Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27].O.[NH2:29][NH2:30]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:29][NH2:30])[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27]
Reactant: NN
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Solvent: O
Product: C[C@H](Nc1nc(NN)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F

Procedure:
An ethanolic solution of 0.5 g (1.15 mmol) of sulfone 1 and 0.13 g (2.54 mmol) of hydrazine hydrate was stirred at 20-25° C. for 2 hours. The solvent was distilled off and the residue was digested with diisopropyl ether, and the residue was then filtered off and washed with diisopropyl ether/hexane 1:1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:16]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)CCCCBr
Product: O=C(CCCCBr)N1CCc2ccccc21

Procedure:
from 2,3-dihydro-1H-indole and 5-bromopentanoyl chloride
Reaction SMILES: Cl.NO.C([N:6](CC)CC)C.[CH3:11][O:12][C:13]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:25]([N:27]2[CH2:32][CH2:31][C:30]3([CH2:41][C:40](=[O:42])[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:43]#[N:44])[CH:38]=4)[O:33]3)[CH2:29][CH2:28]2)=[O:26])[CH:14]=1>CCO>[CH3:11][O:12][C:13]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:25]([N:27]2[CH2:32][CH2:31][C:30]3([CH2:41][C:40](=[O:42])[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:43](=[NH:6])[NH2:44])[CH:38]=4)[O:33]3)[CH2:29][CH2:28]2)=[O:26])[CH:14]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C#N)ccc2O3)nc2c(OC)cccc12
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=N)N)ccc2O3)nc2c(OC)cccc12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
26.1 mg of hydroxylamine hydrochloride, 62.7 μl of triethylamine and 2.5 mL of EtOH were added to 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidine]-6-carbonitrile (115 mg) obtained in Example 16, and stirred at 60° C. for 24 hours. The reaction mixture was concentrated, and the residue was purified through silica gel column chromatography (2% MeOH/CHCl3) to obtain 83.4 mg of 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidine]-6-carboximidamide. 49.1 mg of the product was dissolved in 1.0 mL of DMF along with 9.7 μl of pyridine therein, and 21.6 μl of 2-ethylhexyl chloroformate was added thereto at 0° C. The mixture was stirred at 0° C. for 30 minutes, then diluted with ethyl acetate (15 mL), washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was dissolved in xylene, refluxed for 4 hours, and then concentrated, and the residue was purified through silica gel chromatography (developed with 20% MeOH/EtOAc) to obtain the intended compound. 1H-NMR (CDCl3) δ: 8.50 (1H, d, J=2.4 Hz), 8.11 (1H, dd, J=8.8, 2.4 Hz), 7.78 (1H, dd, J=8.3, 1.0 Hz), 7.47 (1H, dd, J=8.3, 7.8 Hz), 7.21 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.07 (1H, dd, J=1.0, 7.8 Hz), 4.61-4.53 (1H, m), 4.20-4.12 (1H, m), 4.10 (3H, s), 4.01 (3H, s), 3.71-3.62 (1H, m), 3.40-3.31 (1H, m), 2.95 (2H, s), 2.26-1.86 (4H, m). MS [M+H]+=517.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[C:5]2[C:8]([CH3:16])=[C:9]([N+:13]([O-])=O)[CH:10]=[C:11]([CH3:12])[C:4]=2[O:3]1>C(OCC)(=O)C.CCCCCC>[NH2:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:4]2[O:3][C:2]([CH3:1])([CH3:17])[C:6](=[O:7])[C:5]=2[C:8]=1[CH3:16]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1OC(C)(C)C2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(N)c(C)c2c1OC(C)(C)C2=O
Yield: 97 %

Procedure:
Using 2,2,4,7-tetramethyl-5-nitro-1-benzofuran-3(2H)-one obtained in Reference Example 47, the title compound was synthesized in the same manner as in Reference Example 54. Yield 97%. Melting point: 124-126° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[O:8]=[C:4]1[CH:3]=[C:2]([O:1][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:7]=[CH:6][NH:5]1
Reactant: O=c1cc(O)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 90 °C
Yield: 38.7 %

Procedure:
A stirring mixture of 4-hydroxypyridin-2(1H)-one (1.2 g, 10.8 mmol, prepared according to the procedure described at Step A of Example 8), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (4.83 g, 17.3 mmol, prepared according to the procedure described at Step C of Example 1) and potassium carbonate (3.13 g, 22.7 mmol) in DMF (45 mL) was heated at 90° C. for 14 brs and then cooled to room temperature. The resulting mixture was diluted with EtOAc and H2O and the aqueous layer was extracted further with EtOAc (5×). The combined extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residual was purified by flash chromatography on silica gel (0 to 10% MeOH/CH2Cl2) to yield 1.23 g (38.7%) of the product as a pinkish solid. MS (ESI) 295 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH2:11]([Mg]Br)[CH3:12]>>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:11][CH3:12])=[CH:3][C:2]=1[Cl:1]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: CC=Cc1ccc(Cl)c(Cl)c1

Procedure:
With the exception of three compounds, the styrene compounds herein utilized for preparing the α-chloro oximes are known and their preparations are published in the prior art. The compounds not previously known are synthesized following well-known published procedures. Thus, 2-bromobenzaldehyde is allowed to react with a Grignard reagent, ethyl magnesium bromide in anhydrous ether, to yield 1-(2-bromophenyl)propanol. This propanol derivative is then dehydrated by refluxing it in toluene in the presence of p-toluenesulfonic acid catalyst to yield the desired 1-bromo-2-(1-propenyl)benzene. Another previously unknown substituted styrene, namely, 1,2-dichloro-4-(1-propenyl)benzene is prepared by the same general procedure from 3,4-dichlorobenzaldehyde and ethyl magnesium bromide, followed by dehydration of the intermediate substituted propanol.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][NH:12][CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]cc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc3c(=O)n(C)c(=O)n(CC(C)C)c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.8 g, 8.3 mmol), 1-(chloromethyl)-4-methoxybenzene (1.3 mL, 9.9 mmol) and potassium carbonate (1.7 g, 12 mmol) in anhydrous DMF is stirred at room temperature overnight. The mixture is diluted with 100 mL of water, and then extracted with CH2Cl2 three times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is concentrated under vacuum. The residue is purified by silica gel chromatography to give product as pale yellow solids. MS (ESI) m/z 342.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[CH:36]=[C:37]([CH3:39])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][CH:51]1[CH2:56][NH:55][CH2:54][CH:53]([CH3:57])[NH:52]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[CH:36]=[C:37]([CH3:39])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC1CNCC(C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(C)cc(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(C)cc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-5-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added 2,6-dimethylpiperazine (predominantly cis) (26 mg, 0.23 mmol), and AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was purified using a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 90% CH3CN in water at a flowrate of 20 mL/min. Fractions containing product were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}-5-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide as a white solid (50 mg, 43%). LC-MS m/z 757 (M+H)+.
Reaction SMILES: Cl[CH:2]([C:4]1[NH:5][C:6](=[O:14])[C:7]2[CH2:13][O:12][CH2:11][CH2:10][C:8]=2[N:9]=1)[CH3:3].[CH3:15][NH2:16].O>CO>[CH3:15][NH:16][CH:2]([C:4]1[NH:5][C:6](=[O:14])[C:7]2[CH2:13][O:12][CH2:11][CH2:10][C:8]=2[N:9]=1)[CH3:3]
Reactant: CN
Reactant: CC(Cl)c1nc2c(c(=O)[nH]1)COCC2
Solvent: CO
Solvent: O
Product: CNC(C)c1nc2c(c(=O)[nH]1)COCC2
Temperature: 110 °C

Procedure:
To a solution of 2-(1-chloroethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (270 mg, 1.3 mmol) in methanol (1 mL) was added methylamine in water (1.1 mL, 13 mmol, 40%). The mixture was heated via microwave at 110° C. for 10 min., concentrated in vacuo and purified via reverse phase chromatography (Acetonitrile:water) to provide the title compound (260 mg). MS m/z 210.3 (M+1), retention time=0.54 min.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][C:5]1([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1.O>C1COCC1>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][C:5]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:14][NH2:15])=[CH:16][CH:17]=2)[O:9][CH2:8][CH2:7][O:6]1
Reactant: CC(C)(C)CCC1(c2ccc(C#N)cc2)OCCO1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CCC1(c2ccc(CN)cc2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Dissolve 4-[2-(3,3-dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzonitrile (271 mg, 1.046 mmol) in anhydrous THF (10 mL). Add under nitrogen 1M lithium aluminum hydride in THF (2.1 mL, 2.1 mmol) at 0° C. and stir the mixture at room temperature for 2 h. Cool to 0° C., add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the desired intermediate as an oil (0.263 mg) that was used without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]([OH:17])=O)[CH2:13][CH:12]2[CH:10]([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]1([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1>O>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C:20]2([NH:19][C:15]([CH:14]3[CH2:13][CH:12]4[CH:10]([CH2:11]4)[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CC2CC2CC1C(=O)O
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 94.5 %

Procedure:
The title compound (D69) (270 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptane-4-carboxylic acid (D17) (200 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (157 mg). HOBT.H2O: 1.2 eq; Reaction time: 3 hrs.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH2:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28](=[O:40])[CH2:29][N:30]1[C:35](=[O:36])[C:34](Cl)=[N:33][C:32]([Cl:38])=[C:31]1[CH3:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:7]([CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][CH2:17][NH:18][C:34]1[C:35](=[O:36])[N:30]([CH2:29][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:40])[C:31]([CH3:39])=[C:32]([Cl:38])[N:33]=1)[CH3:8])=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CN(Cc1cccc(CCN)c1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 74.8 %

Procedure:
tert-Butyl-N-[3-(2-aminoethyl)benzyl]-N-methylcarbamate (preparation 15) (0.5 g, 1.89 mmol), benzyl-2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (0.6 g, 1.83 mmol) and triethylamine (0.5 ml, 3.66 mmol) in ethyl acetate (30 ml) were stirred at reflux for 24 hr. The resultant mixture was diluted with ethyl acetate (20 ml) and washed with water, sat aq brine, dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a red oil which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 99:1 CH2Cl2:MeOH; 98:2 CH2Cl2:MeOH) to give the desired product (0.76 g, 75%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.20 (s, 3H), 2.80 (s, br, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 4.20 (s, br, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10 (m, 3H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z=555.3 (M+1)+. Found C, 62.50, H, 6.34, N, 9.98%; C29H35N4O5Cl requires C, 62.75, H, 6.36, N, 10.09%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:13]3[N:14]([CH3:18])[C:15](=O)[NH:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:15]1[N:14]([CH3:18])[C:13]2[C:8]([N:3]3[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]3[CH3:7])=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=1
Reactant: Cc1ccc(C)n1-c1cccc2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C)n1-c1cccc2nc(Cl)n(C)c12
Temperature: 85 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of 239 mg (0.991 mmol) of 7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 2 mL of phosphorus oxychloride was stirred at 85° C. for 4 hours. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was diluted with ice and neutralized by aqueous sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2). The combined organic layer was washed with water (X1) and brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-20% ethylacetate/n-hexane gradient mixture to give 185 mg (72%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)([CH3:11])[CH2:9][OH:10])[C:5](O)=[C:4]([CH3:22])[C:3]=1[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]([CH3:22])[C:5]2[O:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)([CH3:11])[C:6]=2[CH:7]=1
Reactant: Cc1c(Br)cc(C(C)(CO)c2ccc(C(C)C)cc2)c(O)c1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(Br)cc2c(c1C)OCC2(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-2,3-dimethylphenol obtained in Reference Example 22 (830 mg, 2.21 mmol) and triphenylphosphine (638 mg, 2.43 mmol) in THF (60 mL) was added diethylazodicarboxylate (a 40% toluene solution, 1.06 g, 2.43 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain oily 5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran 660 mg. To a solution of said compound (660 mg, 1.84 mmol) and benzylamine (0.24 mL, 2.21 mmol) in toluene (10 mL) were added palladium acetate (4 mg, 0.02 mmol) and BINAP (34 mg, 0.6 mmol) at room temperature, and the mixture was stirred under argon stream for 15 minutes. Sodium tert-butoxide (248 mg, 2.58 mmol) was added to the reaction solution at room temperature, and the mixture was heated under argon stream for 18 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, the organic layer was washed with water and a saturated brine and then was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1), to obtain 660 mg (yield 77%) of the title compound as an oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:26][C:27]([CH2:29]Br)=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][CH:16]3[CH2:21][CH2:20][C:19]4[O:22][CH2:26][C:27](=[O:28])[CH2:29][C:18]=4[O:23][CH2:17]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)CBr
Reactant: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(CC1CCC2=C(CC(=O)CO2)OC1)N1CC(c2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
One equivalent of 5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727 Example 1, is treated with one equivalent of 1,3-dibromoacetone and excess potassium carbonate in acetonitrile. The mixture is stirred at room temperature for 18 hours, filtered and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,5-dioxabenzocycloheptan-3-one. One equivalent of this ketone is reduced, at room temperature for one hour, with excess sodium borohydride in methyl alcohol. The reaction mixture is poured into water, made acidic with 1N hydrochloric acid and extracted with methylene chloride. The organic extracts are dried and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-1,5-dioxabenzocycloheptan-3-ol. Hydrolysis with 2.5N sodium hydroxide gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(C2(C(F)(F)F)CCN(C3C=CC(C(Cl)=[O:45])=C([N+]([O-])=O)C=3)C2)C=C(Cl)C=1.FC(F)(F)C1C=C(C2(C(F)(F)F)CCN(C3C=CC(C(Cl)=O)=C([N+]([O-])=O)C=3)C2)C=C(C(F)(F)F)C=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:23]([F:25])([F:26])[F:24])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:19])=[O:45])=[CH:21][CH:22]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(Cl)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: O=C(Cl)c1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Product: O=C(O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1

Procedure:
Representative compounds of the formula (V) and formula (V-a), respectively, include: 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]benzoyl chloride; 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoyl chloride; 4-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-nitrobenzoyl chloride and the like.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:32]1([NH:37][C:38]([NH2:40])=[NH:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:40]=[C:38]([NH:37][CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[N:39]=4)=[C:9]3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(N)NC1CCCC1
Reactant: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2C(=O)C=CN(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (1.05 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) was added N-cyclopentyl guanidine hydrochloride (1.27 g, 7.79 mmol; Prepared by modification of a procedure from Bannard, R. A. B. et al., Can. J. Chem. 1958, 36,1541–1549), followed by potassium carbonate (0.54 g, 3.89 mmol). The resulting solution was heated at reflux for 15 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (4:6 ethyl acetate:hexane) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine (1.06 g, 87%) as a yellow solid. 1H NMR (CDCl3): δ 8.15 (d, 1H), 7.91 (d, 1H), 7.51 (d, 2H), 7.41 (d, 1H), 6.94 (d, 2H), 6.26 (d, 1H), 6.22 (dd, 1H). 5.11 (d, 1H), 4.42 (m, 1H), 4.09 (d, 1H), 3.88 (m, 1H), 3.85 (s, 3H), 2.10–2.01 (m, 4H), 1.76–1.52 (m, 12H); MS m/z 469 (M+1).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][CH:6]1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:3])[CH3:2].[C:28](Cl)(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:16]([N:15]([CH:6]1[O:7][C@H:8]([CH2:13][OH:14])[C@@H:9]([OH:12])[C@H:10]([OH:11])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])[C:28](=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O

Procedure:
3 g of N-(2-acetamido-2-deoxy-D-glucopyranosyl)-dodecylamine, the preparation of which is described in Example 55, were reacted with stearoyl chloride as described in Example 55.