Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[N+:1]([C:4]1[CH:8]=[N:7][N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c[nH]nn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of 4-nitro-1H-triazole (5.00 g, 43.84 mmol) in THF (230 mL), cooled to 0° C., was added sodium hydride (2.28 g, 56.99 mmol) portionwise over 30 min. The mixture was stirred for a further 30 min and then 2-(chloromethoxy)ethyl-trimethyl-silane (7.67 g, 8.15 mL, 46.03 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 2 h, then re-cooled to 0° C. and quenched with water. The mixture was extracted with EtOAc and the organics washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with 5% EtOAc in hexanes to afford 4-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (6.18 g, 56%) and 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole as an off white solid (3.52 g, 33%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:47]2[C:48]([C:53]#[N:54])=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:46])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]3([OH:45])[CH2:44][CH2:43][CH2:42]3)[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[NH:3][C:4](=[O:7])[O:5][N:54]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:46])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]3([OH:45])[CH2:44][CH2:43][CH2:42]3)[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC3(O)CCC3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC3(O)CCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogen carbonate (0.55 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.19 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.064 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.054 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 60%).
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(CC)CC>CS(C)=O.II>[F:1][C:2]1[C:3]([NH2:4])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Reactant: NCc1ccc(F)cc1
Agent: II
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1F
Temperature: 120 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
To a stirred suspension of compound 2 (0.100 g, 0.570 mmol, 1.00 equiv) in dry DMSO (4.6 mL) were added 4-fluorobenzylamine (0.210 g, 1.72 mmol, 3.00 equiv) followed by Et3N (69.6 mg, 0.690 mmol, 1.20 equiv) and I2 (catalytic, 1.00 mg). The reaction mixture was heated to 120° C. and stirred at 120° C. for 24 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 2:23) to afford compound 3 (0.100 g, 62.5%) as yellow solid. TLC: 20% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J=1.60, 9.60 Hz, 1H), 7.31-7.28 (m, 2H), 7.08-7.03 (m, 2H), 6.11-6.03 (m, 3H, 2Exc), 4.82 (br s, 1H, Exc), 4.44 (d, J=5.2 Hz, 2H); LC-MS: m/z=278 (M+-1) at RT 3.64 (91.7% purity)
Reaction SMILES: C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@:24]2(OC)[C@H:29]([OH:30])[C@@H:28]([OH:31])[C@H:27]([OH:32])[C@@H:26]([CH2:33][OH:34])[O:25]2)=[CH:20][C:19]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=1>ClCCl.C(#N)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[C@H:29]([OH:30])[C@@H:28]([OH:31])[C@H:27]([OH:32])[C@@H:26]([CH2:33][OH:34])[O:25]2)=[CH:20][C:19]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][CH3:46])=[CH:42][CH:43]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: -22.5 °C
Reaction time: 0.33 h

Procedure:
To a 100 mL 3-neck flask equipped with magnetic stirrer and under argon atmosphere was added dichloromethane (7.0 mL), acetonitrile (7.0 mL) and triethylsilane (5.09 mL, 31.9 mmol) successively at room temperature. The above mixture was cooled to −20 to −25° C. and BF3.Et2O (3.03 mL, 23.9 mmol) was added in one portion. Another 100 mL flask was charged with crude (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (3.5 g, 7.97 mmol), dichloromethane (7.0 mL) and acetonitrile (7.0 mL), and the resulting mixture was shaking for 20 min at ambient temperature until a clear solution was obtained. Under an atmosphere of nitrogen, the (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution in dichloromethane and acetonitrile was transferred to an addition funnel and was slowly added to the solution of BF3-Et2O and triethylsilane over a period of 1 h while keeping the internal temperature between −15 to −20° C. After the addition was completed, the mixture was stirred at a temperature between −15 to −20° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]([Cl:24])=[O:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (E22, 19 mg), thionyl chloride (2 mL) was added at room temperature, and the mixture was stirred for 2 hours under reflux by heating. The reaction mixture was cooled to room temperature, and then toluene was added to the mixture. The solvent was evaporated under reduced pressure to obtain 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carbonyl chloride (E23) as white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([CH:14]2[O:18][N:17]=[C:16]([CH3:19])[CH2:15]2)=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].O.Cl.[CH3:26]O>O1CCCC1>[CH3:26][C:11]1[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:13]([CH:14]2[O:18][N:17]=[C:16]([CH3:19])[CH2:15]2)[C:4]([Cl:3])=[C:5]([CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2CC(C)=NO2)c1Cl
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1=NOC(c2c(Cl)c(C(=O)O)cc(C)c2S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
69.4 g (174 mmol) of 10% strength sodium hydroxide solution were added to a solution of 38.4 g (116 mmol) of methyl 2-chloro-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoate in 400 ml of methanol and 400 ml of tetrahydrofuran. The mixture was stirred for 12 hours at room temperature, the solvent volume was reduced to half, and the mixture was poured into 1 1 of water. The pH was brought to 1 using 10% strength hydrochloric acid, and the precipitate which formed was filtered off with suction.
Reaction SMILES: C[O-].[CH3:3][O:4][C:5](=O)[CH:6]=[O:7].[CH:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)(=O)C>CO>[CH3:3][O:4][CH:5]1[NH:18][C:16](=[O:17])[N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]1=[O:7]
Reactant: COC(=O)C=O
Reactant: NC(=O)NC1CCCCC1
Agent: C[O-]
Solvent: CO
Solvent: CC(=O)O
Product: COC1NC(=O)N(C2CCCCC2)C1=O
Yield: 31.4 %

Procedure:
750 mg of glyoxylic acid methyl ester methyl alcoholate and 920 mg of N-cyclohexylurea were refluxed in 50 ml of a mixture of acetic acid and methanol (4:1) for 1 hour. After cooling, the solvent was removed by distillation and the residue was purified by column chromatography on silica gel. The obtained crude product was recrystallized from benzene to give 420 mg of 5-methoxy-3-cyclohexylhydantoin (compound 20) in the form of colorless needle crystals.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH2:21][CH:20]([CH3:22])[CH2:19][C:18]1=[O:23])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH2:21][CH:20]([CH3:22])[CH2:19][C:18]1=[O:23]
Reactant: [H][H]
Reactant: CC1CC(=O)N([C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC1CC(=O)N([C@@H]2CCCC[C@H]2N)C1

Procedure:
To a solution of trans-[2-(4-methyl-2-oxo-pyrrolidin-1-yl)-cydohexyl]-carbamic acid benzyl ester (34 mg) in absolute ethanol (4.0 ml) was added 10% Pd on charcoal (5 mg). A hydrogen atmosphere was introduced by repeated evacuation/gas introduction. The suspension was vigorously stirred over night. The catalyst was removed by filtration through dicalite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH/NH3 93/7/0.5) to give the product as a 1:1 mixture of epimers as a colorless liquid (15 mg). MS (ESI): 197.3 (M+H+).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:24])([F:23])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>C1COCC1>[F:24][C:13]([F:12])([F:23])[C:14]1([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:8][O:15]1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(C2(C(F)(F)F)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>CO.O>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][NH:14][CH2:13][CH2:12][NH2:15]
Reactant: COc1ccc(C2CO2)cc1
Reactant: NCCN
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)CNCCN)cc1

Procedure:
N-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-ethylenediamine is prepared by reacting 2-(4-methoxyphenyl)oxirane (37.5 g.) dissolved in methanol (52 cc.) with ethylenediamine (30 cc.) dissolved in a mixture of methanol (52 cc.) and water (20 cc.). On distillation under reduced pressure, a product (22.3 g.), b.p. 165°-169° C./0.2 mm.Hg, is obtained, which crystallises on cooling and melts at 68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[NH:9][C:8](=[O:15])[CH2:7][CH2:6]2.[CH3:16][C:17](C)([O-])C.[K+].C(I)C>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:16]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH:13]=[O:14])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:15])[CH3:17]
Reactant: CC(C)(C)[O-]
Reactant: COc1cc2c(cc1C=O)NC(=O)CC2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1C(=O)CCc2cc(OC)c(C=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde (preparation 3) 60 mg (0.293 mmol) was dissolved in 5 ml of anhydrous THF and the solution was cooled to 0° C. The reaction mixture was treated with 33 mg (0.293 mmol) of potassium t-butoxide whereupon it became yellow in color. After stirring for 30 minutes, the mixture was treated with 23 μl (0.293 mmol) ethyl iodide and slowly warmed to room temperature while stirring for 16 hours (h). The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to an oil. The residue was chromatographed on silica gel eluting with 6/4 ethyl acetate/hexane to afford 34 mg (40%) as a white solid. MS APCI m/e 234 (p+1)
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].BrC[C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1.[CH3:36]N(C=O)C>>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:36][C:34]3[CH:29]=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: Oc1cccc(CBr)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 11 (0.5 g) in DMF (10 mL) was added 60% sodium hydride in mineral oil (0.1 g) and the mixture stirred at room temperature for 1 hour. To this mixture was then added 3-(bromomethyl)phenol (0.4 g) and the mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness and the residue purified (SiO2 chromatography 9:1 dichloromethane:methanol) to give the sub-title compound (0.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[C:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:5]2.ClS([N:23]=[C:24]=O)(=O)=O.CN(C=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[C:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[C:5]2[C:24]#[N:23]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cccnc2)cc2cc(Cl)cc(F)c21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(-c2cccnc2)c(C#N)c2cc(Cl)cc(F)c21
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole (130 mg, 0.50 mmol) in dichloromethane (10 mL) at ambient temperature is added chlorosulfonyl isocyanate (282 mg, 2.0 mmol) and the mixture is stirred for 11 h, whereupon anhydrous DMF (1 mL) is added. After 1 h, the mixture is concentrated and the residue is purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (d, J=1.8 Hz, 3H), 7.46 (dd, J=12.4, 1.8 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.71 (dd, J=7.5, 4.4 Hz, 1H), 8.16 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.83 (dd, J=4.9, 1.6 Hz, 1H), 8.89 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 286.0558 [(M+H)+ Calcd for C15H10ClFN3: 286.0547].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([OH:27])[CH:26]=1.[C:31]([O:36][CH3:37])(=[O:35])[C@H:32]([CH3:34])O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([CH:26]=1)[O:27][C@H:32]([CH3:34])[C:31]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)[C@H](C)O
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Oc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Triphenylphosphine (624.0 mg, 2.38 mmol) was added at room temperature to a solution of 5-bromo-2-nitrophenol A-15 (400.0 mg, 1.83 mmol) and methyl(−)—(S)-lactate (0.149 mL, 1.56 mmol) in anhydrous methylene chloride (18.3 mL) under an atmosphere of argon. After 10 mins of stirring, the reaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate (0.360 mL, 1.83 mmol) was added dropwise. The orange solution was warmed to room temperature, stirred for 12 h, then concentrated to ca. 1.0 mL, diluted with pentane (7 mL) and diethyl ether (8 mL), filtered and rinsed with diethyl ether-pentane (15 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give (R)-methyl 2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-16 as a yellow solid (525.0 mg; Yield=94%). MS (ESI) [M+1]+ 304, 306.
Reaction SMILES: [NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1.[CH:38](=O)[CH3:39].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:38][CH3:39])[CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc3ccccc3c2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc2ccccc2c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(2-naphthylmethylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.50 g) as starting compound, acetaldehyde (0.18 ml) and sodium cyanoborohydride (0.40 g) were reacted and treated in the same manner as in Example 136 to give 1.1 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(2-naphthylmethyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:32]4[C:27](=[CH:28][C:29]([NH:36][CH2:37][CH3:38])=[C:30]([N+:33]([O-])=O)[CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].O>C(O)C.[C].[Pd]>[CH2:37]([N:36]1[C:29]2[C:30](=[CH:31][C:32]3[C:23]([N:20]4[CH2:21][CH2:22][N:17]([C:15]([NH:14][C:11]5[CH:12]=[CH:13][C:8]([O:1][C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)=[CH:9][CH:10]=5)=[O:16])[CH2:18][CH2:19]4)=[N:24][CH:25]=[N:26][C:27]=3[CH:28]=2)[NH:33][C:41]1=[O:42])[CH3:38]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: [H][H]
Reactant: CCNc1cc2ncnc(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)c2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCn1c(=O)[nH]c2cc3c(N4CCN(C(=O)Nc5ccc(Oc6ccccc6)cc5)CC4)ncnc3cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To a solution of 197.5 mg (0.38 mmol) of N-(4-phenoxyphenyl)-4-(7-ethylamino-6-nitro-4-quinazolinyl)-1-piperazinecarboxamide (Compound 109) obtained in Example 109 in 4 ml of ethanol was added 30 mg of 10% palladium-carbon, followed by stirring for 7.5 hours in a stream of hydrogen. The catalyst was separared by filtration with Celite and the solvent was evaporated. The obtained residue was dissolved in 10 ml of dimethylformamide, and 187.2 mg (1.15 mmol) of carbonyldiimidazole was added thereto, followed by stirring at 80° C. for 2 hours in an atmosphere of argon. After the reaction mixture was poured into water, the precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel column chromatography to give 65.7 mg (0.13 mmol) of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=O)[CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[F:20][C:21]1[C:22]([NH2:36])=[N:23][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:25][CH:26]=1>C(Cl)(Cl)Cl>[F:20][C:21]1[C:22]([N:36]=[C:3]([N:2]([CH3:7])[CH3:1])[CH2:4][CH3:5])=[N:23][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[N:25][CH:26]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: CCC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=Nc1nc(OCc2ccc(F)cc2)ncc1F)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of N,N-Dimethylpropionamide (0.202 g, 2.0 mmol) in CHCl3 (2 mL) was added phosphorous oxychloride (POCl3, 0.066 g, 0.43 mmol) and the mixture was agitated on an orbital shaker at room temperature for 1 h. Triethylamine (0.22 g, 2.2 mmol) and 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.40 mmol) were added, and the mixture was agitated at 50° C. for 3 h, cooled to room temperature, partitioned between chloroform and water, the phases separated, and the organics evaporated under reduced pressure. Purification by reverse phase chromatography afforded the title compound (0.042 g, 31% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.07-6.99 (m, 2H), 5.30 (s, 2H), 3.13 (s, 6H), 2.55 (q, J=7.7 Hz, 2H), 1.15 (t, J=7.7 Hz, 3H); HPLC-MS (ESI) m/z 321 (M+H)+.