Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1.[CH3:19]O.[S:21](=[O:25])(=[O:24])([OH:23])[OH:22]>>[CH3:19][O:24][S:21]([O-:23])(=[O:22])=[O:25].[CH3:1][N+:2]1[N:3]([CH3:19])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Reactant: CO
Product: COS(=O)(=O)[O-]
Product: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Yield: 93.5 %

Procedure:
46.8 g (0.2 mol) of 1-methyl-3,5-diphenylpyrazole, 40 g (1.25 mol) of methanol and 20.4 g (0.2 mol) of 96% strength sulfuric acid are added to the filtrate obtained, and the mixture is processed as described above. After working-up, 69.3 g of 1,2-dimethyl-3,5-diphenylpyrazolium methylsulfate with a content of 97.1% (HPLC) of m.p. 157°-159° C. are obtained, which corresponds to a yield of 93.5% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Nc1ccccc1CO
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Solvent: ClCCl
Product: Nc1ccc(Br)cc1CO
Temperature: 25 °C

Procedure:
To a solution of 2-aminobenzyl alcohol (7.12 g, 58 mmol) in methylene chloride (200 mL) at −10° C., 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one (25 g, 61 mmol) was added in portions. During the addition, the temperature of the reaction mixture was maintained between −10° C. and 0° C. The reaction mixture was warmed up to room temperature and then extracted with 2 N sodium hydroxide solution (2×50 mL). The organic layer was washed with water and dried over MgSO4, filtered and concentrated in vacuo to afford 2-amino-5-bromobenzylalcohol as a yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C1C[O:14][CH2:13]C1.CN(C=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:13]=[O:14])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2nccc(Cl)c2s1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (2) (2 g, 11.83 mmol) in THF (40 mL) n-BuLi (2.5M in hexanes, 5.7 mL, 14.2 mmol) was added dropwise at −78° C. and the reaction mixture stirred 1 h. DMF (2.7 mL, 35.5 mmol) was added and stirring continued 1 h more. The reaction mixture was poured into water, extracted with EtOAc, the combined organics dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was triturated with ether and filtered affording title compound 232 (2 g, 10.12 mmol, 86% yield). MS (m/z): 197.9 (36%), (M+MeOH+1) 230.0 (100%).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH2:36][CH2:37][O:38][CH3:39])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:42](O)C>O1CCCC1.ClCCl>[CH:22]1([CH:21]=[C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)[C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH2:36][CH2:37][O:38][CH2:39][CH3:42])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 96 %

Procedure:
A mixture of 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.7 mmol) in ethanol (4 mL), tetrahydrofuran (8 mL) and an aqueous sodium hydroxide solution (10%, 2 mL) was heated at 50° C. for 5 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-vinyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (300 mg, 96%) which was used in the next step without further purification: LC/MS m/e calcd for C24H27FN2O3S [M+H]+ 443.56, observed 443.3.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].[C:24](=[O:27])([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH3:36])[CH2:35]O[CH2:33]1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][O:27][CH3:24])[C:5]=1[O:21][CH3:22]
Reactant: CC1(CBr)COC1
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC(C)(C)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 28.4 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL), was added potassium carbonate (103.5 mg, 0.75 mmol) and 3-bromomethyl-3-methyl-oxetane (123 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40° A) ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 30%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12](O)=[O:13])=[CH:9][C:8]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=2.S(Cl)([Cl:23])=O>>[F:1][C:2]([F:20])([F:19])[C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]([Cl:23])=[O:13])=[CH:9][C:8]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=2
Reactant: O=C(O)c1c(C(F)(F)F)[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(C(F)(F)F)[nH]c2ccc(C(F)(F)F)cc12
Temperature: 70 °C

Procedure:
A mixture of 500 mg (1.68 mmol) of the indolecarboxylic acid from Step 4 and 20 ml of thionyl chloride was heated for 3 at 70° C. The excess of thionyl chloride was removed under reduced pressure and the remaining crude acid chloride was dissolved in 30 ml of dry dichloromethane. This solution was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([CH3:12])[C:10]#[N:11])=[C:4]([Cl:20])[CH:3]=1.Cl.[N:22]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:31]([CH2:33][C:34]([NH:36][C:37](=[O:41])[O:38][CH2:39][CH3:40])=[O:35])#[N:32]>O.C(O)(=O)C>[CH2:39]([O:38][C:37](=[O:41])[NH:36][C:34](=[O:35])[C:33](=[N:22][NH:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)([C:10]#[N:11])[CH3:12])=[CH:6][C:7]=1[CH3:8])[C:31]#[N:32])[CH3:40]
Reactant: Cc1cc(C(C)(C#N)c2ccc(Cl)cc2)c(Cl)cc1N
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(C(C)(C#N)c2ccc(Cl)cc2)cc1C
Yield: 74.1 %

Procedure:
To a stirred and cooled (5°-10° C.) mixture of 15.2 parts of 4-amino-2-chloro-α-(4-chlorophenyl)-α,5-dimethylbenzeneacetonitrile, 14.4 parts of concentrate hydrochloric acid and 125 parts of acetic acid was added dropwise, during a 30 minutes period, a solution of 3.5 parts of sodium nitrite in 15 parts of water at about 10° C. Upon completion, the whole was stirred for 30 minutes and then 10 parts of sodium acetate and 7.8 parts of ethyl (2-cyanoacetyl)carbamate were added, during a period of 2 hours, at room temperature. The reaction mixture was poured into 500 parts of water. The product was filtered off, washed with water and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was stirred in 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 17.5 parts (74.1%) of ethyl[2-[[5-chloro-4-[1-(4-chlorophenyl)-1-cyanoethyl]-2-methylphenyl]hydrazono]-2-cyanoacetyl]carbamate (intermediate 44).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].Cl.[CH3:27][NH:28][CH3:29].C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH3:27][N:28]([CH3:29])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Reactant: CNC
Agent: Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN(C)C)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.27 g), dimethylamine hydrochloride (0.30 g), N,N-diisopropylethylamine (0.53 ml) and KI (0.25 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emmys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 3-[6-{2-[dimethylamino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.10 g); NMR Spectrum: (DMSOd6) 2.12 (s, 3H), 2.25 (s, 6H), 2.69 (m, 2H), 4.19 (m, 2H), 7.49 (m, 2H), 7.57 (s, 1H), 7.69 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 368.
Reaction SMILES: [H-].[Na+].[CH:3]([C:11]1[N:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:14][CH:15]=1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:21](OC)=[O:22].C(=O)(O)[O-].[Na+]>CN(C=O)C>[OH:22][CH:21]=[C:16]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)Cn1cccc1C=Cc1ccccc1
Reactant: COC=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)n1cccc1/C=C/c1ccccc1

Procedure:
Sodium hydride (0.63 g, 0.013 mol) was washed with petrol 60°-80° and suspended in DMF (30 ml) under nitrogen. To this methyl (2-styrylpyrrol-1-yl)acetate (1.6 g, 0.0066 mol) and methyl formate (8.2 ml, 0.13 mol) in DMF (10 ml) was added dropwise at room temperature. After 4 hours it was poured into 200 ml of saturated sodium bicarbonate, extracted with diethyl ether (2×100 ml), then the aqueous layer was neutralised with concentrated hydrochloric acid and extracted again with diethyl ether (2×100 ml). This was washed with brine, dried and evaporated to give methyl 3-hydroxy-2-[(E)-2-styrylpyrrol-1-yl]acrylate (2.Og) as an orange-yellow oil. This was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1SC.O[O:15][S:16]([O-:18])=O.[K+].[CH3:20]O>C(#N)C.O>[CH3:20][S:16]([C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:18])=[O:15]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: COc1cc([N+](=O)[O-])ccc1SC
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
2-Methoxy-1-methylsulfanyl-4-nitro-benzene (797 mg, 4.0 mmol) was dissolved in methanol (10 ml) and acetonitrile (10 ml). A solution of Oxone (1.5 eq, 3.7 g) in 8 ml of water was added and the mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-methanesulfonyl-2-methoxy-4-nitro-benzene (631 mg, 68.2%) as a yellow crystalline solid.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[Si]([O:34][CH2:35][C:36]1[S:40][C:39]([C:41](=[N:43]O)[NH2:42])=[CH:38][CH:37]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O1CCCC1.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]2[O:14][N:43]=[C:41]([C:39]3[S:40][C:36]([CH2:35][OH:34])=[CH:37][CH:38]=3)[N:42]=2)=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)s1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: OCc1ccc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)s1
Yield: 55 %

Procedure:
To a solution of 4-phenoxybenzoic acid (0.12 g, 0.55 mmol) in acetonitrile (5 ml) were added successively 1-hydroxybenzotriazole (88 mg, 0.65 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.60 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxythiophene-2-carboximidamide (0.14 g, 0.5 mmol) that was obtained in Example 4 (4b) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, water (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with 0.1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in tetrahydrofuran (4.0 ml) was added tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 1.0 ml, 11.0 mmol) with stirring, and the resulting mixture was stirred at 60° C. for 3 hours. After stirring, the reaction mixture was poured into water (20 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (97 mg) in a yield of 55% as a white crystalline solid.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17].CC(O)=O.O.O.[Cl:25][Sn]Cl>O.Cl>[ClH:25].[CH:16]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:7]=1[NH:6][NH2:1])[C:11]([OH:13])=[O:12])([CH3:18])[CH3:17]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: CC(C)c1cc(C(=O)O)ccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc(C(=O)O)ccc1NN
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
A solution of 27.7 g of NaNO2 in 250 ml of water is added slowly to a mixture, cooled to -5° C., of 59 g of the product of step C with 1050 ml of AcOH and 1420 ml of concentrated HCl. After 1 hour 20 minutes of stirring at 0° C., the mixture is cooled to -10° C. and a solution of 236 g of SnCl2.2H2O in 250 ml of concentrated HCl is added. The temperature is allowed to rise to RT, and the precipitate is filtered off, washed with concentrated HCl and dried under vacuum to obtain 56.36 g of expected product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:21])C(Cl)=O.[CH3:23][N:24](C=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([N:24]([O:21][CH3:17])[CH3:23])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CON(C)C(=O)c1sccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 3-(benzyloxy)-2-thiophenecarboxylic acid (3.00 g, 12.81 mmol) in CH2Cl2 (30 mL) were added oxalyl chloride (1.34 mL, 15.4 mmol) and DMF (0.05 mL). The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL). Then the solution was added to a mixture of N,O-methylhydroxyamine hydrochloride (1.50 g, 15.37 mmol) and K2CO3 (3.54 g; 25.62 mmol) in ethyl acetate (30 mL) and water (30 mL) at 0° C. The mixture was vigorously stirred at 0° C. for 0.5 hrs, and at room temperature for 1.5 hrs. The organic phase was separated, washed with 1 N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give 3-(benzyloxy)-N-methoxy-N-methyl-2-thiophenecarboxamide as a pale yellow solid (3.473 g, yield; 98%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:35])[N:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13]([C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])=[N:14]2>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:21][C@H:19]([C:13]1[N:12]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:11](=[O:35])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[Cl:8])[N:14]=1)[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of (S)-tert-butyl 1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate (1 g, 2.5 mmol) in dichloromethane (3 mL). The resultant was stirred at room temperature for 3 hours. The solvent was removed in vacuuo to afford (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one 2,2,2-trifluoroacetic acid salt. ES/MS m/z=300.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O.[Cl-].[NH4+]>C(O)C.CN(C)C=O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)=[CH:10][C:11]=1[F:18]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(Oc2cc(Cl)ncn2)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
After dissolving 4-chloro-6-(3-fluoro-4-nitrophenoxy)pyrimidine (9.726 g) in ethanol (100 ml)-N,N-dimethylformamide (100 ml) at room temperature, water (50 ml), ammonium chloride (20 g) and electrolytic iron powder (10 g) were added and the mixture was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature. The insoluble portion was removed using celite prior to washing with ethyl acetate. The filtrate was concentrated under reduced pressure, and then the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was dried under reduced pressure to provide the title compound (8.204 g, 95%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[N:17]([CH3:18])[N:16]=[C:15]([S:19][CH3:20])[CH:14]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:13]1[N:17]([CH3:18])[N:16]=[C:15]([S:19]([CH3:20])=[O:29])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1nc(S(C)=O)cc1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 95.5 %

Procedure:
To a solution of 0.3 g of 5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-3-methylsulfenylpyrazole (compound 33) in 20 ml of anhydrous chloroform was slowly added 0.3 g of 70% m-chloroperbenzoic acid at -10° C. with stirring, followed by stirring for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and the organic layer was separated off and washed with a 5% aqueous sodium hydroxide solution and with brine. After drying the layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, giving 0.3 g of the desired compound in the form of white crystals (quantitative crude yield).
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:18]>O.ClCCl>[C:6]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:1][CH2:2][CH2:3][Br:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Br
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Solvent: O
Solvent: ClCCl
Product: BrCCC=C(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
At 0° C., cyclopropyl-diphenyl-carbinol (10.0 g) is dissolved in a hydrogen bromide solution 48% (40 ml). After being subjected to agitation for 5 hours at 0° C., the medium is diluted with water and dichloromethane, then the organic phase is washed three times with water. The organic phase is dried on MgSO4, filtered and concentrated to obtain the expected product as an orange oil (11.89 g).
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([O:10][P:11]([O:15]CC)[O:12][CH2:13][CH3:14])[CH3:9]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([P:11]([O:12][CH2:13][CH3:14])([O:10][CH2:8][CH3:9])=[O:15])[CH3:7]
Reactant: COC(=O)C(C)Br
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(C)C(=O)OC
Temperature: 110 °C
Reaction time: 48 h

Procedure:
Methyl 2-bromopropionate (100 g, 0.60 mol) and triethylphosphite (109 g, 0.66 mol) were mixed, and the mixture was stirred at 110° C. for 2 days. The reaction mixture was dried under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41]CO)[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][CH2:41][N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCN1CCOCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCN4CCOCC4)cc3)c2cc1OC
Yield: 70.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-morpholino-1-ethanol (34 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (54 mg, yield 60%).