Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[CH3:17]O>>[C:3]1([CH3:11])[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:17])=[O:9])[CH:2]=1
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1C
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1
Temperature: 65 °C
Reaction time: 17 h

Procedure:
A 3 L reaction flask was charged with methyl m-toluic acid (0.5 kg), anhydrous methanol (2 L), and sulfuric acid (100 g). The mixture was heated to reflux (65° C.) and aged for 14-20 hours, then cooled to an ambient temperature, and the acid was quenched with a two molar equivalent of sodium acetate. Methanol was distilled out of the flask and the mixture was washed with 1 L brine. The crude product was vacuum distilled to give 480 g of methyl m-toluate, which had a boiling point of 113° C. at a pressure of 25 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].[OH-].[Na+].CCOC(C)=O>CCO>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(F)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(F)cnn1C
Temperature: 50 °C
Yield: 47 %

Procedure:
4-Fluoro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (205 mg, 0.817 mmol) in EtOH (25 mL) was treated with Sn(II) chloride dihydrate (626.3 mg, 2.45 mmol) and heated to 50° C. for 12 hours. The reaction was allowed to cool to room temperature and 10% NaOH (100 ml) was added. EtOAc (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×50mL) and the organics combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was dissolved in DMSO (5 ml), and purified by preparative HPLC to afford 85 mg (47%) of 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine as a light brown oil. LCMS m/z (%)=222 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 7.38 (d, JH,F=4.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.79 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.64 (d, J=2.8 Hz, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.21 (s, 2H). 19F NMR (376 MHz, CDCl3) δ: −175.50 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])[CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[C:19]([O:29][CH3:30])[CH:18]=1)[CH2:4][CH2:5][CH3:6]>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])=[C:19]([O:29][CH3:30])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OS(=O)(=O)CC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCOc1cc(CCC(=O)O)ccc1CCCc1ccc(OS(=O)(=O)CC)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
ml (0.85 mmol) of aqueous 1N lithium hydroxide solution are added to a solution of 259 mg (0.6 mmol) of methyl 3-{3-butoxy-4-[3-(4-ethanesulfonyloxy-3-methoxyphenyl)propyl]phenyl}propanoate in 3 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 12 hours, concentrated and then taken up in water, acidified by adding hydrochloric acid solution and then extracted with ethyl acetate ethyl. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. After triturating in heptane, 208 mg (83%) of 3-{3-butoxy-4-[3-(4-ethanesulfonyloxy-3-methoxyphenyl)propyl]phenyl)propanoic acid are obtained in the form of white crystals with a melting point of 64° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH-:19].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1C[NH-]
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
5.7 g of 4-(trifluoromethyl)benzoic acid and 4.0 g of 2-methoxybenzylamide were dissolved in 100 ml N,N-dimethylformamide, and 4.8 ml diethyl cyanophosphonate and 4.2 ml triethylamine were added under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours, then poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 8.7 g of N1-(2-methoxybenzyl)-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O1CCCC1>[C:16]1([CH2:15][O:14][C:12]([NH:8][C@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 411.3 %

Procedure:
A mixture of D-allylglycine (2.8 g, 24.3 mmol), 1M aqueous sodium hydroxide solution (25 ml), and tetrahydrofuran (10 ml, distilled from ketyl) was stirred at room temperature until homogeneous then cooled in an ice-bath. To the resulting rapidly stirred solution was added about 5 mL of 1.0M aqueous sodium hydroxide solution then dropwise about 1 g of benzyl chloroformate. This was repeated 4 additional times until a total of 28 mL of 1.0M aqueous sodium hydroxide solution and 4.80 g (95%, 27 mmol) of benzyl chloroformate were added. The reaction mixture was stirred for 15 minutes at 0° C. then 30 minutes at room temperature and then extracted with 50 mL of ether. The aqueous layer was acidified (pH=1.5) the by addition of 6N hydrochloric acid solution (about 10 mL) then extracted with three-50 mL portions of ether. The three ether extracts were combined, dried (magnesium sulfate) and concentrated in vacuo to afford 6.01 g of title product as a colorless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11](B(O)O)=[C:10]([F:18])[CH:9]=1.Br[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[C:10]([F:18])[CH:9]=1
Reactant: OB(O)c1c(F)cc(CCC2OCCO2)cc1F
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2c(F)cc(CCC3OCCO3)cc2F)cc1
Yield: 51.9 %

Procedure:
To 150 ml of N,N-dimethyl formamide (hereinafter abbreviated as “DMF”) were added 7.0 g (27 mmol) of 4-(1,3-dioxolan-2-ylethyl)-2,6-diflurophenyl boronic acid obtained in Step 2, 5.0 g (27 mmol) of 4-bromobenzonitrile, 10 g (99 mmol) of triethyl amine, 0.20 g (0.89 mmol) of palladium acetate and 0.50 g (1.9 mmol) of triphenylphosphine and the mixture was refluxed for 4 hours. The solvent was distilled off under reduced pressure. To the residue of this distillation were added 500 ml of methylene chloride and 250 ml of a 10% aqueous ammonia and the mixture was stirred. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluting solvent: toluene/ethyl acetate=5/1) and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with ethanol and then dried under reduced pressure to afford 4.4 g (14 mmol) of 1-(1,3-dioxolan-2-ylethyl)-3,5-difluoro-4-(4-cyanophenyl)benzene. (Yield: 52%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([O-:43])=[O:42])[CH:8]=[CH:9][CH:10]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(O)C.O>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([OH:43])=[O:42])[CH:8]=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)OC)c1)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 25.6 %

Procedure:
Methyl (1RS, 2SR, 3RS)-3-[2-(3-Carbomethoxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.08 g, crude) was dissolved in propan-2-ol (1 ml) and aqueous sodium hydroxide (1M, 1 ml ,1 mmol) added. The mixture was refluxed for 12 hr. then cooled, diluted with water, acidified with 3M-aqueous hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extract was purified by column chromatography on silical-gel (eluant: 30% EtOAc/hexane/5%AcOH) to give the title compound as a colorless solid (20 mg)
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:20](=[O:21])[C@H:9]2[N:8]([C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)[C:32]1=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Reactant: O=C=NCc1ccccc1
Product: O=C1[C@@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C(=O)N1Cc1ccccc1

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate (see J. Cook et al., Heterocycles, 4(7), 1249-1255 (1976)) and benzyl isocyanate gave after recrystallization from diethyl ether, the title compound as white crystals m.p.: 200-202° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16][CH3:17])=[N:14][N:15]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16][CH3:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSc1nnc(-c2ccc3[nH]cc(I)c3c2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nnc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 2-(3-iodo-1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (7.0 g, 18.7 mmol) in DMF (70 mL) was added NaH 60% in mineral oil (1.5 g, 37.4 mmol) followed by TsCl (5.3 g, 28.1 mmol). The reaction was stirred at RT for 8 h, and the mixture was then poured into ice/H2O. The resulting precipitate was filtered, washed with water and dried to give 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (7.7 g, 78%). MS (ESI, pos. ion) m/z: 528 (M+1); 1H-NMR (DMSO-d6, 300 MHz): 2.3 (s, 3H), 2.8 (s, 3H), 7.4 (d, 2H) 7.8 (d, 1H) 7.95 (m, 3H), 8.1 (d, 1H), 8.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:24]([CH2:23][N:11]([C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:19](=[O:20])[NH2:21])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:25][CH:26]=1
Reactant: NC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CN([C@@H]2CCCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 28 %

Procedure:
The titled compound (321 mg) was prepared in 28% yield from cis-2-(4-chlorobenzenesulfonylamino)-cycloheptanecarboxylic acid amide (800 mg, 2.42 mmol) and methyl 4-(bromomethyl)benzoate according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.83 (m, 4 H), 7.65 (d, 2 H,J=8.0 Hz), 7.45 (d, 2 H, J=12.0 Hz), 7.31 (s br, 1 H), 6.64 (s br, 1 H), 4.60 (AB2,2 H,Δv=16,Jab=92 Hz), 3.96 (m, 1 H), 3.85 (m, 3 H), 2.78 (m, 1 H), 2.28 (m, 1 H), 1.72 (m, 2 H), 1.35 (m, 7 H); MS m/e 479.12 (M+H)+.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)[CH3:22]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:28][CH2:27]4)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3C)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 537.0 [M+H]+; tR=3.18 min (System 1); Rf=0.16 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]#[N:7])[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C#N)Cc1ccccc1

Procedure:
Cyanoacetic acid ethyl ester was alkylated with benzyl bromide in the presence of sodium ethylate in ethanol to give benzyl-cyanoacetic acid ethyl ester [MS: 203 (M)+ ] which was then subsequently hydrolyzed with 1N sodium hydroxide solution in a 9:1 mixture of methanol and water to give the corresponding acid. Recrystallization of the crude product from methylene chloride/hexane yielded benzyl-cyanoacetic acid as crystals of melting point 97°.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:4]=1)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
tert-Butyl 3-[2-(methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.22 g, 0.53 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (77%, 0.12 g, 0.53 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from hexane-ethyl acetate to give the titled compound (0.17 g, 86%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][O:14][CH3:15])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[K+].Cl>>[CH3:1][O:2][C:3]1[C:4]([CH2:13][O:14][CH3:15])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COCc1c(OC)cccc1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COCc1c(OC)cccc1C(=O)O
Reaction time: 16 h
Yield: 91.4 %

Procedure:
6.27 g of methyl 3-methoxy-2-methoxymethylbenzoate was stirred with a 20% aqueous KOH solution (6.7 g, 0.12 mol in 34 g of solution) at 50° C. in an oil bath for 4-5 hours, and then at room temperature for 16 hours. The reaction mixture was acidified with 3N HCl to pH 2 and extracted with CH2Cl2. The CH2Cl2 extract was dried and evaporated to yield 5.35 g of 3-methoxy-2-methoxymethylbenzoic acid (92% yield). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.65 (1H, d), 7.40 (t, 1H), 7.10 (d, 1H), 4.83 (s, 2H), 3.88 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl) -6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:21]([N:26]=[C:27]=[O:28])(=[O:25])[C:22]([CH3:24])=[CH2:23]>ClCCCl>[C:21]([NH:26][C:27](=[O:28])[O:8][CH:7]([C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)N=C=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Yield: 102.1 %

Procedure:
Into a three-necked flask purged with nitrogen gas, benzoin (2.12 g; 10 mmol) was charged, and chloroform (30 ml) was added thereto. To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (7 g) was dropwise added in 5 minutes under nitrogen stream while stirring. Chloroform and 1,2-dichloroethane were removed by evaporation under reduced pressure to give benzoylbenzyl N-methacryloylcarbamate (3.3 g), which was recrystallized from a mixture of benzene and chloroform to give colorless transparent plates. M.P., 161°-163° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2[S:7](=[O:10])(=[O:9])[NH:8][C:11](=[O:13])[C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)O)c(S(N)(=O)=O)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2c(s1)S(=O)(=O)NC2=O
Yield: 49 %

Procedure:
A mixture of 0.1 gm (0.45 millimols) of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid, 50 ml of anhydrous toluene and 5 mgm of p-toluene-sulfonic acid was heated for 10 hours in a vessel equipped with a water trap. The reaction mixture was evaporated to dryness in vacuo and separated by column chromatography. 0.40 mgm (49% of theory) of 5-methyl-thieno[3,2-d]isothiazole-3(2H)-one-1,1-dioxide were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][S-:11].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C[S-]
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1cc(Cl)nc(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine (11.5 g, 70.6 mmol, Aldrich) and sodium methanethiolate (5.93 g, 85 mmol, Aldrich) in toluene (50 mL) was stirred at 25° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with brine, and dried over Na2SO4. The crude product was purified by recrystallization from hexane to give 4-chloro-2-methyl-6-(methylthio)pyrimidine (5.5 g, 31.5 mmol, 44.6% yield) as white crystals. 1H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H); 2.64 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 175 (M+H)+.
Reaction SMILES: [Br:1][C@@H:2]([CH2:6][OH:7])[C:3](O)=[O:4].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:3](=[O:4])[C@@H:2]([Br:1])[CH2:6][OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)[C@@H](Br)CO
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)[C@@H](Br)CO

Procedure:
In one of the embodiments of the present invention, the compound (2S)-2-bromo-3-hydroxypropanoic acid of Formula-XVIII is subjected to react with benzylamine in presence of a base and an activator under mixed anhydride coupling condition to get (2S)-N-benzyl-2-bromo-3-hydroxypropanamide of Formula-XIX. The mixed anhydride coupling reaction conditions as described by Anderson, et al., in JACS, 1967, 89, 5012-5017, the contents of which are incorporated herein by reference. The activators used to activate the carbonyl group are selected from optionally substituted alkyl or aryl chloroformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, pivolyl chloride, 1,1-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N,N′-dicyclohexylcarbodiimide. The preferred activator used is alkyl chloroformate selected from methyl chloroformate, ethyl chloroformate and isobutyl chloroformate wherein the most preferred activator used is isobutyl chloroformate. The base used in the reaction is selected from N-methylmorpholine, pyridine, N,N-diisopropylethylamine and triethylamine wherein the preferred base used is N-methylmorpholine. The reaction is carried out in the presence of solvent at temperature in the range of −20° C. to 30° C. The solvent used for the reaction is selected from dichloromethane, ethyl acetate, toluene and tetrahydrofuran. The preferred solvent used for the reaction is ethyl acetate. Accordingly, the compound (2S)-2-bromo-3-hydroxypropanoic acid of Formula-XVIII is taken in ethyl acetate and the isobutyl chloroformate is charged at 20-30° C. Stirred and cooled the reaction mixture to −20° C. Maintaining the temperature at −20° C. charged base N-methylmorpholine and benzylamine to the reaction mass. The reaction is maintained between −20° C. to 30° C. for 4-10 hours. After completion of the reaction, concentrated the reaction mass under reduced pressure, maintaining temperature below 40° C. to get the residual mass. Charged non polar solvent to isolate the compound (2S)-N-benzyl-2-bromo-3-hydroxypropanamide of Formula-XIX. The non polar solvent used for isolation of the compound is selected from hexane, heptane and diisopropyl ether, wherein the preferred non polar solvent used is diisopropyl ether. Stirred and filtered the separated solid product, washed with water and dried to get the compound (2S)-N-benzyl-2-bromo-3-hydroxypropanamide of Formula-XIX.