Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([O:15][CH3:16])(=[O:14])[NH:12][NH2:13]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:13][NH:12][C:11]([O:15][CH3:16])=[O:14])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: COC(=O)NN
Reactant: CCC(=O)c1ccncc1
Solvent: CCO
Product: CCC(=NNC(=O)OC)c1ccncc1
Yield: 62.7 %

Procedure:
A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 2.70 gm (0.03 mole) of methyl carbazate and 100 ml of absolute ethanol is refluxed 6 hr. The solution is evaporated in vacuo to give a solid. The crude product is crystallized from ethyl acetate/Skellysolve B to yield 3.90 gm (63%) of the title compound having a melting point of 216.2° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([Cl:17])=[O:13])=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloroindole-2-carboxylic acid (59 mg, 0.30 mmol) was suspended in dichloromethane (10 mL). Oxalyl chloride (41 μL, 0.45 mmol) and N,N-dimethylformamide (5 μL) were added, and the reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated, and the residue was dried under high vacuum to provide the crude product which was used without additional purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Li]CCCC.[CH3:17][C:18]1([CH3:21])[CH2:20][O:19]1.CO>C1COCC1>[CH3:17][C:18]([OH:19])([CH3:21])[CH2:20][C:8]1[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:11]=[CH:10][N:9]=1
Reactant: c1cn(C2CCCCO2)cn1
Reactant: CC1(C)CO1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)Cc1nccn1C1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To the solution of 1-(tetrahydro-pyran-2-yl)-1H-imidazole (7.6 g, 50 mmol) in dry THF (500 ml) at −78° C. was added n-BuLi solution (2.5 M in hexanes, 25 mL, 60 mmol, 1.2 equiv). The reaction mixture was slowly warmed to 0° C. and stirred at 0° C. for 30 min. After it was cooled to −78° C., 2,2-dimethyloxirane (7.2 g, 100 mmol) was added and it was stirred for 1 h. The reaction mixture was warmed to r.t. slowly and stirred at r.t. overnight. MeOH was added and the reaction mixture was concentrated by a rotary evaporator. Water (30 ml) was added and it was extracted with CH2Cl2 (15 ml×3). The organic layer was dried over MgSO4, concentrated, and purified by neutral Al2O3 column chromatography (CH2Cl2: MeOH=100:1) to give 8 gm of 2-methyl-1-[1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-propan-2-ol (75%). 1H NMR (CDCl3): δ 7.04 (s, 1H), 6.95 (s, 1H), 5.13 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.82 (d, J=12.0 Hz, 2H), 2.01-1.89 (m, 4H), 1.92 (m, 1H), 1.69-1.60 (m, 3H), 1.24 (m, 6H)
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24](N)[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31])([O:4]P(OP(O)(O)=O)(O)=O)(=[O:3])[OH:2].[C@@H]1(N2C3N=CN=C(O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:34].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C(C)=CC=CC=1>[CH:27]1[NH:28][C:29]2[N:20]([C@@H:18]3[O:19][C@H:15]([CH2:14][O:13][P:1]([OH:2])([OH:4])=[O:3])[C@@H:16]([OH:31])[C@H:17]3[OH:30])[CH:21]=[N:22][C:23]=2[C:24](=[O:34])[N:26]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1C
Product: O=c1nc[nH]c2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Escherichia coli cells containing the recombinant DNA collected in Example 2 (3) were suspended (cell concentration was 100 g wet cell weight/ml) in 100 mM Tris-hydrochloride buffer (pH 8.0) containing 10 mM ATP, 10 mM inosine and 5 mM magnesium sulfate. Xylene was added to the suspension in a concentration of 10 ml/l. After thoroughly stirring, the mixture was allowed to stand at 30° C. for an hour. The reaction solution was analyzed by HPLC and an amount of 51 -IMP in the reaction solution was quantitatively determined. Almost all transformants did not produce 5'-IMP but 5'-IMP-producing bacteria were obtained in a proportion of 1 out of 50,000 samples, The thus obtained 5'-IMP-producing bacteria are transformants carrying a recombinant DNA containing inosine guanosine-kinase gene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:20]([C:18]2[N:17]([CH3:23])[N:16]=[C:15]([NH:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:19]=2)=[O:22])[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)NCC2CC2)n(C)n1
Yield: 80 %

Procedure:
As described for example 163c, 3-((3-(5-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (92 mg, 0.28 mol) was converted, using aminomethylcyclopropane instead of isopropylamine, to the title compound (85 mg, 80%) which was obtained as a white solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17](O)=[O:18])[N:10]([C:24](=[O:34])[C:25]3[C:30]([F:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=3[F:33])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:68][C:69]1[O:73][N:72]=[C:71]([NH2:74])[CH:70]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17]([NH:74][C:71]3[CH:70]=[C:69]([CH3:68])[O:73][N:72]=3)=[O:18])[N:10]([C:24](=[O:34])[C:25]3[C:30]([F:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=3[F:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)no1
Reactant: O=C(O)COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)COc2ccccc2C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)no1
Reaction time: 12 h

Procedure:
To a solution of {2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetic acid (0.031 mmol) in DMF (1 mL) is added DIEA (0.058 mmol), HATU (0.058 mmol) and 5-methyl-isoxazol-3-ylamine (0.058 mmol). The reaction mixture is stirred for 12 hours. The mixture is purified by preparative LC/MS (20-100% MeCN/H2O) to give 2-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-N-(5-methyl-isoxazol-3-yl)-acetamide: 1H NMR (400 MHz, CDCl3) δ 7.55-7.51 (m, 3H), 7.35-7.26 (m, 2H), 7.05-6.96 (m, 3H), 6.85 (d, J=8 Hz, 1H), 6.69 (t, J=7.6 Hz, 2H), 6.56 (s, 1H), 4.72 (s, 2H), 2.33 (s, 3H); LC/MS (ES+): 571.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1)[NH2:5].[Sn](Cl)Cl.O.[OH-].[Na+]>CCO>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:5])[C:6]([NH2:9])=[CH:7][CH:8]=1
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1N
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Br)ccc(N)c1N
Temperature: 70 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and the resulting solution was stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and poured into water, and 1 N aq. NaOH was added to adjust to pH>7. The resulting mixture was extracted with CH2Cl2 (2×), and the combined extracts were dried over Na2SO4. The drying agent was filtered off and solvent was removed in vacuo to give the title compound as an oil (0.34 g, 88%).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][N:8]([CH2:10][C:11]1[O:15][C:14]([CH2:16][SH:17])=[CH:13][CH:12]=1)[CH3:9].Cl[CH2:19][CH2:20][NH:21][C:22]([NH:27][CH3:28])=[CH:23][N+:24]([O-:26])=[O:25].[OH-].[K+]>O>[CH3:9][N:8]([CH2:10][C:11]1[O:15][C:14]([CH2:16][S:17][CH2:19][CH2:20][NH:21][C:22]([NH:27][CH3:28])=[CH:23][N+:24]([O-:26])=[O:25])=[CH:13][CH:12]=1)[CH3:7]
Reactant: CN(C)Cc1ccc(CS)o1
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 2.5 h
Yield: 45.7 %

Procedure:
To a stirred mixture of 5-[(dimethylamino)methyl]-2-furanmethane-thiol oxalate (1:1) (1.31 g) and N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (1.08 g) in water (20 ml) at 45° under an atmosphere of nitrogen was added a solution of potassium hydroxide (1.04 g) in water (3 ml). The solution was stirred at 45° for 2.5 hr. and at room temperature for 15 hr. The solution was then evaporated in vacuo, the residue dissolved in water and a stream of air passed into the mixture for 15 mins. The mixture was extracted with ether (2×15 ml) and the aqueous fraction evaporated in vacuo. To the residue was added tetrahydrofuran (70 ml), an excess of anhydrous sodium carbonate, and decolourising charcoal. After 1 hr the mixture was filtered, the filtrate evaporated in vacuo and the oily residue dissolved in 4-methyl-pentan-2-one (8 ml). The solid which separated was filtered and washed with 4-methylpentan-2-one to give the title compound (0.72 g), m.p. 63°-66°, which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent Specification No. 1565966.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[CH2:21]([N:24]=[C:25]=[O:26])[CH:22]=[CH2:23]>CN(C=O)C>[CH2:21]([NH:24][C:25]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:26])[CH:22]=[CH2:23]
Reactant: C=CCN=C=O
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Solvent: CN(C)C=O
Product: C=CCNC(=O)NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (50 mg, 0.16 mmol) in anhydrous DMF (1 mL) was treated with allyl isocyanate (21 mg, 0.25 mmol), shaken at room temperature for 4 h, treated with tris-(2-aminoethyl)amine polystyrene (0.20 g, 0.75 mmol), shaken at 35° C. for 16 h, treated with polystyrene methylisocyanate (0.22 g, 0.32 mmol) and DMF (2 mL) and shaken for a further 6 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound (55 mg, 86%) as a yellow solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:24]=[C:23]([F:25])[C:22](Br)=[CH:21][C:20]=1[O:27][CH3:28])[C:14]([CH3:29])=[CH:13][C:12]2=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:20]([O:27][CH3:28])=[CH:21][C:22]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)=[C:23]([F:25])[CH:24]=1)[C:14]([CH3:29])=[CH:13][C:12]2=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(Br)c(F)cc1-n1c(C)cc(=O)c2cc(SCc3ccccc3)ccc21
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: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(C)cc(=O)c2cc(SCc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a suspension of 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-methylquinolin-4(1H)-one (1.0 g, 2.06 mmol) and 3-fluorophenylboronic acid (0.462 g, 3.30 mmol) in 1,4-dioxane (7.74 mL) and water (2.58 mL) was added potassium carbonate (0.856 g, 6.19 mmol) and tetrakis(triphenylphosphine)palladium (0.239 g, 0.206 mmol). The reaction was sparged with argon and then stirred at 80° C. After 1 hour, the reaction mixture was partitioned between water and ethyl acetate, and the organic layer was concentrated. The crude product was purified by column chromatography, eluting with 10-50% (3:1 ethyl acetate/ethanol) in heptane to provide 6-(benzylthio)-1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (1.0 g, 2.0 mmol, 97% yield) as a yellow oil. m/z (ESI) 500.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH2:16][N:17]([CH:33]4[CH2:35][CH2:34]4)[C:18]([C@@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]4)=[O:19])=[CH:13][CH:14]=3)[N:9]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH2:16][N:17]([CH:33]4[CH2:34][CH2:35]4)[C:18]([C@@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:21]4)=[O:19])=[CH:13][CH:14]=3)[N:9]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCCn1nc(C2=CCCCC2)c2ccc(CN(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCO3)C3CC3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCCn1nc(C2CCCCC2)c2ccc(CN(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCO3)C3CC3)cc21
Yield: 34.9 %

Procedure:
10% Palladium-Carbon (30 mg) was added to a solution of tert-butyl(2R)-2-{[{[3-cyclohex-1-ene-1-yl-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (300 mg) in ethanol (5 ml) and the mixture was stirred under normal pressure of hydrogen atmosphere at room temperature for 5 hours. Insolble materials were filtered through Celite and the filtrate was concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=1/2) to give tert-butyl(2R)-2-{[{[3-cyclohexyl-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (105 mg) as a colorless oil.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[N:26]#[C:27][NH2:28]>O1CCOCC1>[ClH:1].[NH:2]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)[C:27]([NH2:28])=[NH:26]
Reactant: N#CN
Reactant: COC(=O)CCc1ccc(-c2nc(-c3cccc(N)c3)c[nH]2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc(-c2nc(-c3cccc(NC(=N)N)c3)c[nH]2)cc1

Procedure:
Prepared from 4-(3-amino-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazole-hydrochloride by refluxing for three hours with cyanamide in dioxane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5](C)[C:4]=1[N+:11]([O-:13])=[O:12].[C:14](=[O:17])([O-])[O-:15].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>C(OC(=O)C)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]([OH:15])=[O:17])[C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc[n+]([O-])c(C)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: COc1ccnc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxy-2-methyl-3-nitropyridine-N-oxide (mixture with the positional isomer, 10.97 g, 48.5 mmol) was stirred in acetic anhydride (100 mL) at 80° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and in methanol (100 mL), potassium carbonate (33 g, 0.243 mol) was added to the resulting residue at room temperature and stirred at that temperature for 2 hours. The solvent was evaporated off under reduced pressure, and the resulting residue was diluted with ethyl acetate, and washed with water. The resulting organic layer was dried with magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was suspended in water (100 mL), and potassium permanganate (23 g, 0.145 mol) was added thereto at room temperature. The reaction solution was stirred at 90° C. for 16 hours, then potassium permanganate (20 g, 0.126 mol) was added thereto and stirred at 90° C. for 3 hours. The reaction solution was cooled to room temperature, methanol was added thereto, and stirred at room temperature for 2 hours. The reaction liquid was filtered, concentrated, and 2 N hydrochloric acid was added to the resulting residue, and the solution was controlled to have a pH of 2. The reaction solution was stirred at 0° C. for 1 hour, then the resulting milky white solid was taken out through filtration and dried to obtain the intended compound (1.35 g, 3 steps, 14%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([C:34](O)=[O:35])=[CH:4]1)[CH3:2].ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:33])[C:5]([CH2:34][OH:35])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCn1cc(CO)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a suspension of 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (22 g, 44.9 mmol) in Tetrahydrofuran (THF) (300 mL) was added TEA (6.89 mL, 49.4 mmol) and isobutyl chloroformate (6.49 mL, 49.4 mmol). The resulting mixture was stirred at r.t. for 1 h. Then the mixture was cooled down to −78° C. and a solution of DIBAL-H (90 mL, 135 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 1.5 h, LCMS indicated completion of the reaction. The reaction was quenched with sat. NH4Cl (aq.), and subsequently warmed up to r.t. concentrated, diluted with sat. NH4Cl and extracted with dichloromethane twice. The organic phase was filtered through Celite to remove gummy precipitate, and was then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-ethyl-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (20 g, 23.55 mmol, 52.4% yield) as yellow solid, which was used in the next oxidation step without further purification. LCMS: (M+H)+: 476.3.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([N:22]2[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]3[C:31]4[C:36]([CH:37]=[CH:38][C:23]2=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:19]=[CH:20][CH:21]=1>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[CH:17]=[C:18]([N:22]2[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]3[C:31]4[C:36]([CH:37]=[CH:38][C:23]2=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:19]=[CH:20][CH:21]=1)=[O:6]
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Reactant: O=C(O)c1ccccc1I
Solvent: O=S(Cl)Cl
Product: O=C1CC(=O)N(c2cccc(NC(=O)c3ccccc3I)c2)c2ccc3ccccc3c2N1
Yield: 38.4 %

Procedure:
2-Iodobenzoic acid (50 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 53, (1), the title compound (21 mg, yield 38%) was obtained as pale brown crystals in the same manner as that of Example 1, (4). The structure was confirmed by NMR and MS.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[CH:29])[CH:27]=3)=[N:19][CH:18]=[N:17][C:9]2=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].N#N.C(Cl)[Cl:33]>C(#N)C>[C:28]([C:26]1[CH:27]=[C:22]([NH:21][C:20]2[C:8]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:7]=3[Cl:33])[N:17]=[CH:18][N:19]=2)[CH:23]=[CH:24][CH:25]=1)#[CH:29]
Reactant: ClCCl
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Agent: N#N
Solvent: CC#N
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)c(Cl)c23)c1
Reaction time: 0.5 h

Procedure:
300 mg erlotinib was dissolved in 200 mL CH2Cl2 at −78° C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material erlotinib, were mixed to form the modified erlotinib mixture compound library for drug property screening to identify components with improved properties over erlotinib. A component with m/z value corresponding to mono-chlorinated erlotinib was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 428.1370 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-chlorinated erlotinib (m/z(calc)=428.1372), molecular formula: C22H23ClN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the quinazoline ring of erlotinib (fragment at m/z 118.0649, calc: 118.0651 for C8H8N+ indicates the 3-ethynylphenyl ring is not substituted) and are not on the side chain of the quinazoline ring (elimination of two C3H6O groups from the side chains). 1H-NMR spectra data indicate the chlorine substitution is at the 5-position of the quinazoline ring of erlotinib. 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.42 (s, 3H), 3.46 (s, 3H), 3.83 (m, 4H), 4.27 (s, 1H), 4.36 (m, 4H), 7.39 (s, 1H), 7.49 (dd, J=8.5, 8.3, 1H), 7.66 (ddd, J=8.5, 2.5, 2.2, 1H), 7.87 (dd, J=2.5, 1.8, 1H), 7.91 (ddd, J=8.3, 2.2, 1.8), 8.93 (s, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[B:21](OC)([O:24]C)[O:22]C.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:15]1([O:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[B:21]([OH:24])[OH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COB(OC)OC
Reactant: Brc1ccccc1COC1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1COC1CCCCC1
Reaction time: 2 h

Procedure:
31.2 ml of n-butyllithium (1.6 M) in solution in n-hexane are added dropwise at −70° C. to 13.45 g of 1-bromo-2-[(cyclohexyloxy)methyl]benzene, obtained in step 1.1, in solution in 150 ml of tetrahydrofuran. After 2 hours at −70° C., 10.2 ml of trimethyl borate are introduced dropwise and the temperature of the reaction medium is allowed to rise to −30° C. The medium is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate and the organic phase is dried with anhydrous sodium sulfate. After evaporation, 11.7 g of a yellow oil are obtained.