Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CS(O[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)=O.[H-].[Na+]>CN(C=O)C>[CH2:24]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Reactant: CS(=O)(=O)OCCOCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)COCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 3-hydroxy-2,2-dimethylpropanoate (353 mg, 2.03 mmol) and 2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate (47) (500 mg, 1.82 mmol) in DMF (6 mL) at 0° C. was added NaH (60 wt % in oil) (109 mg, 2.73 mmol), and the reaction mixture was allowed to stir at RT for 30 min. The reaction mixture was quenched with sat. NH4Cl (aq.) (1 mL) diluted with water (20 mL) and washed with EtOAc (4×20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g, 0-40% Et2O in isohexane) to afford tert-butyl 3-(2-(2-(benzyloxy)ethoxy)ethoxy)-2,2-dimethylpropanoate (48) (619 mg, 96%) as a colourless oil: m/z 375 (M+Na)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.32-7.25 (m, 5H), 4.54 (s, 2H), 3.66-3.56 (m, 8H), 3.41 (s, 2H), 1.40 (s, 8H), 1.10 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:17](C4CCCCO4)[N:16]=[CH:15][CH:14]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:24].CC(OC)(C)C>CO>[ClH:24].[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:13]3[CH:14]=[CH:15][NH:16][N:17]=3)=[CH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(-c3ccnn3C3CCCCO3)cn2)cc1
Agent: Cl
Solvent: CO
Solvent: COC(C)(C)C
Product: c1ccc(-c2ncc(-c3cc[nH]n3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Phenyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidine (Step A, 51 mg) was added to a 1 N hydrochloric acid solution in methanol (5 mL). The solution was stirred at room temperature for two hours. MTBE (40 mL) was added to precipitate a white solid which was filtered and rinsed with MTBE and dried under high vacuum. The title compound was obtained as a white powder (11.4 mg, 27% yield); melting point 264-273° C.; 1H-NMR (300 MHz; CD3OD) δ 10.0 (s, 1H), 9.29 (s, 2H), 8.44 (dd, 2H), 7.86 (d, 1H), 7.54 (m, 3H), 6.95 (d, 1H); MS (ESI+) m/z 223 (M+1); H-PGDS FPBA IC50: 2.4 μM.
Reaction SMILES: CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[F:28][C:29]1[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:30]=1[C:31]([NH:33][C:34]1[CH:38]=[CH:37][N:36]([CH2:39][C:40]2[CH:45]=[C:44]([N+:46]([O-])=O)[CH:43]=[CH:42][C:41]=2[CH3:49])[N:35]=1)=[O:32]>[Pd].C(OCC)(=O)C.C(O)C>[NH2:46][C:44]1[CH:43]=[CH:42][C:41]([CH3:49])=[C:40]([CH2:39][N:36]2[CH:37]=[CH:38][C:34]([NH:33][C:31](=[O:32])[C:30]3[C:29]([F:28])=[CH:53][CH:52]=[CH:51][C:50]=3[F:54])=[N:35]2)[CH:45]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(N)cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 1.5 h

Procedure:
To 10% palladium on activated carbon degussa type E101 NE/W (wet) (280 mg) was added a slight suspension of 2,6-difluoro-N-{1-[(2-methyl-5-nitrophenyl)methyl]-1H-pyrazol-3-yl}benzamide (for a preparation see Intermediate 47)(1.27 g, 3.41 mmol) in a mixture of ethyl acetate (20 ml) and ethanol (50 ml) under vacuum. The suspension was hydrogenated for 1.5 h at ambient temperature. The suspension was filtered and the residue washed with methanol (30 ml). The solvent was removed in vacuo to leave a white solid (1.09 g); LCMS (System 4) MH+=343, tRET=1.43 min.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(Cl)Cl.C(N(CC)CC)C.[CH2:32]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1)=[O:36])[CH3:33]>O1CCCC1>[ClH:21].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:44]([NH:43][C:40]3[CH:39]=[CH:38][C:37]([C:35]([O:34][CH2:32][CH3:33])=[O:36])=[CH:42][CH:41]=3)=[O:45])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 62.8 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (7.54 g; 20 mmole), methylene chloride (50 ml), tetrahydrofuran (50 ml), triethylamine (8.4 ml; 60 mmole) and 4-ethoxycarbonylphenyl isocyanate (3.8 g; 20 mmole). Recrystallization from methanol provided the title compound (3.11 g; 34% yield) as colorless crystals, m.p. 233°-234° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[Br:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH2:22]Br>>[Br:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1[CH2:22][N:3]1[C@@H:2]([CH3:1])[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4]1=[O:13]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Agent: [Li]CCCC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (0.386 g, 2.13 mmol) in THY (7 mL) at −78° C. under N2 was added n-butyllithium (2.5M in hexanes; 0.94 mL, 2.35 mmol), and the mixture was stirred at −78° C. for 30 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.678 g, 2.13 mmol) was added, and the reaction was warmed to room temperature and stirred overnight. Once no starting material was seen by analytical LCMS, the mixture was transferred to a separatory funnel and partitioned between EtOAc and H2O. The organic layer was separated and washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:24](OCC)=[O:25].[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(N(C(C)C)CC)(C)C>C(Cl)CCl.ClCCl>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:14]([NH:13][C:8]1[C:7]2[N:6]=[CH:5][C:4]3[C:24](=[O:25])[N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:2][C:3]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:23]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CBr
Reactant: COCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCCN1Cc2c(cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 4-bromomethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (100 mg), 2-methoxyethylamine (18.7 mg) and N,N-diisopropyl-N-ethylamine (134 mg) in ethylene chloride (1 ml) was stirred for 2 hours at ambient temperature. The mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (methanoldichloromethane) to give 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-2-(2-methoxyethyl)-1H-pyrrolo-[3,4-c]quinolin-3-one (76 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>CN1CCN(C)C1=O>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C:11]1[N:1]=[C:2]2[CH:3]=[C:4]([Cl:8])[N:5]=[CH:6][N:7]2[CH:10]=1)[CH3:18]
Reactant: Nc1cc(Cl)ncn1
Reactant: CCOC(=O)NC(=O)CCl
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)Nc1cn2cnc(Cl)cc2n1
Temperature: 130 °C
Yield: 9.4 %

Procedure:
A solution of 6-amino-4-chloropyrimidine (1) (0.504 g, 3.89 mmol) and N-chloroacetylurethane (0.770 g, 4.65 mmol) in 1,3-dimethyl-2-imidazolidinone (10 mL) was heated to 130° C. under nitrogen for 3 h. N-Chloroacetylurethane (0.770 g, 4.65 mmol) was added and the mixture was heated to 130° C. under nitrogen for a further 3.5 h. The black oily solution was poured onto ice (200 g) and the aqueous solution was extracted with ethyl acetate (3×250 mL). The organic fractions were combined, removal of solvent in vacuo gave an oily solid which was triturated with ether. Filtration of the solid and washing with ether gave urethane (2) (88 mg, 9%) as a solid. APCI-MS Found [M+H]+=241, 243.
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I:23]I>O>[Cl:11][C:10]1[C:2]([I:23])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: II
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(I)c(Cl)cc1C(=O)O
Temperature: 5 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a stirred solution of 4-amino-5-chloro-2-methoxybenzoic acid (5 g, 24.8 mmol) in water (10 mL) at 0° C., concentrated sulfuric acid (50 mL) was added. Then a solution of NaNO2 (1.9 g, 27.3 mmol) in water (10 mL) was added dropwise while keeping the internal temperature around 0° C. KI (4.5 g, 27.3 mmol) and I2 (3.5 g, 13.64 mmol) were dissolved in water and added dropwise to the stirred reaction mixture. The reaction was stirred at 5° C. for 2 h and then extracted with ethyl acetate. The organic layer was washed with water, Na2SO3 (aq, 10%) and brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford desired product (1.55 g, 19% yield). ESI-MS m/z: 311.1[M+H]+.
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:30]([OH:32])=[O:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[C:1]([N:9]1[C:13]2([CH2:14][CH2:15][CH:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)[S:12][CH2:11][C@H:10]1[C:30]([OH:32])=[O:31])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 77.4 %

Procedure:
In 4 ml of methanol was suspended 0.40 g of (3R)-4-benzoyl-8-[4-(methoxycarbonyl)phenoxy]-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid. After adding thereto 4.40 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the resulting mixture was stirred at ambient temperature for 6 hours. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and then the product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether and ethyl acetate was added to the residue, and the deposited crystal was collected by filtration to obtain 0.30 g of (3R)-4-benzoyl-8-(4-carboxyphenoxy)-1-thia-4-azaspiro[4.5]-decane-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH2:20][O:21][C:22]4[C:31]5[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[N:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH2:20][O:21][C:22]4[C:31]5[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[N:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:35])=[O:5]
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)c(F)c5)cn34)ccnc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(N)=O)c(F)c5)cn34)ccnc2c1
Reaction time: 0.5 h

Procedure:
A solution of 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoic acid (0.192 g, 0.43 mmol), HATU (0.26 g, 0.69 mmol), and Hunig'sBase (0.30 ml, 1.7 mmol) in DMF (10.75 mL) was allowed to stir for 30 minutes. Ammonia (0.0093 ml, 0.43 mmol) was then bubbled through the mixture for another 30 minutes. The solution was concentrated in vacuo and purified using via flash chromatography, eluting with 5-10% MeOH/NH4OH in DCM. There remained an unidentified peak in the NMR, so the solid was triturated in MeCN, filtered, and quickly washed with DCM to wash through the impurities. Concentration in vacuo yielded 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][C:23]([N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)([CH3:25])[CH3:24])=[C:19]([O:39][CH3:40])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][C:23]([CH3:24])([N:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)[CH3:25])=[C:19]([O:39][CH3:40])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1C#CC(C)(C)N1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (0.122 g, 0.225 mmol) in methylene chloride (4 mL) was added with trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then the residue was dissolved in water (10 mL). The solution was added with saturated aqueous sodium hydrogencarbonate (10 mL), and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[3-methyl-3-(piperazin-1-yl)but-1-ynyl]benzofuran-3(2H)-one (0.0259 g, 26%).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[C:1]1([S:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Sc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Sc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A mixture of methyl 4-(phenylthio)benzoate (5 g, 20.4 mmol), lithium hydroxide monohydrate (1.1 g, 26 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 4-(phenylthio)benzoic acid as a white solid (4.5 g, 96%). LRMS (M+H+) m/z: calcd 230.04. found 230.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:38])=[CH:32]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:38])=[CH:32]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (115 mg, 0.28 mmol), (prepared as described for the starting material in Example 12), 5-hydroxy-2-methylindole (50 mg, 0.33 mmol) and potassium carbonate (60 mg, 0.42 mmol) in DMF (1.5 ml) was stirred at 100° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5 and 1/0/9) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (60 mg, 41%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[SH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[F:1][C:2]1[C:7]([C:8](=[O:9])[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: Sc1ccccn1
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Product: O=C(Sc1ccccn1)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Following the general procedure described above, reaction of pentafluorobenzoyl chloride (6.92 g, 30.0 mmol) with 2-mercaptopyridine (3.33 g, 30.0 mmol) in THF (30 mL) for 30 min at room temperature afforded pale yellow solid after precipitation (7.97 g, 87%): mp 51° C.; 1H NMR δ 7.37-7.42 (m, 1H), 7.75-7.79 (m, 1H), 7.81-7.87 (m, 1H), 8.67-8.71 (m, 1H); Anal. Calcd for C12H4NOS: C, 47.22; H, 1.32; N, 4.59. Found: C, 47.59; H, 1.29; N, 4.38.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](CBr)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].C1N2CN3CN(C2)CN1C3.[C:23](O)(=[O:25])C.Cl>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:23]=[O:25])=[CH:7][CH:6]=1)([O:2][CH3:1])=[O:4]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccccc1CBr
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc(C=O)cc1
Reaction time: 2 h
Yield: 71 %

Procedure:
A mixture of 68.7 g (0.3 mole) of methyl-α-bromotoluate, 84 g (0.6 mole) of hexamethylenetetraamine, 150 ml of acetic acid and 150 ml of water were refluxed with stirring for two hr. Ninety ml of concentrated hydrochloric acid was then added and kept at room temperature for 15 min. The cooled solution was extracted with ether, washed with water, 10% NaHCO3 solution, water and dried. Evaporation of the solvent and recrystallization of the residue from petroleum ether gave 35 g of p-carbomethoxybenzaldehyde, yield 71% m.p. 61°-63° C. (lit. m.p. 61°-63° C.). The infrared spectrum showed absorption at 1720 cm-1 ##STR6## 1690 cm-1 (--CHO). NMR (CDCl3) δ3.8 (s,--COOCH3,3), 7.8-8.2 (m, aromatic, 4), and 10.2 (s,--CHO,1)
Reaction SMILES: Cl[C:2]1([CH2:7][Cl:8])[O:5][C:4](=[O:6])[CH2:3]1.[CH3:9][OH:10]>C(=O)(O)[O-].[Na+]>[CH3:9][O:10][C:4](=[O:6])[CH2:3][C:2]([CH2:7][Cl:8])=[O:5]
Reactant: O=C1CC(Cl)(CCl)O1
Reactant: CO
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CC(=O)CCl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7.8 Parts of 4-chloro-4-chloromethyloxetan-2-one are dissolved in 200 parts of methanol containing 4.2 parts of anhydrous sodium bicarbonate. After stirring for 20 hours at room temperature, the solids are filtered off, the filtrate is evaporated and the residue distilled to give methyl-γ-chloroacetoacetate, b.p. 48°-50° C./0.8 mb.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH2:21](O)[CH3:22]>>[CH2:21]([O:12][C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:22]
Reactant: CCO
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
To a stirred solution of (4-nitro-phenyl)-acetic acid (3 g, 16.4 mmol) in ethanol (30 mL) was added sulphuric acid (1 mL) and the reaction mixture was heated to reflux for 16 hours. The reaction mixture was neutralized with 2N aq. NaOH solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a light yellow oil in 98% yield, 3.4 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>C(OCC)(OCC)(OCC)CCC>[Cl:1][C:2]1[C:11]2[N:10]([C:9]([CH2:4][CH2:5][CH3:6])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: NNc1nc2ccccc2nc1Cl
Agent: CCCC(OCC)(OCC)OCC
Product: CCCc1nnc2c(Cl)nc3ccccc3n12
Temperature: 100 °C

Procedure:
A reaction mixture of 5 g of 2-chloro-3-hydrazinoquinoxaline in 15 ml of triethyl orthobutyrate was heated at 100° C. for three hours. Upon cooling, the precipitated solid was filtered, washed with cyclohexane, and dried giving 4.0 g of 4-chloro-1-propyl[1,2,4]triazolo[4,3-aquinoxaline having a mp of 172°-175° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14].C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: Cc1nc(N)sc1C
Reactant: CCOC(=O)CC(=O)CCl
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Product: Cc1sc2nc(CCl)cc(=O)n2c1C
Yield: 144 %

Procedure:
This compound was synthesized from 2-amino-4,5-dimethylthiazole (5.0 g, 30.365 mmol) and ethyl chloroacetoacetate (6.519 g, 42.511 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 10.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 229.60 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:18][O:19][CH3:20])[C:9](=[O:10])[CH2:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][N:22]=[C:23]=[S:24].CC(C)([O-])C.[K+]>CN(C)C=O>[OH:10][C:9]1[C:4]([CH2:18][O:19][CH3:20])([CH2:3][O:2][CH3:1])[O:5][C:6]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=2[C:8]=1[C:23](=[S:24])[NH:22][CH3:21]
Reactant: COCC1(COC)Oc2ccc([N+](=O)[O-])cc2CC1=O
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)C1=C(O)C(COC)(COC)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
To a mixture of 5.1 g of 3,4-dihydro-2,2-bis(methoxymethyl)-6-nitro-2H-1-benzopyran-3-one and 60 ml of dried N,N-dimethylformamide was added 1.35 ml of methyl isothiocyanate under nitrogen stream with stirring under ice-cooling. Subsequently, 2.2 g of potassium tertiary butoxide was added therein. The mixture was stirred for 15 minutes and then further stirred at 5° C. for 11 hours. Ice water was added therein and the resultant reaction solution was washed with ether. A water layer was acidified to be hydrochloric acid and it was extracted with ether. An organic layer was washed with water and dried, and the solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =2:98) to obtain 2.8 g of 3-hydroxy-2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide with a melting point of 97°-101° C.