Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1)(O)=O.[H-].[O:23]1CCCC1>C1(C)C=CC=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][OH:23])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: C1CCOC1
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (3.74 g, 11.5 mmol) in dry tetrahydrofuran (50 ml) was cooled to -78° C. under argon, and a solution of diisobutyl alumninum hydride in toluene (30 ml of 1M) was added dropwise. The mixture was stirred at -78° C. for 1.5 hours, then allowed to slowly warm to room temperature. The reaction was quenched by pouring onto iced dilute acetic acid, the product was extracted into methylene chloride and the organic extracts were washed with water, 5% sodium carbonate solution and brine The dried, concentrated product was a light tan solid (3.32 g). Crystallization from ethanol/water gave 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole; mp 98°-101° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[CH3:37][N:38](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]2)[C:5]2[C:10]([C:37]#[N:38])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(N4CCC(CNC(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(N4CCC(CNC(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A mixture of tert-butyl (1-(2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (418 mg, 0.647 mmol), Pd2(dba)3 (60 mg, 0.065 mmol), dppf (72 mg, 0.130 mmol) and Zn(CN)2 (91 mg, 0.778 mmol) in DMF (5 mL) was stirred at 70° C. for 20 h. DMF was removed in vacuo. The residue was loaded to a flash column, eluted with a gradient of 10-30% EtOAc in hexane to give tert-butyl (1-(2-chloro-5-cyano-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (180 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(NC1NC2C(N=C(OC)N=2)=C(N)N=1)CCC.C(=O)([O-])[O-].[K+].[K+].BrCCCCCCl.N1CCCCCC1.C(N(CC)CC)C.[CH2:52]([NH:56][C:57]1[N:65]=[C:64]2[C:60]([N:61]=[C:62]([O:78]C)[N:63]2[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][N:71]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]2)=[C:59]([NH2:80])[N:58]=1)[CH2:53][CH2:54][CH3:55]>CN(C=O)C>[NH2:80][C:59]1[N:58]=[C:57]([NH:56][CH2:52][CH2:53][CH2:54][CH3:55])[N:65]=[C:64]2[C:60]=1[NH:61][C:62](=[O:78])[N:63]2[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][N:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCCN3CCCCCC3)c2n1
Agent: C1CCCNCC1
Agent: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: ClCCCCCBr
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCCCN3CCCCCC3)c2n1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (192 mg, 0.547 mmol) and potassium carbonate (189 mg, 1.368 mmol) were suspended in DMF (3 ml) and heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and 1-bromo-5-chloropentane (0.072 ml, 0.547 mmol) was added and the reaction stirred for a further 18 hours. Hexahydro-1H-azepine (54.2 mg, 0.547 mmol) and triethylamine (0.076 ml, 0.547 mmol) were added and the reaction mixture heated to 70° C. for 24 hours. LCMS showed a major peak with MH+404 consistent with the formation of N2-butyl-9-[5-(hexahydro-1H-azepin-1-yl)pentyl]-8-(methyloxy)-9H-purine-2,6-diamine. The solvent was removed in vacuo and the residue partitioned between DCM (2 ml) and water (2 ml). The aqueous was extracted again with DCM (2 ml) and the combined organic extracts were concentrated and the residue was dissolved in 1:1 MeOH:DMSO (2 ml) and purified by MDAP (Method C). Evaporation of the product containing fractions gave a residual TFA salt which LCMS indicated had undergone hydrolysis of the 8-methoxy group, presumably on concentration in the presence of TFA. This crude material was dissolved once more in 1:1 MeOH:DMSO (2 ml) and re-purified by MDAP (Method A). Product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a white solid (39 mg).
Reaction SMILES: Cl.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:65]=[C:64]([N+:66]([O-])=O)[CH:63]=[CH:62][C:45]=1[O:46][C:47]1[C:52]2=[CH:53][C:54]([C:56]3[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1>>[F:43][C:44]1[CH:65]=[C:64]([NH2:66])[CH:63]=[CH:62][C:45]=1[O:46][C:47]1[C:52]2=[CH:53][C:54]([C:56]3[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3cc(-c4cccnc4)cc23)c(F)c1
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Nc1ccc(Oc2ncnn3cc(-c4cccnc4)cc23)c(F)c1
Yield: 46.7 %

Procedure:
Following a procedure similar to that for the synthesis of Compound C of Example 36, 4-(2-fluoro-4-nitrophenoxy)-6-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazine (35 mg, 0.10 mmol) was converted to the title compound (15 mg, 46%). MS(ESI+) m/z 322.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.O.C(OO)(=[O:24])C.CCOC(C)=O>C(O)(=O)C.CCCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([OH:24])[CH:5]=[N:4][C:3]=1[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: CC(=O)OO
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ncc(O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-chloro-2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 34, 297.6 g, 897.9 mmol) in acetic acid:water (2.2 L:1.0 L) at 0° C. was added peracetic acid (191 mL; 1.077 mol) and the reaction was allowed to warm gradually to room temperature. After 4 hours the reaction was complete and was quenched with 0.5 M solution of sodium thiosulfate (225 mL). The resulting dark solution was evaporated to dryness and the residue was passed through a plug of silica (flushed with neat heptane gradually up to 10% EtOAc:heptane) to remove base line boronate salts. The filtrate evaporated to give a pale yellow viscous oil which contained 8% of the wrong regio-isomer. Further column chromatography was performed (SiO2 80 g/1.5 Kg using 30% EtOAc in heptane as eluent). Relevant fractions were evaporated to give a pale yellow solid which was triturated with heptane, dried under suction to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[CH3:18]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1Br
Temperature: 25 °C

Procedure:
2-bromo-5-chlorobenzoic acid (4 g, 0.016 mol) was dissolved in MeOH (20 ml) and sulphuric acid (1 ml) was added. The reaction was refluxed for 3 h then cooled at RT. Water (20 ml) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17 g of the title compound as oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCBr
Product: O=C(Cl)CCCCCCCCCCBr

Procedure:
11-Bromoundecanoic acid (400 g) was added to thionyl chloride (600 ml) and the solution heated at 80° for 0.5 hour. The thionyl chloride was distilled off and the dark oily residue distilled in vacuo to give 11-bromoundecanoyl chloride, b.p. 144°, 0.7 mm Hg, (346.8 g, 81%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.[Cl:13]C(Cl)(Cl)[C:15]([C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:13].[NH2:12][C:9]1[NH:10][CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][NH:3][C:15]([C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[N:8]=1
Reactant: NCCCc1c[nH]c(N)n1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(CCCNC(=O)c2ccc[nH]2)c[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16 (0.100 g, 0.458 mmol), 2-trichloroacetyl pyrrole 6 (0.103 g, 0.488 mmol), and anhydrous sodium carbonate (0.172 g, 1.63 mmol), were dissolved in anhydrous N,N-dimethylformamide (5 mL). The reaction was stirred at ambient temperature for 16 h. Evaporation of the reaction under reduced pressure and purification of the residue by column chromatography (CH2Cl2/MeOH sat. NH3 85:15) afforded the desired compound in its free base form. Addition of a single drop of concentrated hydrochloric acid to a methanol solution (8 mL) and evaporation under reduced pressure yielded 0.078 g (63%) of the title compound 17 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.59 (s, 1H), 11.45 (s, 1H), 8.14 (t, 1H, J=5.1 Hz), 7.30 (s, 2H), 6.81 (m, 2H), 6.74 (s, 1H), 6.59 (s, 1H), 6.04 (s, 1H), 3.19 (dt, 2H, J=6.6, 12.6 Hz), 2.42 (t, 2H, J=6.9 Hz), (tt, 2H, J=6.6, 13.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.74, 146.76, 126.43, 126.40, 121.13, 110.28, 108.65, 108.50, 37.59, 28.14, 21.60; HRMS (ESI) calcd for C11H16N5O (MH+) 234.1349. found 234.1354.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:36])[N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][OH:35])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.C(=O)([O-])O.[Na+].O>ClCCl>[OH:35][CH2:34][CH2:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:22]([CH3:23])[C:21](=[O:36])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
At 0° C., trfluoroacetic acid (4 ml) was added to a solution of N-((1 R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (986 mg, 1.95 mmol) in dichloromethane (4 ml). The solution was stirred for 3 h at 0° C. Dichloromethane (50 ml) was added. A saturated solution of sodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogen carbonate was added until pH 7 was obtained. Water was added until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using dichloromethne/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 730 mg of (2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1.[I:17]I>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.C1COCC1.ClCCl>[Cl:9][C:10]1[CH:15]=[C:14]([I:17])[C:13]([Cl:16])=[CH:12][N:11]=1
Reactant: II
Reactant: Clc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Clc1cc(I)c(Cl)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (11 mL of a 2 M in heptane/THF/ethylbenzene, 22 mmol) in THF (30 mL) at −78° C. was added a solution 2,5-dichloropyridine (3.3 g, 22 mmol) in THF (20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, and a solution of iodine (5.6 g, 22 mmol) in THF (20 mL) was added. The reaction mixture was stirred for 15 min, quenched with water, and warmed to rt. The reaction mixture was diluted with EtOAc, washed with water (1×), saturated Na2S2O3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The crude reaction mixture was dissolved in dichloromethane (˜50 mL), diluted with hexanes (˜100 mL), and concentrated to a volume of ˜100 mL. The solid was collected by filtration, and washed with hexanes to give 2,5-dichloro-4-iodopyridine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18](Br)[C:19]#[CH:20].C(O)(=O)C>C1COCC1.O>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH2:20][C:19]#[CH:18])[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: C#CCBr
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C#CCC(C(=O)OC)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
FIG. 4 shows a synthetic scheme useful in preparing 10-propargyl-10-dAM in accordance with the invention. A mixture of 60% NaH in oil dispersion (1.06 g, 26.5 mmol) in 18 mL of sieve-dried THF was cooled to 0° C. The cold mixture was treated with a solution of homoterephthalic acid dimethyl ester (5.0 g, 24 mmol compound 1 in FIG. 4) in dry THF (7 mL), and the mixture was stirred for 1 hour at 0° C. Propargyl bromide (26.4 mmol) was added, and the mixture was stirred at 0° C. for an additional 1 hour, and then at room temperature for 16 hours. The resulting mixture was treated with 2.4 mL of 50% acetic acid and then poured into 240 mL of water. The mixture was extracted with ether (2×150 mL). The ether extracts were combined, dried over Na2SO4, and concentrated to an orange-yellow oil. Chromatography on silica gel (600 mL of 230-400 mesh) with elution by cyclohexane-EtOAc (8:1) gave the product α-propargylhomoterephthalic acid dimethyl ester (compound 2) as a white solid (4.66) which appeared by TLC (cyclohexane-EtOAc, 3:1) to be homogeneous. Mass spectral data on this product, however, showed it to be a mixture of the desired product 2, and the dipropargylated compound. No starting material 1 was detected. HPLC shows the ratio of mono- to di-propargylated products to be about 3:1. Since the dipropargylated product, unlike compound 1, cannot produce an unwanted coproduct in the next step of the reaction, this material was suitable for conversion to compound 3. Absence of starting compound 1 in the product used to proceed in the synthesis is very important in order to avoid the sequential formation of 10-dAM during the transformations lading to the final product, because complete removal from 10-dAM from 10-propargyl-1-dAM is very difficult.
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH3:8].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:1][C:2]1([CH3:9])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH3:8])(=[O:12])[CH3:11]
Reactant: CC1C(=O)C=CC1(C)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1(C)C=CC(=O)C1C

Procedure:
Into the same flask as used in Example 1, dl-3-hydroxy-2,3-dimethyl-4-cyclopentenone (12.6 g) and acetic anhydride (30 g) were charged, and the resultant mixture was stirred at 80°-100° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 11, followed by purification to give 16.2 g of dl-3-acetoxy-2,3-dimethyl-cyclopentenone. Yield, 96.5%. B.P., 52°-55° C./0.4-0.5 mmHg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7].Cl[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]=[N:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7]
Reactant: COCCOC(=O)NNC(=O)OCCOC
Agent: [Na+]
Agent: [O-]Cl
Solvent: Cc1ccccc1
Product: COCCOC(=O)N=NC(=O)OCCOC
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution obtained by adding 1,2-hydrazinedicarboxylic acid bis(2-methoxyethyl) ester (200 mg, 0.85 mmol) and toluene (2 mL) to a 10 mL flask, followed by cooling with an ice bath, was added dropwise a 5% sodium hypochlorite solution (1.39 g, 0.85 mmol), and the reaction was allowed to proceed for one hour. After the reaction, the solution was washed with water (1 mL,×2), and dehumidified with anhydrous magnesium sulfate, followed by concentration to dryness. The resulting solid was recrystallized with toluene (1 mL) and hexane (5 mL), to give azodicarboxylic acid bis(2-methoxyethyl) ester as a pale yellow crystal (73 mg, yield: 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[ClH:27].O1CCOCC1>CO.C(Cl)Cl>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (2.3 g) in 30% MeOH/DCM (60 mL) at 0° C. was added dropwise 4M HCl/1,4-dioxane (10 mL). After all solid material had dissolved, the mixture was concentrated under reduced pressure, and to the residue was added 30% CH3CN/H2O (80 mL) and the mixture was sonicated until all solid material had dissolved. The mixture was frozen and lyophilized overnight to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol hydrochloride (100%). 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 6.02 (s, 1H), 6.20 (s, 1H), 7.27 (t, 2H), 7.60 (qt, 2H), 7.80 (t, 1H), 8.08 (t, 1H), 8.23 (d, 1H), 8.83 (d, 1H), 12.16 (s, 1H), 14.51 (b, 1H); LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+].C(Cl)(Cl)Cl>C(O)C>[CH3:12][C:11]1[C:3]([CH2:2][S:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Cc1cc2c(cc1CCl)OCO2
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1CSCC(=O)O)OCO2
Yield: 20.5 %

Procedure:
A suspension of 6.0 g of 5-chloromethyl-6-methyl-1,3-benzodioxole, 6.0 g of mercaptoacetic acid and 6.5 g of sodium hydroxide in 130 ml of 50% hydrous ethanol was heated under reflux for 1 h. The reaction mixture was concentrated. Water was added thereto and the mixture was washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid. After extraction with chloroform, the extract was dried over magnesium sulfate. The solvent was distilled off and the product was isolated according to silica gel column chromatography (chloroform). The crystals thus obtained were recrystallized from diisopropyl ether to obtain 1.6 g of the intended compound in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CO.[NH4+].[Cl-]>[Fe].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cccnc1Nc1cccc(Cl)c1
Temperature: 90 °C
Yield: 29.3 %

Procedure:
To a mixture of (3-chlorophenyl)-(3-nitropyridin-2-yl)amine (111 mg, 0.45 mmol) in a 3:1 mixture MeOH:water (20 mL) were added NH4Cl (154 mg, 2.88 mmol) and iron powder (107 mg, 1.92 mmol) and the reaction mixture heated at 90° C. for 3 h. After cooling to RT, the solid was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a brown solid (29 mg, 30%). LCMS (Method C): RT 1.84 min [M+H]+ 220.1.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.C(N1CCNCC1)C>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: CCN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 204.6 %

Procedure:
In a 100 ml three-mouth bottle 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and N-ethylpiperazine (10.3 g) is added thereto at the temperature within 20 min. The above mixture is reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then is dried in vacuum at 50 for 5 h to obtain solid purin (13.0 g). The yield is about 70.0%.