Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:31](I)([CH3:33])[CH3:32]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:31]([CH3:33])[CH3:32])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1c[nH]nc1-c1cccc(Cl)c1)c1cnn2cccnc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(NC(=O)c2cnn3cccnc23)c(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (68.9 mg, 0.203 mmol, 1 eq) was dissolved in 4 mL N,N-dimethylformamide. To this solution was added cesium carbonate (148 mg, 0.454 mmol, 2.23 eq) and isopropyl iodide (23.0 μL, 0.230 mmol, 1.13 eq). The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 47.2 mg (61%) of N-(3-(3-chlorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=381.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.99 (s, 1H), 9.37 (d, 1H), 8.85 (d, 1H), 8.70 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.77 (d, 1H), 7.57 (t, 1H), 7.48 (d, 1H), 7.34 (d of d, 1H), 4.59 (d of q, 1H), 1.48 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(I)cc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: Fc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 65 °C
Yield: 63.1 %

Procedure:
To THF (90 mL) degassed by purging argon was added 4-fluoroiodobenzene (4.5 g, 20.2 mmol), 4-bromophenylboronic acid (4 g, 20.2 mmol), and tetrabutylammonium flouride (1M in THF, 40.5 mL, 40.5 mmol), and the mixture was degassed again. Pd(dppf)Cl2 (732 mg, 1 mmol) was added and the mixture was degassed again for 15 minutes. The reaction mixture was heated at 65° C. in an oil bath overnight. TLC (heptane eluent) showed the reaction was complete. The reaction mixture was diluted with ethyl acetate and extracted with brine. The organic layer was dried (sodium sulfate) and concentrated to yield the crude product. Purification by column chromatography (60-120 mesh silica, heptane eluent) yielded 3.2 g of 4-bromo-4′-fluoro-1,1′-biphenyl.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:16])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(NCC(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1Cl
Temperature: 120 °C

Procedure:
To a mixture of 1-[4-(benzyloxy)-2-chlorophenyl]ethanone (500 mg) and toluene (15.0 mL) were added p-toluenesulfonic acid (110 mg) and tert-butyl glycinate (0.800 mL), followed by heating at 120° C. for 18 hours. After completion, the reaction mixture was left to be cooled, and then concentrated under reduced pressure. To the residue was added methanol (10.0 mL), and the sodium borohydride (90.0 mg) was added there to under ice-cooling, followed by stirring under ice-cooling for 2 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-{1-[4-(benzyloxy)-2-chlorophenyl]ethyl}glycinate (560 mg).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[C:21]([CH3:28])=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=4)[N:14]=3)[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]3[C:21]([CH3:28])=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=3)[N:14]=2)[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2cc(-c3ccnc(Oc4cc(N)c(F)cc4C)n3)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)c(N)cc1Oc1nccc(-c2cn[nH]c2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
A solution of 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine (0.5 g, 1.2 mmol) in dichloromethane (20 mL) was treated with TFA (5 mL) at 0° C. The mixture was then stirred at RT for 12 h. The solvent was removed in vacuo, the residue was washed with ether and treated with saturated ammonia solution. The solid was collected via filtration and dried under vacuum to give 5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine (240 mg, 68%, yield). 1H NMR (400 MHz, MeOD): δ 8.41 (d, J=5.2 Hz, 1H), 8.21 (br s, 2H), 7.40 (d, J=5.2, 1H), 6.90 (d, J=11.6 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 1.99 (s, 3H). MS (ESI) m/z: 286.1 (M+H+).
Reaction SMILES: [N+]([CH:4](C1C=CC=CC=1)[C:5](NC1C=CC=CC=1)=[O:6])([O-])=O.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:24]=[CH:25][CH:26]=1.B.O>O1CCCC1>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([OH:20])[CH:22]=2)[C:5](=[O:6])[CH3:4])=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=C(Nc1ccccc1)C(c1ccccc1)[N+](=O)[O-]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1cccc(O)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(CCc1ccc([N+](=O)[O-])cc1)c1cccc(O)c1

Procedure:
10 g (0.4 mol) of the nitrophenylacetanilide prepared in 1a) was placed in a flask and borane in tetrahydrofuran (THF) (1 M, 250 ml) was added carefully. The resulting solution was heated under reflux and water (12 ml) in THF (100 ml) was added dropwise over 1 hour. A further 50 ml of water was added and the mixture was heated for 15 mins. The THF was evaporated under reduced pressure and methanol (100 ml) was added to dissolve the oil. Thin layer chromatography (tlc)(silica H. 2 0% methanol in chloroform) gave a Rf much higher than the starting acetanilide.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:19])C.[NH3:21]>CO>[CH3:17][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7]([CH3:19])=[C:6]([CH2:5][C:4]([NH2:21])=[O:3])[C:10]=2[CH:11]=1)[CH3:18]
Reactant: CCOC(=O)Cc1c(C)oc2ccc(CN(C)C)cc12
Reactant: N
Solvent: CO
Product: Cc1oc2ccc(CN(C)C)cc2c1CC(N)=O
Temperature: 70 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
A solution of (5-dimethylaminomethyl-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (744 mg, 2.70 mmol) in a mixture of methanol (5 mL) and liquid ammonia (40 mL) is stirred for 3 days in an autoclave at 70° C. After careful evaporation of the ammonia, the remaining solvent is evaporated in vacuo to afford the title compound as beige solid (662 mg, 2.42 mmol, 90%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=7.48 (bs, 1H), 7.42 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.93 (bs, 1H), 3.45 (s, 2H), 3.38 (s, 2H), 2.38 (s, 3H), 2.15 (s, 6H). MS (ES+): 247 (M(C16H14O4)+H)+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:14]([C:11]1[O:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=1)#[N:15]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C#N)o1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(S(N)(=O)=O)o1

Procedure:
A solution of N-(tert-butyl)-5-cyanofuran-2-sulfonamide (the product of example 50, step i) (1.0 g) in trifluoroacetic acid (30 mL) was stirred at room temperature for 24 h. The mixture was evaporated to dryness in vacuo to leave a crude yellow oil that was triturated with Et2O and filtered. The filtrate was evaporated to dryness in vacuo to give the subtitle compound as a pale yellow oil. Yield: 0.29 g.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:11]2[C:12]([CH3:14])([CH3:13])[CH:9]([CH2:10]2)[CH2:8][CH:7]=1.C=CC1C=CC=CC=1>>[CH3:5][C:6]1[CH2:11][CH2:10][C@@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:8][CH:7]=1
Reactant: CC1=CCC2CC1C2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C=Cc1ccccc1
Product: C=C(C)[C@H]1CC=C(C)CC1
Yield: 58.1 %

Procedure:
Same procedure as that described in Comparative Example 1, except that 7.0 g of aluminum chloride and a blend of alpha pinene and styrene (60:40 weight ratio) were employed. The resulting resin had the following properties: s.p.=76.1° C., yield=58.1%, neat color=5 Gardner.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]([CH2:34][CH3:35])[C:25]4[C:30]([CH:31]=3)=[C:29]([Cl:32])[C:28]([Cl:33])=[CH:27][CH:26]=4)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[ClH:32].[N:11]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]([CH2:34][CH3:35])[C:25]4[C:30]([CH:31]=3)=[C:29]([Cl:32])[C:28]([Cl:33])=[CH:27][CH:26]=4)=[O:22])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2c(Cl)c(Cl)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCn1c(C(=O)Nc2ccc(N3CCNCC3)cc2)cc2c(Cl)c(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 212.8 %

Procedure:
A mixture of 4-{4-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (750 mg, 1.45 mmol) in 15 mL of methylene chloride and 2 mL of 4M hydrogen chloride in dioxane was stirred at room temperature for 24 hr. The solvent was removed to afford 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride salt (700 mg, 99% yield) as an off white solid. LCMS for C21H22Cl2N4O calcd. (m/e) 416, observed 417 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH3:17])=[C:4]([Cl:9])[CH:3]=1
Reactant: CCI
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Br)cc1Cl
Reaction time: 68 h

Procedure:
To a mixture of 4-bromo-2-chlorophenol (10.81 g) and potassium carbonate (8.65 g) in DMF (10 ml) was added at room temperature ethyl iodide (4.17 ml), and the mixture was stirred for 68 hours. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give pale yellow oil of 4-bromo-2-chloro-1-ethoxybenzene (12.28 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:29][N:30](C)C(Cl)=O.C[Si](C#N)(C)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][C:8]([C:29]#[N:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(-c3ccccc3)ccnc2c1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(-c3ccccc3)cc(C#N)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 7-methyl-4-phenylquinoline (10.0 g, 41.7 mmol) and m-CPBA (13.5 g, 54.8 mmol) in chloroform (230 mL) was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted twice with dichloromethane. The combined organic layers were washed with water, brine, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the resulting crude product was dissolved in chloroform (220 mL). N,N-Dimethylcarbamoyl chloride (8.44 mL, 91.4 mmol) and trimethylsilyl cyanide (11.5 mL, 91.4 mmol) were added to this solution and stirred at room temperature for 2 d. Saturated aqueous NaHCO3 solution was added and stirred for 30 min. The organic layer was removed, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, brine, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the resulting crude product was used in the next step without further purification. 1H NMR (400 MHz, acetone-d6): δ 8.01 (s, 1H), 7.92 (d, 1H), 7.80 (s, 1H), 7.60-7.67 (m, 6H), 2.63 (s, 3H).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:22]1COCC1.[H-].[Na+].CI>O>[CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCCCCCCCCc1ccc2cc(OC)ccc2c1
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, 6-n-decyl-2-hydroxynaphthalene (5.68 g, 20 mmol) and a THF (200 ml) solution of 55% NaH (oil dispersion, 880 mg, 20 mmol) were stirred at room temperature for 40 minutes. CH3I (1.48 ml, 24 mmol) was added to the mixed solution, and the mixed solution was heated under reflux for 12 hours. Water (20 ml) was added to the mixture at 0° C., and the mixture was washed with saline water. Organic layers were combined, and dried with MgSO4, and condensed with an evaporator. The condensed solution was recrystallized from methanol to obtain 6-n-decyl-2-methoxynaphthalene (compound (3)-64) (5.0 g, 85%) as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>CN(C)C=O>[O:9]=[C:8]1[N:7]([CH2:18][CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[O:10]1
Reactant: O=Cc1ccc(OCCCl)cc1
Reactant: O=c1[nH]c2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1

Procedure:
Dissolve benzoxazolinone (0.024 mol) in dimethylformamide and add potassium carbonate (0.047 mol). Heat at reflux for 20 minutes and then add the compound obtained in Step A (0.021 mol). Stir magnetically at reflux for 80 minutes. Hydrolyse the reaction mixture in 150 ml of water, suction-filter off the resulting precipitate and recrystallise it from a 5/5 cyclohexane/toluene mixture.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2].[CH2:17]([OH:19])[CH3:18]>>[C:17]([NH:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])(=[O:19])[CH3:18]
Reactant: CCO
Reactant: CCC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Product: CCC(Cc1cccc(NC(C)=O)c1)C(=O)O

Procedure:
In a manner similar to Description 13, 2-ethyl-3-(3-nitrophenyl)propenoic acid was reduced and acetylated to give 2-(3-acetamidobenzyl)butanoic acid, m.p. 131°-132° C. (from aqueous ethanol) which was cyclised and the product hydrolysed to afford 5-amino-2-ethylindan-1-one, m.p. 105.5°-108° C. (from acetonitrile). Acetylation of the latter afforded 5-acetamido-2-ethylindan-1-one, m.p. 154°-155° C. (from acetonitrile).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)[CH3:3].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>>[C:11]1(=[O:16])[N:1]([CH:2]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)[CH3:3])[C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: Cc1ccc(C(C)N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Product: Cc1ccc(C(C)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A mixture of 9.2 g of 4-(1-aminoethyl)toluene and 10 g of phthalic anhydride was stirred at 145° to 150° C. for 30 minutes. The reaction mixture was purified by silica gel column chromatography (eluted with benzene) to yield 10 g of 4-(1-phthalimidoethyl)toluene; m.p. 65°-66° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18](=[O:19])[C:17]3[CH:16]=[CH:15][C:14]([OH:20])=[CH:13][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[CH:16]=[CH:15][C:14]([O:20][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:13][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2coc3cc(OC(=O)C(C)(C)C)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Formononetine (90 g; 335 mmol) was suspended in acetonitrile, K2CO3 was added and the mixture was stirred for about 20 minutes at r.t. Pivaloyl chloride (59.85 g; 496 mmol) was dropped into the mixture, then the reaction was stirred for further 15 minutes and quenched into water. The solid was filtered, washed with water, dissolved in CHCl3; the solution was dried and evaporated to dryness to obtain the title compound, which can be crystallised from hot toluene. 102 g of a white crystalline powder were obtained.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:19])=[CH:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[H-].[Na+].CS(O[CH2:27][CH2:28][CH2:29][C:30]1([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(=O)=O>C(OCC)(=O)C.O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:19])=[CH:13][C:14](=[O:18])[N:15]2[CH2:27][CH2:28][CH2:29][C:30]2([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:32][CH2:31]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(C)cc(=O)[nH]c2c1
Reactant: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To 5 mL of an N,N-dimethylformamide suspension containing 0.50 g of 7-methoxy-4-methylquinolin-2(1H)-one, 0.11 g of 60% sodium hydride was added, and the mixture was stirred at 60° C. for 20 minutes. Thereto was added 1.09 g of 1-tert-butyl 4-ethyl 4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate, the temperature of the reaction mixture was increased to 70° C., and the reaction mixture was stirred for 4 hours. Thereto was added 0.11 g of 60% sodium hydride, and the resultant solution was stirred for 4 hours. Water and ethyl acetate were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to obtain 0.45 g of a yellow oily substance, 1-tert-butyl 4-ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=[C:23]([CH3:35])[C:19]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:20](=[O:21])[C:19]3[C:23]([CH3:35])=[CH:24][CH:25]=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:18]=3[CH3:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1C(=O)O
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1C(=O)Nc1cccc2c(NC(C)(C)C)ncnc12
Yield: 5.1 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 275 mg, 1.27 mmol), 2,6-dimethyl-3-(pivalamidomethyl)benzoic acid (Intermediate-4, 401 mg, 1.52 mmol), oxalyl chloride (230 mg, 1.82 mmol), DMF (1 drop) and DIPEA (392 mg, 3.04 mmol) in CH2Cl2 (10 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.68 (s, 1H), 8.70-8.67 (d, J=7.8 Hz, 1H), 8.44 (s, 1H), 8.13-8.10 (d, J=8.4 Hz, 1H), 7.94 (t, 1H), 7.49-7.43 (m, 2H), 7.13-7.11 (m, 2H), 4.23 (d, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.52 (s, 9H), 1.12 (s, 9H); MS [M+H]+: 462.44.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:39])[C@H:7]([CH:36]([CH3:38])[CH3:37])[CH2:8][C@H:9]([OH:35])[C@@H:10]([N:32]=[N+]=[N-])[CH2:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[CH:13]([OH:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.C(O)(=O)C.[Pd]>[CH2:1]([NH:5][C:6](=[O:39])[C@H:7]([CH:36]([CH3:38])[CH3:37])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH2:32])[CH2:11][C@@H:12]([CH:29]([CH3:30])[CH3:31])[CH:13]([OH:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@@H](C(C)C)C(O)c1ccc(OC)c(CCOCOC)c1)N=[N+]=[N-])C(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@@H](C(C)C)C(O)c1ccc(OC)c(CCOCOC)c1)C(C)C

Procedure:
40 mg of 5(S)-azido-4(S),8(R,S)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-octanoic acid (N-butyl)-amide are hydrogenated in 10 ml of methanol/acetic acid (9:1) in the presence of 20 mg of 10% Pd/C at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by FC (2.4 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.17; HPLC Rt =11.44 and 12.63 minutes (diastereoisomeric mixture); FAB-MS (M+H)+ =525.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:9])=[C:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17][C:11]2=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1CCCC(=C(N)c2ccc(Cl)cc2)C(=O)C1
Reaction time: 30 h
Yield: 70 %

Procedure:
0.22 g of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylate was dissolved in 12 ml of methanol, 0.19 g of wet Raney-nickel was added and the mixture was hydrogenolyzed at 3.4 atmospheres and at room temperature for 30 hours. The catalyst was removed by filtration and washed on the filter firstly with ethanol and then with dichloromethane. The filtrate was evaporated and the residue was purified by chromatography on silica gel using ethyl acetate for the elution. There was obtained 0.155 g of methyl 4-[(4-chlorophenyl)(amino)methylene]-3-oxocycloheptanecarboxylate of melting point 154°-155° C.