Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.CS(C)=O>O>[CH3:19][N:18]1[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=[C:14]1[C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13]
Reactant: Cn1c(C(=O)N2CC(c3nccnc3Cl)C2)nc2ccccc21
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(C(=O)N2CC(c3nccnc3N3CCCCC3)C2)nc2ccccc21
Temperature: 120 °C
Yield: 63.3 %

Procedure:
To a mixture of [3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone (0.10 g, 0.30 mmol), piperidine (0.052 g, 0.60 mmol) and triethylamine (0.091 g, 0.90 mmol) was added DMSO (4 mL). The solution was heated to 120° C. for 5 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give (1-methyl-1H-benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone (0.072 g, 0.19 mmol, 63% yield) as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C[Si]([N:13]=[C:14]=[O:15])(C)C>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:14]([NH2:13])=[O:15])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)N=C=O
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(N)=O)CC1

Procedure:
(1-methyl-piperidin-4-yl)-urea was prepared from 1-methyl-piperidin-4-ylamine and trimethylsilylisocyanate, in analogy to Example 5.0; 1H-NMR (300 MHz, d6-DMSO) 5.86 (1H, d), 5.32 (2H, s), 3.21-3.38 (1H, m), 2.58-2.67 (2H, m), 2.11 (3H, s), 1.88-1.98 (2H, m), 1.65-1.72 (2H, m), 1.22-1.35 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[N:24]([CH3:23])[CH:25]=[CH:26]5)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ccc2cc(-c3cnc(N)c(-c4nnc(C5CC5)o4)c3)ccc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (500 mg, 1.77 mmol) in dioxane (15.0 mL) and water (5.0 mL) were added K2CO3 (730 mg, 5.31 mmol) and N-methylindole-5-boronic acid (140 mg, 1.95 mmol) in a sealed tube. The reaction mixture was degassed with argon for 20 min, then Pd(PPh3)4 (100 mg, 0.088 mmol) was added and stirred for 18 h at 100° C. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude title compound. Crude product was purified by column chromatography using 100-200 mesh silica gel and compound was eluted with 40% ethyl acetate in petroleum ether to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([OH:22])[CH2:19][C:20]#C>>[F:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([C:20]#[C:19][CH2:18][OH:22])=[CH:3][C:4]=2[O:16][CH3:17])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(Br)ccc1Oc1cccc(F)n1
Reactant: C#CCCO
Product: COc1cc(C#CCO)ccc1Oc1cccc(F)n1

Procedure:
According to the procedure of example 11(a) except substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by 2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine (0.98 mmol; 300 mg) and 3-butyn-1-ol by propargylic alcohol (2.50 mmol; 150 μL), the title compound was obtained as a yellow solid (71%, 191 mg) after purification on silica gel (cyclohexane/ethyl acetate gradient).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([CH2:14][CH3:15])[CH2:12][CH2:11][NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1.[CH3:27]C1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Br:24][C:22]1[N:23]=[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:9](=[O:16])[NH:10][CH2:11][CH2:12][N:13]3[CH2:14][CH3:15])=[CH:6][CH:7]=2)[C:19](=[O:26])[N:20]([CH2:25][CH3:27])[CH:21]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CCN1CCNC(=O)C1c1ccc(N)cc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(CC)c2=O)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 33 (450 mg, 2.05 mmol), isopropanol (5 mL), 13 (603 mg, 2.26 mmol) and DL-10-camphorsulfonic acid (813 mg, 3.50 mmol), and the reaction mixture was then stirred at reflux for 16 h. After this time, the reaction mixture was cooled to room temperature, filtered and the filter cake washed with isopropanol (10 mL). The resulting solid was dissolved in methylene chloride/methanol (3:1), absorbed onto silica gel and purified by flash chromatography to afford 34 in 79% yield (654 mg) as an orange solid: mp 152-153° C.; 1H NMR (500 MHz, CDCl3) 8.28 (bs, 1H 7.73 (d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 6.74 (s, 1H), 5.90 (d, 1H, J=3.5 Hz), 4.12 (s, 1H), 3.60 (m, 1H), 3.52 (s, 3H), 3.36 (m, 1H), 3.12 (m, 1H), 2.60 (m, 2H), 2.28 (m, 1H), 1.00 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 406.0 (M+H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[C:8]([CH3:19])=[N:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)=[O:6]>CO.O>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[O:10][N:9]=[C:8]([CH3:19])[C:7]=2[C:5]([OH:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide (2 g, 47.7 mmol) was added to a solution of 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (7 g, 23.6 mmol) in MeOH (50 mL) and H2O (10 mL), and the reaction was stirred at 60° C. for 1 hour. Acidic work-up the title compound.
Reaction SMILES: NC1C=C(OC)C=CC=1[C:4](O)=[O:5].[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=[O:23].[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=[O:23].[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]([C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[NH:13][C:4]([NH:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)=[O:5])=[O:23]
Reactant: Nc1nccs1
Reactant: COc1ccc(C(=O)O)c(N)c1
Agent: COc1ccc(C(=O)c2ccccc2OC)c(N)c1
Product: COc1ccc(C(=O)c2ccccc2OC)c(NC(=O)Nc2nccs2)c1
Yield: 68 %

Procedure:
(2-Amino-4-methoxy-phenyl)-(2-methoxy-phenyl)-methanone (720 mg, 28%) was prepared from 2-amino-4-methoxy-benzoic acid (1.67 g, 0.1 mol) following the general procedure S. N-[2-(2-Methoxy-benzoyl)-5-methoxy-phenyl]-N′-(thiazol-2-yl)urea (131 mg, 68%) was prepared from (2-amino-4-methoxy-phenyl)-(2-methoxy-phenyl)-methanone (129 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[OH-:12].[K+].Cl>O>[Cl:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c(Cl)nc2[nH]ccc12

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 2.13 mmol) in a 2M aqueous potassium hydroxide solution (12 mL) was heated to 100° C. for 4 h. At this time, the resulting mixture was poured onto iced water and then acidified to pH 6.5 with a 6M aqueous hydrochloric acid solution. The acidic solution was extracted with ethyl acetate. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was triturated with acetonitrile and ether to afford 2-chloro-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one. 1HNMR (400 MHz, DMSO-d6) δ ppm 6.40-6.48 (m, 1H) 7.01-7.10 (m, 1H) 12.0 (s, 1H) 12.8 (s, 1H).
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[C:5]([SiH2:9][O:10][C:11]([CH3:23])([CH3:22])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH2:21])[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[C:5]([SiH2:9][O:10][C:11]([CH3:23])([CH3:22])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:21][C:1](=[O:2])[CH3:3])[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCN)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
AcCl (0.063 mL, 0.88 mmol) was added to a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethylamine (252 mg, 0.840 mmol) and DIPEA (0.575 mL, 3.36 mmol) in CH2Cl2 (8.4 mL). The mixture was stirred at rt for 30 min, and aq. sat. NH4Cl was added. The layers were separated, and the org. layer was washed with aq. 1M NaOH, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (190 mg, 66%). LC-MS: tR=1.09 min; ES+: 342.19.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:20]O)[CH:8]=2)[NH:3]1.[Se](=O)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:8]=2)[NH:3]1
Reactant: O=C1Nc2ccc(-c3cccc(C=NO)c3)cc2C12CCCCC2
Agent: O=[Se]=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)c1
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A solution of 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde oxime (0.48 g, 1.49 mmol) in chloroform (10 cm3) was treated with selenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16 h, the mixture was concentrated and the residue purified by column chromatography (SiO2,EtOAc: hexane 1:4) and the product re-crystallized from EtOAc-hexane to afford the title compound (0.161 g, 0.53 mmol, 35%) as a white solid: mp. 190-191° C.; 1H NMR (CDCl3) δ 1.59-1.87 (m, 6H), 1.88-2.09 (m, 4H), 7.03 (d, 1H, J=8 Hz), 7.42 (dd, 1H, J=8, 2 Hz), 7.54 (t, 1H, J=8 Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, J=7,2 Hz), 7.83 (m, 1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O:30][C:31](=O)[C:32]([F:35])([F:34])[F:33])C>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH:15][C:31](=[O:30])[C:32]([F:35])([F:34])[F:33])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 130 h

Procedure:
112.5 g (0.41 mmol) of O-benzyltyrosine is suspended in 1 liter of dry methanol and combined at room temperature with 58.9 ml (0.42 mol) of triethylamine. After adding 67 ml (0.53 mol) of trifluoroacetic acid ethyl ester, the mixture is stirred at room temperature for 130 hours under exclusion of moisture. The mixture is separated from unreacted starting material and volatile components are removed by shaking with ethyl acetate/aqueous hydrochloric acid. The ethyl acetate phase is decolorized with activated carbon. Evaporation of the solvents yields 120.7 g (80% of theory) of colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.NCC1CN(C(O[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=O)CC=1.C(=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>CO>[CH2:29]([NH:1][CH2:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCC1=CCN(C(=O)OCc2ccccc2)C1
Reactant: NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=Cc1ccccc1
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@H](CNCc2ccccc2)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture (310 mg) of (3S,4R)-3-aminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine and 3-aminomethyl-1-benzyloxycarbonyl-3-pyrroline was dissolved in methanol (4 mL). To this solution, molecular sieves 4A (130 mg) and benzaldehyde (0.13 mL) were sequentially added and the mixture was stirred at room temperature for 1 hour. Subsequently, a borane-pyridine complex (0.19 mL) was added and the mixture was further stirred at room temperature for 4 hours. This was followed by addition of 6 mol/L hydrochloric acid (2 mL) and stirring at room temperature for 1 hour. Subsequently, a 30% aqueous solution of sodium hydroxide was added to make the mixture basic and the mixture was extracted with diethyl ether (3×10 mL). The diethyl ether extracts were combined and the combined diethyl ether layer was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=dichloromethane: methanol=10:1) to give 177 mg of (3S,4R)-3-benzylaminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][S:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 72 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and (2-chlorophenyl)methanesulfonyl chloride, the title compound (yield 72%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCO
Yield: 94 %

Procedure:
Prepared from 4-[(3-Chloro-4-fluorophenyl)amino]-7-{3-[(tert-butyl-dimethylsilyl)oxy]propyloxy}-6-nitroquinazoline by splitting off the protective silyl group with tetrabutyl ammonium fluoride in tetrahydrofuran. Yield: 94% of theory; Rf value: 0.61 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); mass spectrum (ESI−): m/z=391, 393 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(O)(=O)C.C([O-])(=O)C.[Na+].[Br:42]Br>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[C:32]([Br:42])=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cc2c(cc1Br)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) in THF (6 ml) were added acetic acid (3 ml) and sodium acetate (100 mg) at room temperature, and bromine (0.04 ml) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr., sodium acetate (100 mg) was added, and bromine (0.04 ml) was added dropwise at room temperature. The reaction mixture was further stirred at room temperature for 1 hr., and bromine (0.04 ml) was added dropwise. The mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue and crystals were collected by filtration. The crystals were further washed with ethyl acetate to give the title compound (250 mg).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][C:5]#[C:6]/[CH:7]=[CH:8]\[CH2:9][CH3:10].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].CN(C)C(=O)C>[I-].[Na+].O>[C:12]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6]/[CH:7]=[CH:8]\[CH2:9][CH3:10])(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: CC/C=C\C#CCCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC/C=C\C#CCCCCOC(C)=O
Temperature: 122.5 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed Z-7-decen-5-yn-yl chloride (170.7 g: 1.0 mol), sodium acetate (98.4 g: 1.2 mol), sodium iodide (8.9 g: 0.06 mol) and N,N-dimethylacetamide (113.2 g), and stirred at from 120 to 125° C. for 6 hours. After the completion of the reaction was confirmed by gas chromatography, water (350.0 g) was added to the reaction mixture. The organic phase separated from the aqueous phase was washed with an aqueous 1.0% by weight sodium bicarbonate solution (250.0 g). The organic phase was subjected to removal of solvent under reduced pressure, followed by dehydration. The residue was then distilled under reduced pressure to obtain Z-7-decen-5-yn-yl acetate [bp: from 75 to 79° C./0.13 KPa, 181.4 g, 0.93 mol]. [Yield: 93.4%]
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[C:6]([NH:19][C@H:20]([C:22]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26](=[O:34])[C:25]3=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]3[N:23]=2)[CH3:21])[N:5]=[CH:4][N:3]=1.[OH-].[Li+]>O1CCCC1.O>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=2)[C:11]([OH:13])=[O:12])=[C:6]([NH:19][C@H:20]([C:22]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26](=[O:34])[C:25]3=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]3[N:23]=2)[CH3:21])[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc(O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(C(=O)O)c3)n(-c3ccccc3)c(=O)c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
(S)-Methyl 3-(4-amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-hydroxybenzoate (35 mg, 0.07 mmol) was dissolved in 5 mL tetrahydrofuran. Lithium hydroxide in 5 mL water was added and the mixture was stirred at 50° C. for 4 h. The solvent was evaporated and the residue was re-dissolved in dichloromethane. The aqueous phase was acidified with 2N hydrochloric acid. The aqueous was further extracted with dichloromethane and was washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1 ® Purification System to obtain 25 mg (72% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([OH:9])=O)[C:2]=1[C:10]([OH:12])=[O:11].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:13]([NH:25][C:7]([C:3]1[C:2]([C:10]([OH:12])=[O:11])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)c1nccnc1C(=O)O
Reactant: CCCCCCCCCCCCN
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCNC(=O)c1nccnc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Pyrazine-2,3-dicarboxylic acid (624 mg, 4.0 mmol), 1-dodecylamine (740 mg, 4.0 mmol), benzotriazole-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (2.6 g, 4.8 mmol) and 4-dimethylaminopyridine (488 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature overnight. The reaction mixture was poured into water, then extracted three times with ethyl acetate. The isolated organic phase was dried with anhydrous Na2SO4. The solvent was removed by vaporizing under reduced pressure. The residue was purified by silica column chromatography (developing agent: dichloromethane/methanol=30/1) to produce 3-(dodecylcarbamoyl)pyrazine-2-carboxylic acid (650 mg).