Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:18]([C:23](=O)[CH2:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([C:18]1[N:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:5]2=[N:8][C:23]=1[CH2:24][CH3:25])=[O:20]
Reactant: Nc1ncc(Cl)nc1-c1ccc(Cl)cc1Cl
Reactant: CCC(=O)C(Cl)C(=O)OC
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nc(Cl)cn2c1C(=O)OC
Temperature: 170 °C

Procedure:
5-Chloro-3-(2,4-dichlorophenyl)-2-pyrazineamine (1.1 g, 4.0 mmol) and methyl 2-chloro-3-oxopentanoate (5.7 mL) were mixed, and the mixture was heated under stirring at 170° C. 3 hours. After being allowed to cool, the reaction mixture was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), and the resulting residue was washed with hexane to give the title compound (0.56 g) as pale yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N:10]([O-])=O.[Na+].O>CC(O)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:10]=[CH:9]2
Reactant: O=N[O-]
Reactant: Cc1cc(I)ccc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.8 %

Procedure:
To a solution of 4-iodo-2-methylaniline (1.09 g, 4.68 mmol) in CH3CO2H (40 mL), were added NaNO2 (0.39 g, 5.65 mmol) and water (1 mL) at 10° C. The resulting mixture was stirred at room temperature for 6 hours. Upon completion, the reaction mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜40% EtOAc in petroleum ether) affording the title compound (0.90 g). 1H NMR (DMSO-d6, 400 MHz): δ 13.23 (br, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.57 (d, 1H), 7.41 (d, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[C:10]([NH:14][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thiophene-2-sulfonyl chloride (15 g, 0.082 mol) was dissolved in CHCl3 (200 mL) under N2 atmosphere and then cooled to 0° C. tert-Butylamine (25.9 mL, 0.246 mol) dissolved in CHCl3 (50 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h at room temperature and then at reflux for 10 min. Toluene (700 mL) was added and the organic phase was washed with water (3×50 mL), dried, and concentrated in vacuo. The sub-title product was used without further purification in the next step.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]1[NH:27][C:8](=[O:10])[C:7]2[CH:6]=[C:5]([F:11])[CH:4]=[N:3][C:2]=2[N:26]=1
Reactant: N=C(N)COCCc1cc(F)ccc1F
Reactant: O=C(O)c1cc(F)cnc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cc(F)ccc2F)nc2ncc(F)cc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,5-difluoropyridine-3-carboxylic acid and 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 78.2). Light brown solid. MS: m/e=336.3 [M+H+].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].C(OC(=O)C)(=O)C.[N+:26]([O-])([OH:28])=[O:27]>C(O)(=O)C>[N+:26]([C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:18])[C:6]3([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:17][CH2:16][CH2:15][C:13]=1[C:14]=23)([O-:28])=[O:27]
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1Nc2ccc([N+](=O)[O-])c3c2C1(CCCCBr)CCC3
Temperature: 15 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A 100 mg (0.32 mmol) portion of 2a-(4-bromobutyl)-2a,3,4,5-Tetrahydrobenz [cd] indole-2 (1H) -one was dissolved in 2 ml of acetic acid, and the resulting solution was cooled to 15° C. Thereto was added acetic acid solution (1 ml) containing 46 al (0.48 mmol) of acetic anhydride and 19 μl (0.48 mmol) of nitric acid, and the mixture was stirred overnight at 15° C. The reaction solution was extracted with chloroform and washed with water and sodium bicarbonate aqueous solution in that order. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (20 cc; elution with ethyl acetate-hexane=1:2) to obtain 83 mg of the title compound (73% in yield). 1H-NMR (CDCl3): δ 1.25 (1 H, m), 1.46 (2 H, m), 1.73-2.02 (5 H, m), 2.18 (2 H, m), 3.24 (2 H, m), 3.33 (2 H, t), 6.89 (1 H, d), 8.15 (1 H, d), 9.07 (1 H, s). EI m/z 352, 354 (1:1) (M+H)+
Reaction SMILES: [H][H].Cl[C:4]1[N:5]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][N:8]=1>[Pd]>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[N:5]1[C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][N:8]=[CH:4]1
Reactant: CC1(C)OB(c2cnc(Cl)n2C2CCCCO2)OC1(C)C
Reactant: [H][H]
Agent: [Pd]
Product: CC1(C)OB(c2cncn2C2CCCCO2)OC1(C)C

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole was prepared by hydrogen with palladium reduction of 2-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C([Mg]Cl)(C)C.[C:15]1([CH:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[C:23]2=[O:32])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:33]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([OH:31])([C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=3[OH:9])[C:23]2=[O:32])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Cc1ccc(O)cc1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a stirred solution of 3,4-dimethylphenol (2.50 g, 20.5 mmol) in tetrahydrofuran (100 mL) was added isopropylmagnesium chloride (10.2 mL, 2.0 M tetrahydrofuran solution, 20.40 mmol) at 0° C. The mixture was allowed to stir for 1 h at 0° C., then the solvent was removed in vacuo. Dichloromethane (200 mL) was added, followed by the addition of 1-(diphenylmethyl)-1H-indole-2,3-dione (5.00 g, 15.95 mmol). The mixture was stirred for 54 h at ambient temperature, quenched with saturated ammonium chloride solution. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, the residue was purified by column chromatography to give 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one (5.10 g, 73%): 1H NMR (300 MHz, CDCl3) δ7.49-7.45 (m, 1H), 7.35-7.27 (m, 10H), 7.08-7.04 (m, 2H), 6.93 (s, 1H), 6.81-6.75 (m, 1H), 6.52 (s, 1H), 6.49-6.46 (m, 1H), 2.15 (s, 3H), 2.02 (s, 3H); MS (ES+) m/z 418.1 (M−17).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:15][C:16]1[CH:17]=[C:18]([NH:22][S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=1>CC(O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:4]2[O:3][C:2]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][S:23]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Solvent: CC(C)O
Product: N#Cc1ccc(-c2cnc(Nc3cccc(NS(=O)(=O)Cc4ccccc4)c3)o2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)benzonitrile 2 (0.20 g, 0.98 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 4 (0.256 g, 0.98 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, a white solid precipitated out which was filtered off, washed with 2-propanol, and dried. This was then triturated with ether and filtered to yield the title product, a white solid, as the hydrochloride salt of 5 (0.15 g, 36%). Free amine containing filtrate was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 5 (0.15 g, 36% yield) as pale yellow solid. MS (ES) m/z 431 (M+H+).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.O>[C:1]1(=[O:19])[N:5]([CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH2:22])=[O:8])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C(N)=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a stirred solution of 2-phthalimido-4-methylpentanoic acid (1.32 g, 5.0 mmol) in tetrahydrofuran (25 mL) are added carbonyldiimidazole (0.81 g, 5.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 1 hour, then 1 mL of concentrated ammonium hydroxide is added. After 10 minutes, the reaction mixture is diluted with 50 mL water. The resulting slurry is partially concentrated to remove the tetrahydrofuran and filtered. The solid is washed with water and dried in vacuo (60° C., <1mm) to afford 1.16 g (89%) of 2-phthalimido-4-methylpentanamide as a white powder: mp 173-176° C.; 1H NMR (DMSO-d6, 250 MHz) δ7,95-7.79 (m, 4H, Ar), 7.61 (br s, 1H, CONH2), 7.22 (br s, 1H, CONH2), 4.73-4.60 (m, 1H), 2.30-2.10 (m, 1H), 1.95-1.80 (m, 1H), 1.45-1.25 (m, 1H); 13C NMR (DMSO-d6) d: 170.4, 167.7, 134.4, 131.5, 123.1, 51.3, 36.4, 24.7, 23.2, 20.6. Anal. Calculated for C14H16N2O3. Theoretical: C, 64.60; H. 6.20; N, 10.76. Found: C, 64.63; H, 6.11; N, 10.70.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].O.[NH2:21]N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:21]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propen-1-yl]phenyl]methyl]-acetamide (i.e. the product of Step A) (10.0 g, 35.7 mmol) and hydrazine hydrate (2.6 mL, 53.6 mmol) in methanol (100 mL) was stirred at room temperature for 20 h. The reaction mixture was then cooled to −5° C. and filtered, resulting in the title product as a solid (2.0 g), which was used in the next step without purification.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[NH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:14][CH2:13]1.C(Cl)Cl>CCOCC>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][N:12]([NH:11][C:8]([NH:7][C:3]3[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:13][CH2:14]2)=[CH:21]1
Reactant: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc(NC(=O)NN2CCN(CCc3c[nH]c4ccccc34)CC2)c1
Reaction time: 2 h

Procedure:
3.34 G of m-tolylisocyanate are added dropwise to a stirred solution of 6.13 g of 3-[2-(4-aminopiperazin-1-yl)ethyl]indole in 100 ml. of dry methyene chloride while maintaining the reaction temperature below 35° C. After 2 hours a fine precipitate appears, 50 ml. of ether are added and stirring is continued for 3 additional hours. More ether is added and the product is filtered and washed with ether. The solid product is recrystallized from an ethanol and water mixture to give white flakes, m.p. 186°-188°C. of 1-[1-(indol-3-ylethyl)piperazin-4-yl]-3-m-tolylurea.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)C=CC=CC=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1>>[N:13]1[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:30]2[CH2:31][CH2:32][N:27]([CH2:26][C:24]3[CH:23]=[CH:22][C:21]4[O:17][CH2:18][O:19][C:20]=4[CH:25]=3)[CH2:28][CH2:29]2)=[O:16])=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: O=C(Nc1ccncc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from pyridin-4-yl-carbamic acid phenyl ester and 1-benzo[1,3]dioxol-5-ylmethyl-piperazine. 1H NMR (400 MHz, CDCl3): 8.33 (d, J=5.3 Hz, 2H), 7.35-7.34 (m, 2H), 6.79 (s, 1H), 6.68-6.67 (m, 2H), 5.89 (s, 2H), 3.48-3.45 (m, 4H), 3.39 (s, 2H), 2.43-2.40 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][CH:36]([F:45])[N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[CH:39]=[N:38][N:37]([CH:36]([F:45])[F:35])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cnn(C(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 22.7 %

Procedure:
A mixture of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (500 mg, 0.998 mmol), 1-(difluoromethyl)-1H-pyrazol-4-ylboronic acid (808 mg, 4.99 mmol), bis(triphenylphosphine)palladium chloride (70.1 mg, 0.100 mmol) in dioxane (15 mL) and 2M saturated sodium carbonate (2 mL) were heated to 100° C. in a microwave for 30 min. The solution was concentrated and was purified by preparatory HPLC eluting with water (10 mM NH4HCO3) and ACN/water (80/20 v/v, 15-30% gradient, 10 mM NH4HCO3) to give the title compound as a white solid (132 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9H), 1.52 (s, 9H), 1.55-1.56 (m, 1H), 2.46-2.47 (m, 1H), 3.57-3.59 (m, 2H), 3.81-3.84 (m, 3H), 4.61-4.62 (m, 1H), 4.78 (s, 2H), 6.61 (d, J=6.35 Hz, 1H), 7.15 (d, J=6.83 Hz, 1H), 7.97 (s, 1H), 8.54 (s, 1H), 9.24 (s, 1H). [M+H] calc'd for C26H33F3N6O6, 583. found, 583.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([NH2:30])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([N:30]=[C:41]=[O:43])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCC(F)(F)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-amine (125 mg, 0.29 mmol) (see Example 102 for preparation) and DIPEA (109 uL, 81 mg, 0.63 mmol) in THF (6 mL) was added to a solution of triphosgene (34 mg, 0.14 mmol) in THF (6 mL) at 0° C. The reaction mixture was stirred for 30 at 0° C. and 30 min at room temperature, then directly used for next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([CH2:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[CH2:27][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)COc1ccccc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)COc1ccccc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and phenoxyacetyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxyacetamide as an off white powder, m.p. 61.5° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.12 (t, J=6.0 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 1.2 Hz, 1H), 7.44(dt, J=7.5, 1.2 Hz, 1H), 7.29-7.21 (m, 3H), 6.96-6.88 (m, 3H), 6.62 (s, 2H), 4.60 (t, J=7.2 Hz, 2H), 4.42 (s, 2H), 3.16 (q, J=6.9 Hz, 2H), 1.83 (quintet, J=7.2 Hz, 2H), 1.47 (quintet, J=7.2 Hz, 2H); IR (KBr) 3311, 3180, 2937, 1664, 1618, 1583, 1527, 1493, 1480, 1396, 1244, 755 cm−1; MS (EI) m/e 389.1844 (389.1852 calcd for C22H23N5O2).
Reaction SMILES: CO.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]2=[O:28])[CH2:6][CH2:5]1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13](=[O:28])[N:12]2[CH2:11][CH2:10][N:7]2[CH2:8][CH2:9][CH:4]([NH:3][CH2:39][C:30]3[CH:31]=[CH:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:29]=3)[CH2:5][CH2:6]2)=[CH:17][CH:18]=1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4ccccc4c3)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 119.6 %

Procedure:
To 4 mL of a methanol solution containing 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide, 55 mg of 2-naphthoaldehyde and 40 μL of acetic acid were added, and stirred at room temperature for 80 min. To the reaction mixture, 52 mg of sodium cyanoborohydride was added, and stirred at the same temperature for 75 min. After the solvent was removed under reduced pressure, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=30:1], to give 0.21 g of 7-methoxy-N-methyl-1-(2-(4-((naphthalen-2-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide as a yellow foam.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH3:13][C:14]1[C@@H:31]([O:32][C:33]([C@H:35]([OH:52])[C@@H:36]([NH:43][C:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:45])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:30][C@:26]2([OH:53])[C:27]([CH3:29])([CH3:28])[C:15]=1[C@@H:16]([O:71][C:72]([CH3:74])=[O:73])[C:17]([C@@:19]1([CH3:70])[C@H:24]([C@@H:25]2[O:54][C:55]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[O:56])[C@:23]2([O:65][C:66]([CH3:68])=[O:67])[CH2:63][O:64][C@@H:22]2[CH2:21][C@@H:20]1[OH:69])=[O:18]>ClCCl>[C:72]([O:71][C@@H:16]1[C:15]2[C:27]([CH3:28])([CH3:29])[C@@:26]([OH:53])([CH2:30][C@H:31]([O:32][C:33](=[O:34])[C@H:35]([O:52][C:8]([O:10][CH2:11][Cl:12])=[O:9])[C@@H:36]([NH:43][C:44](=[O:45])[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:14]=2[CH3:13])[C@@H:25]([O:54][C:55](=[O:56])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:24]2[C@:23]3([O:65][C:66](=[O:67])[CH3:68])[CH2:63][O:64][C@@H:22]3[CH2:21][C@H:20]([O:69][C:8]([O:10][CH2:11][Cl:12])=[O:9])[C@@:19]2([CH3:70])[C:17]1=[O:18])(=[O:73])[CH3:74]
Reactant: O=C(Cl)OCCl
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1C(=O)[C@]2(C)[C@@H](OC(=O)OCCl)C[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](OC(=O)OCCl)[C@@H](NC(=O)c3ccccc3)c3ccccc3)C(C)=C1C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.9 %

Procedure:
Pyridine (0.026 g, 23.0 mmol, 2.0 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8](0.02 g, 23.0 mmol, 2.0 eq) in dry dichloromethane under an argon atmosphere at 0° C. At 0° C., a solution of paclitaxel [4114] (0.10 g, 11.7 mmol, 1.0 eq) in dry dichloromethane was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After 2 h the reaction mixture was diluted with dichloromethane (25 ml), washed with a 10% solution of NaHCO3 (15 ml), brine (10 ml), and then dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum gave a white solid, [312], (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4-(((chloromethoxy)carbonyl)oxy)-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate, (0.11 g, 90%)
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH3:14])[N:8]2[N:15]=[CH:16][CH:17]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[Br:18]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:17]1[CH:16]=[N:15][N:8]2[C:9]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]=12
Reactant: CCCCc1cc(CCCC)n2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(CCCC)n2ncc(Br)c2n1
Temperature: 0 °C
Reaction time: 0.12 h
Yield: 76.8 %

Procedure:
A solution of 7.0 g (0.03 mol) of 5,7-di-n-butylpyrazolo[1,5-a]-pyrimidine in 75 ml chloroform was treated with 5.8 g (0.035 mol) of N-bromosuccinimide at room temperature. The mixture was stirred for 5-10 minutes, then poured into ice water, made alkaline with 6N NaOH, and the organic layer separated and dried (Na2SO4). The chloroform solution was chromatographed on neutral alumina (Woelm, grade I) with chloroform as the eluant. Evaporation of the solvent and recrystallization from ligroine gave 7.15 g (72%) of the product, mp 47°-48° C.