Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl-].Cl[C:19](=[N+:21]([CH2:24][CH3:25])[CH2:22][CH3:23])Cl>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Reactant: CC[N+](CC)=C(Cl)Cl
Agent: [Cl-]
Product: CCN(CC)c1nc2cc(-c3ccccc3C#N)ccc2[nH]1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (4.78 mmoles, 1.0 g) was reacted as described in Example 31 with (dichloromethylene) diethylammonium chloride (1.435 mmoles, 2.73 g prepared following the procedure described in Angew, Chem, Int. Ed. 12:806 (1973)) to yield 0.91 g of 5-(2-cyanophenyl)-2-diethylamino-1H-benzimidazole.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Br:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Br:14].C([O-])([O-])=[O:16].[Ca+2]>O1CCOCC1.O>[Br:14][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:13])[C:3]=1[CH2:2][OH:16])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(Br)c(CO)c(Br)c1
Temperature: 100 °C

Procedure:
To a stirred solution of methyl 3,5-dibromo-4-(bromomethyl)benzoate (INTERMEDIATE 24) (12.53 g, 32.4 mmol, 1 eq) in dioxane (100 mL) and water (100 mL) was added CaCO3 (8.1 g, 81 mmol, 2.5 eq). The mixture was warned to and stirred at 100° C. until reaction was complete by HPLC analysis. The mixture was cooled and the solvent removed under reduced pressure. The residue was diluted with water and extracted 3× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated giving methyl 3,5-dibromo-4-(hydroxymethyl)benzoate. The material was taken immediately to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=[C:10]([N+:12]([O-])=O)[CH3:11].[N+](CC)([O-])=O.ClC1C=CC=C(Cl)C=1C=O.[C:30](OC)(=[O:36])[CH2:31][C:32]([O:34][CH3:35])=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH:10]([CH3:11])[NH:12][C:30](=[O:36])[CH:31]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: CC(=Cc1c(Cl)cccc1Cl)[N+](=O)[O-]
Reactant: COC(=O)CC(=O)OC
Agent: O=Cc1c(Cl)cccc1Cl
Solvent: CC[N+](=O)[O-]
Product: COC(=O)C1C(=O)NC(C)C1c1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorophenyl)-2-nitropropylene (m.p. 49°-50° C., b.p. 90°-102° C./0.33 mm. Hg.)is prepared from nitroethane and 2,6-dichlorobenzaldehyde by a similar process to that described in the second and third parts of Example 4. This compound is reacted with dimethyl malonate and the product hydrogenated by a similar process to that described in the fourth and fifth parts of Example 4, and the 4-(2,6-dichlorophenyl)-3-methoxycarbonyl-5-methylpyrrolidin-2-one thus obtained is separated into two geometrical isomers thereof by repeated chromatography on a silica gel column, using a 2:1 v/v mixture of toluene and ethyl acetate as eluant. The two isomers have m.p. 157°-158° C. (first isomer) and 143°-144° C. (second isomer). These two esters are separately hydrolysed and decarboxylated by a similar process to that described in the sixth part of Example 4, and there are thus obtained a first isomer, m.p. 182°-184° C., and a second isomer, m.p. 173.5°-175° C., of 4-(2,6-dichlorophenyl)-5-methylpyrrolidin-2-one, the isomers differing by cis- and trans- relationship of the 4-(2,6-dichlorophenyl)- and 5-methyl-substituents.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]4[N:30](C5CCCCO5)[N:29]=[CH:28][CH:27]=4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.CCO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]4[CH:27]=[CH:28][NH:29][N:30]=4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2ccnn2C2CCCCO2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cc[nH]n2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thiazole-4-carboxamide (13 mg, 0.025 mmol) was added into a flask under nitrogen atmosphere. 10% HCl/EtOH (0.028 ml, 0.062 mmol) was added and the reaction mixture was stirred in RT for 3 h. The reaction mixture was diluted with ethyl acetate and washed with 1M Na2CO3. The organic phase was dried, filtered and evaporated. Yield 94%. 1H-NMR (400 MHz; MeOD): δ 1.30 (d, 3H), 4.38 (dd, 1H), 4.45 (dd, 1H), 4.59 (m, 1H), 6.75 (d, 1H), 6.83 (d, 1H), 7.61 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.84 (dd, 1H), 7.95 (d, 1H), 8.06 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][O:12][C:11]2=[O:21])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH:22](OCC)(OCC)OCC>>[CH3:9][C:6]1[C:7]2[NH:8][CH:22]=[N:1][C:2]=2[CH:3]=[C:4]([N:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][O:12][C:11]2=[O:21])[CH:5]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(N2C(=O)OC[C@@H]2c2ccccc2)cc(N)c1N
Product: Cc1cc(N2C(=O)OC[C@@H]2c2ccccc2)cc2nc[nH]c12

Procedure:
The (S)-3-(3,4-diamino-5-methylphenyl)-4-phenyloxazolidin-2-one was dissolved in triethyl orthoformate and was refluxed for 30 minutes. After cooling the excess of triethyl orthoformate was removed under reduced pressure. The final product was purified via FPLC using a chloroform-methanol gradient (0→10%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:16]([Mg]Br)=[CH2:17].Cl>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]([OH:10])([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:16]=[CH2:17])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C=C[Mg]Br
Reactant: O=C(c1cc(F)cc(F)c1)c1nccs1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)(c1cc(F)cc(F)c1)c1nccs1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of (3,5-difluorophenyl)(thiazol-2-yl)methanone (1 g, 4.4 mmol, Step 2) in dry THF (40 mL) was added at 0° C. (4.4 mL, 4.4 mmol) of a 1.0M THF solution of vinyl magnesium bromide (Aldrich). The reaction mixture was stirred for 30 min. and then transferred to a 1N aqueous HCl solution. The resulting mixture was extracted with EtOAc and the combined organic phase were washed with brine, dried over MgSO4 and evaporated to give a residue which was chromatographed on silica gel eluting with 85:15 mixture of hexane: EtOAc to afford 635 mg (56%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([Br:18])=[CH:16][N:15]=[C:14]([Cl:19])[N:13]=1)(C)(C)C.Cl>C(#N)C.O1CCOCC1>[ClH:19].[Br:18][C:17]1[C:12]([NH:11][CH2:10][CH2:9][CH2:8][NH2:7])=[N:13][C:14]([Cl:19])=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: NCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5.0 g (13.7 mmol) of [3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propyl]-carbamic acid-tert-butyl-ester in 150 ml of acetonitrile is mixed with 25 ml of a 4 molar solution of hydrochloric acid in dioxane and stirred at room temperature. After 4 hours, the solvent is drawn off in a rotary evaporator, and the residue is dried in a drying oven. 4.1 g (13.7 mmol, corresponding to 100% of theory) of the product is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=O)[CH3:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([F:21])[CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[C:1](=[CH2:2])[C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6]2=[O:8])=[C:16]([F:21])[CH:15]=1
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: Nc1ccc(Cl)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: C=C1c2ccccc2C(=O)N1c1ccc(Cl)cc1F
Reaction time: 2 h

Procedure:
A mixture of 8.2 parts of 2-acetylbenzoic acid, 7.27 parts of 4-chloro-2-fluoroaniline and 0.01 part of p-toluene-sulfonic acid was heated in an oil bath with occasional stirring at 150°-170° for 2 hours. The melt was poured into 100 parts of chloroform and washed successively with 50 parts of 10% aqueous hydrochloric acid solution, 50 parts of 10% aqueous sodium carbonate solution and 100 parts of a saturated aqueous sodium chloride solution. After drying the organic phase with anhydrous sodium sulfate, the solvent was evaporated at 300 mm. Hg at 50° C and the residue was crystallized from 100 parts of methanol to yield 8 parts of 2-(4-chloro-2-fluorophenyl)-3-methylene-1H-isoindol-1-one melting 86°-87°.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([O:15][CH3:16])=[O:14])[N:10]=2)[CH2:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([O:15][CH3:16])=[O:14])[N:10]=2)[CH2:5]1)(=[O:20])=[O:19]
Reactant: COC(=O)NCc1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCc1csc(N2CC(OS(C)(=O)=O)C2)n1
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of 3-hydroxy-1-[4-(methoxycarbonylamino-methyl)-1,3-thiazol-2-yl]azetidine (426 mg, 1.75 mmol) (obtained as described in Reference Example 63(2)) in methylene chloride (20 ml) were added methanesulfonyl chloride (0.16 ml, 2.10 mmol) and triethylamine (0.29 ml, 2.10 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-[4-(methoxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (448 mg, yield 80%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.O>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Combine 4-hydroxy-3-methyl-benzaldehyde (401 mg, 2.94 mmol), K2CO3 (570 mg, 4.12 mmol) and 6-chloronicotinonitrile (408 mg, 2.94 mmol) in DMF (6 ml), heat at 100° C. After 4 h cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Dry under vacuum at 45° C. overnight to get the title compound (680 mg, 97%). 1H-NMR (CDCl3, 400 MHz): 9.99 (s, 1H), 8.43 (d, 1H, J=2.5 Hz), 7.97 (dd, 1H, J=2.5 and 8.8 Hz), 7.84 (bs, 1H), 7.80 (dd, 1H, J=2.5 and 8.8 Hz), 7.22 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 2.24 (s, 3H).
Reaction SMILES: [C:1]([CH:4]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1)[CH3:10])[C:5](OC)=[O:6])(=O)[CH3:2].O.[NH2:26][NH2:27]>C(O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([CH:9]([C:4]3[C:5](=[O:6])[N:26]=[N:27][C:1]=3[CH3:2])[CH3:10])[CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NN
Reactant: COC(=O)C(C(C)=O)C(C)c1ccc(OC)c(OC2CCCC2)c1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)C2=C(C)N=NC2=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.4 %

Procedure:
To a stirred solution of methyl 2-acetyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-butanoate (362 mg, 1.08 mmol) in absolute ethanol (10 ml) at 0° C. was added hydrazine monohydrate (54 mg, 1.08 mmol) in one portion. The resulting solution was stirred at 0° C. for 45 minutes and then refluxed at 80° C. for 3 hours. Further hydrazine monohydrate (15.6 mg, 3.1×10-4 mol) was added and refluxing continued for a further 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2 ; methylene chloride/ethanol/ammonia (97.5:2.5:0.25)) to afford the title compound as a white solid (76 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:22])=[O:21]
Reactant: CCOC(=O)CCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 85.3 %

Procedure:
A solution of non-polydispersed ethyl 6-hydroxyhexanoate (50.76 ml, 50.41 g, 227 mmol) in dry dichloromethane (75 ml) was chilled in a ice bath and placed under a nitrogen atmosphere. Triethylamine (34.43 ml, 24.99 g, 247 mmol) was added. A solution of methanesulfonyl chloride (19.15 ml, 28.3 g, 247 mmol) in dry dichloromethane (75 ml) was added dropwise from an addition funnel. The mixture was stirred for three and one half hours, slowly being allowed to come to room temperature as the ice bath melted. The mixture was filtered through silica gel, and the filtrate was washed successively with water, saturated NaHCO3, water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo to a pale yellow oil. Final purification of the crude product was achieved by flash chromatography (silica gel, 1/1 hexanes/ethyl acetate) to give the non-polydispersed product (46.13 g, 85%) as a clear, colorless oil. FAB MS: m/e 239 (M+H), 193 (M−C2H5O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17].N1(CC(O)=O)CCCCC1>C1C=CC=CC=1>[CH2:21]([O:20][C:14](=[O:19])[C:15]([C:16](=[O:17])[CH3:18])=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=1)[CH3:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C(O)CN1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cc(OC)c(O)c(OC)c1)C(C)=O

Procedure:
Condensation of 3,5-Dimethoxy-4-hydroxy benzaldehyde (syringaldehyde) with ethyl acetoacetate in the presence of piperidine—acetic acid and benzene as the reaction medium at reflux temperature yields the title product. The reaction takes about 3.5 hours for completion.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Cl:33][C:34]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:35]=1[CH:36]=O>>[Cl:33][C:34]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:35]=1[CH:36]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C(O)CCCCCCCCC=Cc1ccc(Cl)cc1Cl
Yield: 61.2 %

Procedure:
By the similar procedure of compound B7, B2 (2.25 g, 4.38 mmol) and 2,4-dichlorobenzaldehyde (500 mg, 2.86 mmol) were used as starting materials to afford (10 E or 10Z))-11-(2,4-dichlorophenyl)undec-10-enoic acid (B9) (576 mg, 1.75 mmol, 61%). Then this compound (210 mg, 0.638 mmol) was dissolved in ethyl acetate (10 mL) and Pd/BaSO4 (21 mg) was then added. The mixture was stirred at room temperature under hydrogen for 12 h. The mixture was filtered through Celite pad and washed with ethyl acetate. The combined filtrate was concentrated and dried in vacuum to afford compound B16 (210 mg, 0.634 mmol, 99%) as white solids. mp: 78° C. 1H-NMR (CDCl3, 400 MHz) δ 7.32 (d, J=1.9 Hz, 1H), 7.09-7.15 (m, 2H), 2.65 (t, J=7.8 Hz, 2H), 2.33 (t, J=7.5 Hz, 2H), 1.53-1.63 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 180.00, 162.19, 159.80, 130.90, 125.31, 110.69, 103.44, 34.11, 30.15, 29.44, 29.36, 29.33, 29.19, 29.16, 29.03, 28.41, 24.69. HRMS (ESI) calculated for C17H24Cl2O2Na [M+Na]+: 353.1051, found: 353.1046.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:7][CH2:8]N1C=NC2C1=NC(N)=NC=2)(=[O:3])[CH3:2].[NH2:24][C:25]1[N:33]=[C:32]2[C:28]([NH:29][C:30]([Cl:34])=[N:31]2)=[C:27]([Cl:35])[N:26]=1>>[C:1]([O:4][CH2:5][CH:6]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:7][CH2:8][N:31]1[C:30]([Cl:34])=[N:29][C:28]2[C:32]1=[N:33][C:25]([NH2:24])=[N:26][C:27]=2[Cl:35])(=[O:3])[CH3:2]
Reactant: Nc1nc(Cl)c2[nH]c(Cl)nc2n1
Reactant: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Product: CC(=O)OCC(CCn1c(Cl)nc2c(Cl)nc(N)nc21)COC(C)=O

Procedure:
Moreover, U.S. Pat. No. 5,138,057 discloses a process for preparing 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine of Formula (I), in which 2-amino-6,8-dichloropurine of Formula (X) is reacted with 2-acetoxymethyl-4-halobut-1-yl-acetate of Formula (VII) to give 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-amino-6,8-dichloropurine of Formula (XI) which is then reduced under a pressurized condition in the presence of palladium, as shown in Scheme 3 below.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]12[NH:31][CH2:30][CH:27]([NH:28][CH2:29]1)[CH2:26][CH2:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH:23]5[NH:31][CH2:30][CH:27]4[CH2:26][CH2:25][CH2:24]5)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CC2CNC(C1)CN2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 0.71 g (2.5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.54 g (2.7 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 1.13 ml (7.5 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 15 ml of acetonitrile was heated under reflux for 1.5 hr. The reaction mixture was stirred overnight at room temperature and filtered to obtain 0.40 g of the title compound, mp 268°-271° dec.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]#[N:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:17][SH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:10][C:9]1[CH2:8][N:7]2[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=[C:2]2[S:18][C:17]=1[C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCCn1c(=O)cc(Cl)n(CC#N)c1=O
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCn1c(=O)cc2n(c1=O)CC(N)=C(C(=O)OCC)S2

Procedure:
A solution of 6-chloro-1-cyanomethyl-3-propylpyrimidine-2,4(1H,3H)-dione (1.5 g), ethyl thioglycolate (0.88 g) and potassium carbonate (1 g) in ethanol (30 ml) was refluxed for 15 hours. The reaction solution was concentrated to dryness, and the resulting residue was purified by column chlomatography on silica gel. The resulting crude crystals were recrystalized from ethyl acetate-hexane to give colorless plates (0.23 g, 11%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.C(O[C:13](=N)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:13]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 1,2-phenylenediamine (1.0 eq) and ethyl 3-ethoxy-3-iminopropanoate hydrochloride (1.3 eq) in ethanol was stirred at 90° C. overnight. The reaction was cooled to room temperature and the solvent was removed in vacuo. Water and CH2Cl2 were added to the residue. The organic layer was separated, dried over Na2SO4 and the solvent removed. The solid recovered was used without purification. LC/MS m/z 205.2 (MH+), Rt 1.44 minutes.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:18]([NH:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COCc1cc(F)c([N+](=O)[O-])cc1C(=O)OC
Reactant: CC(C)(C)N
Solvent: c1ccncc1
Product: COCc1cc(NC(C)(C)C)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 5.50 g of methyl 4-fluoro-2-(methoxymethyl)-5-nitrobenzoate and 55.0 mL of pyridine was added 7.20 mL of tert-butylamine, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and to the residue was added water. Then, 1 M hydrochloric acid was added thereto to adjust the pH to about 4, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 6.82 g of methyl 4-(tert-butylamino)-2-(methoxymethyl)-5-nitrobenzoate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[Br:11]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: N#CCc1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1cc(Br)ccc1N
Temperature: 0 °C
Yield: 53.2 %

Procedure:
To a cooled solution of (2-aminophenyl)acetonitrile (13 g, 98 mmol) in dimethylformamide (150 mL) at 0° C., was added N-bromosuccinimide (19.3 g, 108 mmol) in portions for 30 minutes and maintained at 0° C. for 1 hour. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3×100 mL) and saturated sodium chloride (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in petroleum ether as eluent to afford (2-amino-5-bromophenyl)acetonitrile (11 g, 53%) as solid. 1HNMR (CDCl3) δ 7.35 (s, 1H), 7.25 (d, 1H), 6.65 (d, 1H), 3.7 (br, 2H), 3.52 (s, 2H).
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[C:45]([F:50])[C:44]=1[Cl:51]>>[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:45]([F:50])[C:44]=1[Cl:51]
Reactant: Nc1ccc(Br)c(Cl)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3ccc(Br)c(Cl)c3F)c2cc1N

Procedure:
Starting material: N4-(4-bromo-3-chloro-2-fluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 4-bromo-3-chloro-2-fluoro-aniline; other starting materials were prepared as example 1.