2.3 g): 1H NMR (300 MHz, DMSO-d6) δ 8.39–8.36 (m, 2H), 8.09–8.02 (m, 2H), 7.95 (d, J=6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:12])[CH:6]=1)[CH3:2].C1COCC1.C1(O)C=CC=CC=1.[I:26]I>C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([I:26])[C:8]([OH:11])=[C:7]([Br:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(Br)c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1cc(Br)c(O)c(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a mixture of 3-bromo-4-hydroxybenzoic acid ethyl ester (69.2 g, 282 mmol) in 2N aqueous potassium carbonate (423 mL) was added sufficient THF to completely dissolve the phenol and make the solution clear (˜300 to 500 mL). The solution was cooled to 0° C. and I2 (158 g, 621 mmol) was added portionwise at such a rate as not to accumulate a large amount of solid 12 on the bottom of the flask. After addition was complete, the ice bath was removed, and the solution was allowed to warm to room temperature. The reaction was complete in 2 h. Worked up by adding (slowly with caution) solid sodium bisulfite at a rate so excess foaming doesn't occur. Sodium bisulfite was added until nearly decolorized. The mixture was acidified with concentrated hydrochloric acid, extracted several times with ethyl acetate, the organic layers combined, washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give 3-bromo-4-hydroxy-5-iodobenzoic acid ethyl ester (94.6 g, 90%) as a pale yellow solid. NMR indicated it was suitable for use in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ1.39 (t, J=6.8 Hz, 3H, —CO2CH2CH3), 4.32 (t, J=6.8 Hz, 2H, —CO2CH2CH3), 8.14 (d, 1H, arom), 8.32 (d, 1H, arom).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:46][C:47]#[N:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:46]/[C:47]#[N:48])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C#N)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
To a mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (580 mg), diethylphosphonoacetonitrile (230 mg) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 56.0 mg) at 0° C., and the mixture was stirred at room temperature for 5 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 over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenonitrile (460 mg, yield 76%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from acetone-hexane. melting point: 184-185° C.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18]C)[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24]C)[CH2:3][CH2:4][CH2:5][CH2:6]C.[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[OH:1][CH:2]([C:8]1[C:9](=[O:24])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:20][CH3:21])[CH:13]=[CH:12][C:11]=2[O:22][CH3:23])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(O)c1cc(OC)c2c(OC)ccc(OC)c2c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCCCC(O)C1=CC(=O)c2c(OC)ccc(OC)c2C1=O
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
3.6 g (10.3 mmole) of 2-(1-hydroxyhexyl)-1,4,5,8-tetramethoxynaphthalene was dissolved in 50 ml of acetonitrile and then a solution of 14.2 g (25.0 mmole) of cerium (IV) ammonium nitrate dissolved in 50 ml of distilled water was added dropwise thereto over 30 minutes through a dropping funnel in a cooling bath (0°-5° C.). The reaction mixture was stirred at normal temperature for 2 hours. After adding 100 ml of distilled water thereto, the reaction mixture was extracted twice with dichloromethane solvent, dried over anhydrous magnesium sulfate and then filtered through filter paper. The resulting filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel 4.0×15 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 5:1 to 1:3, to obtain 1.2 g of the title compound as a yellow precipitate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H-].[Na+].[CH3:21]I>CN(C=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:21])[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCOCC1)c1ccc(N)cc1

Procedure:
N-methylation of N-(4-nitrophenyl)morpholine-4-carboxamide was effected by allowing it to react with sodium hydride and methyl iodide in DMF, and the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain N-(4-aminophenyl)-N-methylmorpholine-4-carboxamide. F: 236.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[Cl:40][C:41]1[CH:42]=[N:43][NH:44][CH:45]=1.N1C=CC=CC=1>O>[CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:43]3[CH:42]=[C:41]([Cl:40])[CH:45]=[N:44]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1cn[nH]c1
Solvent: c1ccncc1
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cc(Cl)cn2)cc1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.14 g), 4-chloro-1H-pyrazole (0.053 g), cuprous acetate (0.093 g) and pyridine (3 mL) was heated at 50° C. for 116 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as a colourless oil (0.13 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:5]2[N:19]=[CH:20][CH:21]=[C:4]2[N:3]=1.CC(C[AlH]CC(C)C)C.C1COCC1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:5]2[N:19]=[CH:20][CH:21]=[C:4]2[N:3]=1
Reactant: COC(=O)c1c(C)nc2ccnn2c1-c1ccc(C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-c2c(CO)c(C)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a stirred solution of methyl 5-methyl-7-p-tolylpyrazolo[1,5-a]pyrimidine-6-carboxylate (950 mg, 3.38 mmol) in CH2Cl2 (50 mL) was added DIBAL-H, 1M in THF (16.9 mL, 16.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h before being quenched with saturated NH4Cl solution. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (482 mg, 56.3%). 1H-NMR (500 MHz, CDCl3) δ ppm 1.64 (1H, t, J=4.9 Hz), 2.45 (3H, s), 2.78 (3H, s), 4.58 (2H, d, J=4.9 Hz), 6.60 (1H, d, J=2.4 Hz), 7.34-7.40 (2H, m), 7.42-7.49 (2H, m), 8.00 (1H, d, J=2.4 Hz).
Reaction SMILES: CO[C:3]1[CH:19]=[C:18]([NH:20]C)[C:17]([N+:22]([O-])=O)=[CH:16][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](NC)=O)C=1.[CH3:25][CH2:26]O>[Pd]>[N:9]1([CH2:10][CH2:11][CH2:6][O:5][C:4]2[CH:16]=[C:17]([NH2:22])[C:18]([NH2:20])=[CH:19][CH:3]=2)[CH2:8][CH2:12][CH2:26][CH2:25]1
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Reactant: CCO
Agent: [Pd]
Product: Nc1ccc(OCCCN2CCCC2)cc1N
Reaction time: 18 h

Procedure:
To a solution 2-Nitro-4-(3-pyrrolidinylpropoxy)phenylamine 1 in EtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged (×3) with nitrogen, and then stirred under a hydrogen atmosphere for 18 h. The product is filtered through a Celite plug, and the plug washed with 25 mL of EtOH, to yield 2. LCMS 236.2 Rt 0.94 min.
Reaction SMILES: [CH2:1]([N:4]([CH2:10]Cl)[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH:2]=[CH2:3].[CH3:12][O:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:4]([CH2:10][O:16][CH2:15][CH2:14][O:13][CH3:12])[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CCl)C(=O)C(Cl)Cl
Reactant: COCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCN(COCCOC)C(=O)C(Cl)Cl

Procedure:
A solution of N-allyl-N-chloromethyldichloroacetamide (21.7 g., 0.1 mole) and 2-methoxyethanol (8.4 g., 8.7 ml., 0.11 mole) in dry chloroform (50 ml.) is placed in a round-bottomed, four-necked flask of 250 ml, equipped with a calcium chloride tube, reflux condenser, mechanical stirrer, dropping funnel and thermometer. Triethylamine (10.1g., 13.9 ml., 0.1 mole) is added under stirring and external cooling in such a rate that the temperature does not exceed 35° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. The mixture is washed with water (2×70 ml) for removing the triethylamine hydrochloride formed, the chloroform solution is dried over anydrous sodium sulfate and, after distillation of the chloroform, the product is dried under reduced pressure to give 23.6 g. (92%) of a pale yellow oil which is the named compound of 95% purity according to an analysis by gas chromatography; nD25 =1.4801. This product is directly useful for practical purposes.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[NH:22][NH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[NH:22][NH:23][C:8](=[O:10])[C:7]1[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=1[O:11][CH3:12]
Reactant: COc1nccc(I)c1C(=O)O
Reactant: NNc1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1nccc(I)c1C(=O)NNc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of 4-iodo-2-methoxynicotinic acid (1.00 g) obtained in Step C of Example 6 in DMA (10 mL) were added (2,6-difluorophenyl)hydrazine hydrochloride (647 mg), EDCI hydrochloride (824 mg) and HOBt (581 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (1.32 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
To a stirred solution of 2-nitrophenol (1.5 g, 0.0101 mole) in DMF (15 mL) was added cesium carbonate (16.4 g, 0.0505 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 0.0101 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (20% ethyl acetate in hexane) to afford 1.5 g (47%) of 4-(2-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 323.15 (M+1)+, 98%,
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:14])[CH3:13].[C:23](Cl)(=[O:25])[CH3:24]>O>[C:12]([C:16]1[CH:21]=[C:20]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Aluminium chloride (44.4 g, 333 mmol) was cooled to −45° C., followed by addition of toluene (1.25 L). 2-tert-butylphenol (50.0 g, 333 mmol) was added further and stirred for 2 hours. Further, acetyl chloride (26.1 g, 333 mmol) was added dropwise and stirred for 2.5 hours. The resultant reaction solution was added to ice-cooled water (250 mL) dropwise and stirred at room temperature. Crystals were collected by filtration and dried under reduced pressure (50° C.) to give 48.7 g of the captioned compound as white crystals (yield: 76.1%; HPLC purity: 99.8%).