Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:26])[CH2:13][NH:14][C@H:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([OH:25])=[CH:20][CH:21]=4)[CH2:16]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[CH:28]([N:31]([CH2:35]C)[CH:32](C)C)(C)[CH3:29].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:40].O>C(Cl)Cl.[Cl-].[Na+].O.CO>[CH3:1][C:2]1([CH3:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:26])[CH2:13][NH:14][C@H:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([O:25][CH2:29][C:28]([N:31]([CH3:35])[CH3:32])=[O:40])=[CH:20][CH:21]=4)[CH2:16]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)OCc2cc([C@@H](O)CN[C@H]3CCc4ccc(O)cc4C3)ccc2O1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc3c(c1)COC(C)(C)O3)CC2
Temperature: -15 °C

Procedure:
(-)-(1R)-1-(2,2-Dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]-ethanol (5.15 g) and 11.3 ml of N,N-diisopropylethylamine were added to 125 ml of methylene chloride, a solution of 5.51 ml of trifluoroacetic anhydride in 16 ml of methylene chloride was added to the resulting suspension with stirring at -15° C., and the mixture was subjected to 30 minutes of reaction. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The resulting residue was dissolved in 63 ml of N,N-dimethylformamide, 5.0 g of molecular sieves 4A powder, 3.24 g of 2-bromo-N,N-dimethyl-acetamide and 19.0 g of cesium carbonate were added to the solution, and the mixture was stirred at room temperature for 2 hours. Then, 2.02 ml of diethylamine was added and the mixture was subjected to 20 minutes of reaction at room temperature. After adding 90 ml of water and 180 ml of methanol to the reaction solution under ice-cooling, the mixture was stirred at room temperature for 1.5 hours. Then, brine was added and the mixture was extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate) to give 3.22 g of (-)-(2R)-2-[(2S)-2-[[2-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide in an oily form.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[Na].[CH3:16][SH:17].O>CO>[CH3:16][S:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CS
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: CSCC(=O)c1ccc(C(F)(F)F)cc1
Yield: 97.7 %

Procedure:
To 13.2 g of 2-bromo-4'-(trifluoromethyl)acetophenone dissolved in 40 ml of methanol was added under ice-cooling 34.6 g of a 15% aqueous solution of methyl mercaptan sodium salt. After the reaction at room temperature for 1 hour with stirring, the resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by evaporation of the solvent to obtain 11.3 g of oily product of 2-methylthio-4'-(trifluoromethyl)acetophenone (yield: 97.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A solution of m-nitrophenol (1.8 g, 13 mmol) in dichloromethane (13 mL) was treated with dihydropyran (1.7 mL, 19 mmol) followed by pyridinium p-toluenesulfonate (0.32 g, 1.2 mmol) and stirred at 25° C. for 16 h. The reaction mixture was diluted with dichloromethane and washed with 1:1 brine/water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude oil. This material was purified by flash column chromatography to give the desired product (2.5 g, 88%) as a clear oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CO.CCOC(C)=O>[CH3:23][S:24]([O:13][CH2:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1cc(-c2ccccc2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 5-phenylisoxazole-3-carbaldehyde (500 mg, 2.89 mmol) in MeOH (10 mL) at 0° C., was added NaBH4 (327 mg, 8.67 mmol). The reaction was slowly warmed to room temperature, stirred for 15 h and concentrated in vacuo. The solid obtained was dissolved in EtOAc, washed with H2O (1×) and saturated NH4Cl (3×). The organic layers were combined, dried over MgSO4, filtered, concentrated and dissolved in anhydrous CH2Cl2 (8 mL). The mixture was cooled to 0° C., followed by addition of Et3N (1.02 mL, 7.25 mmol) and methanesulfonyl chloride (337 μL, 4.35 mmol). The reaction was slowly warmed to room temperature and stirred for 15 h. Upon completion, the reaction was quenched with aqueous NaHCO3 (5 mL) and extracted with EtOAc. The combined organic layers were washed with NaHCO3 (2×), dried over MgSO4, filtered, concentrated and carried onto the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>ClCCl>[C:22]1([CH3:23])[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCc1ccc(CCCCO)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 1.1 g of 4-(4-butylphenyl)butanol, 1.05 g of tosyl chloride, 0.48 ml of pyridine and a catalytic amount of dimethylaminopyridine in dichloromethane was allowed to stand at room temperature overnight. The reaction mixture was poured into 50 ml of ice water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane: 1:6) to give 1.2814 g of 4-(4-butylphenyl)butyl p-toluenesulfonate as a colorless, oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:30]O.Cl>CO.CO.O.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:20][NH:30][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(Cl)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
A solution of cis-methyl 2-(4-chlorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.45 g, 3.80 mmol) in MeOH (10 mL) was added to a solution of sodium hydroxide (3.16 mL, 3.80 mmol) in MeOH/H2O (2.981 mL/0.179 mL) at −30° C. After 10 min a solution of hydroxylamine hydrochloride (0.528 g, 7.59 mmol) and sodium hydroxide (0.304 g, 7.59 mmol) in MeOH (10 mL) and H2O (10 mL) was added. Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (6.33 mL, 37.97 mmol) at 80° C. and heated at 80° C. for 1 hour. Concentration of the organic solvent and extraction with diethyl ether (×3), drying over Na2SO4 and evaporation gave a yellow foam. Purification using prepLC (2 injections, pH=3, large column 20-80% MeCN over 30 min) yielded cis-methyl 2-(4-chlorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (557 mg, 41%). 1H NMR (400 MHz, cdcl3) δ 1.83-2.00 (m, 3H), 2.02-2.12 (m, 1H), 2.59 (dd, 1H), 2.77 (dd, 1H), 2.97-3.02 (m, 1H), 3.08-3.20 (m, 1H), 3.62 (s, 3H), 4.00 (dd, 1H), 4.21-4.29 (m, 1H), 5.73 (s, 1H), 7.04 (d, 2H), 7.21-7.25 (m, 2H). MS m/z 351, 353 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(C)(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:16]=1[S:23]([NH2:26])(=[O:25])=[O:24]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:6]2[CH:5]=[CH:4][C:3]([F:8])=[CH:2][CH:7]=2)[OH:22])=[CH:17][C:16]=1[S:23]([NH2:26])(=[O:25])=[O:24]
Reactant: Fc1ccccc1Br
Reactant: NS(=O)(=O)c1cc(C=O)ccc1Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(O)c2ccc(F)cc2)ccc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
A solution of 590 mg of 1-bromofluorobenzene (1.11 mmol, 3 equivalent) in 10 mL of anhydrous tetrahydrofuran is stirred at −78° C. as 3.9 mL of tert-butyllithium (1.7 M in cyclohexane, 6.66 mmol, 6 equivalent) is added drop-wise. The reaction mixture is stirred at −78° C. for 2 h, then is transferred to a previously prepared a solution of 243 mg of 2 chloro-5-formyl-benzenesulfonamide (1.11 mmol, 1 equivalent) and 0.65 mL of tert-butyllithium (1.7 M in cyclohexane, 1 equivalent) in 10 mL of anhydrous tetrahydrofuran. The reaction is allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction is quenched with 0.1 N HCl and then extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and concentrated in vacuo to give 65 mg of the title compound which is carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)=[O:4].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)#[N:14].[O-2].[Al+3].[O-2].[O-2].[Al+3]>C1C=CC=CC=1>[C:3](=[O:4])([O:2][CH3:1])[O:5][C:6]1[CH:12]=[CH:11][C:9]([N:10]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)Oc1ccc(N)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: COC(=O)Oc1ccc(N=Cc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 0.835 g. of p-methoxycarbonyloxyaniline and 0.655 g. of p-cyanobenzaldehyde is gassed with argon in 50 ml. of benzene and heated under reflux for 1 hour (bath temperature 130°). The resulting water is separated with a water separator. During an additional hour, benzene condensed in the reflux condenser is now passed back into the reaction vessel through a layer of 20 g. of aluminium oxide (act. I). After cooling, the reaction mixture is freed from solvent in vacuum at 50°C. bath temperature, whereby there remain 1.395 g. of yellowish crystals which are recrystallized several times from isopropanol up to constant melting point and clearing point and up to the disappearance of side-products in the gas chromatogram. The pure, slightly yellowish p-[(p-cyanobenzyliden)amino]phenyl methyl carbonate obtained has a melting point of 145.1°-146.2° and a clearing point of 163.4°. UV (EtOH): ε270 = 20,250, ε324 = 10,800 (shoulders at 243 and 221 nm; minima at 312 and 233 nm).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:12])=[CH:9][C:10]=1[OH:11])=[O:4].[CH2:13]([O:15][C:16](=[O:22])[C:17](OCC)=O)[CH3:14].Cl>C(O)C.C(OCC)C.O>[CH2:13]([O:15][C:16]([C:17]1[O:11][C:10]2[CH:9]=[C:8]([OH:12])[CH:7]=[CH:6][C:5]=2[C:3](=[O:4])[CH:2]=1)=[O:22])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1

Procedure:
To a warm, stirred solution of 18.4 g (0.8 mole) of sodium metal in 250 ml of absolute ethanol was added dropwise a solution of 30.4 g (0.2 mole) of 2,4-dihydroxyacetophenone and 58.5 g (0.4 mole) of diethyloxalate in 50 ml of absolute ethanol and 50 ml of absolute ethyl ether over a 30-min period. The mixture was heated at reflux for 4 hr and then poured into a solution of 200 ml of concentrated hydrochloric acid and 1.8 liter of water. The mixture was extracted with two 500-ml portions of ethyl ether and the combined extracts were concentrated under reduced pressure to give a solid residue.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27](I)[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:27][CH3:28])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
In the same manner as in Example 81, 143 mg of the title compound was prepared from 265 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 0.063 ml of ethyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:4].[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1sccc1OC
Temperature: 55 °C
Yield: 108.4 %

Procedure:
To a mixture of 3-hydroxy-thiophene-2-carboxylic acid methyl ester (5 g, 31.6 mmol) and K2CO3 (22.2 g, 161 mmol) in acetone (50 mL) is added CH3I (10.8 mL, 173 mmol,) dropwise at 0° C. The reaction mixture is heated at 55° C. for 4 hours, cooled to room temperature, filtered through diatomaceous earth, and the filtrate is concentrated under vacuum. The residue is diluted with water (100 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layer is washed with brine solution (50 mL), dried over Na2SO4, and evaporated under vacuum to give title compound as a brown solid (5.9 g). ESI/MS m/z 173.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[NH:29][C:28](=[O:42])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[NH:29][C:28](=[O:42])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NCc4ccc(F)cc4)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 69 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one 3e obtained from step 4 of Example 3 as starting materials to obtain (Z)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 19 (57 mg, yield 69%) as a carmine solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([CH3:46])[CH:45]=1)[C:6]([C:8]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([N:22](CC3C=CC(OC)=CC=3)[C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:18]=[C:19]([F:21])[CH:20]=2)[C:12](=[O:38])[NH:11][C:10](=[O:39])[C:9]=1[CH:40]([CH3:42])[CH3:41])=[O:7])#[N:2].O>C(#N)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([CH3:46])[CH:45]=1)[C:6]([C:8]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:18]=[C:19]([F:21])[CH:20]=2)[C:12](=[O:38])[NH:11][C:10](=[O:39])[C:9]=1[CH:40]([CH3:41])[CH3:42])=[O:7])#[N:2]
Reactant: COc1ccc(CN(C(=O)C(F)(F)F)c2cc(F)cc(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)c2)cc1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)cc(NC(=O)C(F)(F)F)c2)c1
Reaction time: 24 h
Yield: 76.2 %

Procedure:
N-{3-[6-(3-Cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2 H-pyrimidin-1-ylmethyl]-5-fluoro-phenyl}-2,2,2-trifluoro-N-(4-methoxy-benzyl)-acetamide (389 mg, 0.61 mmol) was dissolved in acetonitrile (6 ml). With stirring, ceric ammonium nitrate (669 mg, 1.2 mmol) and distilled water (3 ml) were added in this order. After 24 hr., the mixture was diluted with ethyl acetate, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexane (1:2)) to afford 240 mg (76%) of a white solid. 1H NMR (200 MHz, DMSO-d6) δ 1.03 (3H, d, J=6.8 Hz), 1.18 (3H, d, J=6.8 Hz), 2.09 (1H, m), 2.32 (3H, s), 4.42 (1H, d, J=16.8 Hz), 4.97 (1H, d, J=16.8 Hz), 6.80 (1H, m), 7.08 (1H, s), 7.31 (1H, m), 7.91 (1H, s), 7.96 (1H, s), 8.16 (1H, s), 11.28 (1H, s), 11.69 (1H, s).
Reaction SMILES: C[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[NH2:13])=O.[NH2:14][C:15](N)=[O:16].[C:18](O)(=O)C>O>[CH3:18][C:10]1[CH:9]=[C:8]([O:11][CH3:12])[CH:7]=[C:6]2[C:5]=1[C:3]([CH3:2])=[N:14][C:15]([OH:16])=[N:13]2
Reactant: NC(N)=O
Reactant: CC(=O)O
Reactant: CCC(=O)c1ccc(OC)cc1N
Solvent: O
Product: COc1cc(C)c2c(C)nc(O)nc2c1
Temperature: 100 °C

Procedure:
To methyl 1-(4-methoxy-2-aminophenyl)ethanone (1 eq) was added urea (5 eq) and few mls of acetic acid the mixture was heated to 100° C. for 16 h. To the crude was added water and the precipitated solid was filtered to give methyl 7-methoxy-4-methylquinazolin-2-ol in quantitative yield. ES/MS m/z 191 (MH+).
Reaction SMILES: [OH:1][C@H:2]([C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[O:26][CH2:27][C:23]=2[C:22]=1[CH3:31])[CH2:3][N:4]1[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.[ClH:32]>O1CCOCC1>[Cl-:32].[OH:1][C@H:2]([C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[O:26][CH2:27][C:23]=2[C:22]=1[CH3:31])[CH2:3][N:4]1[CH2:13][C:8]2([CH2:9][CH2:10][CH2:11][CH2:12]2)[NH2+:7][CH2:6][CH2:5]1
Reactant: Cl
Reactant: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C3(CCCC3)C2)ccc2c1COC2=O
Solvent: C1COCCO1
Product: Cc1c([C@@H](O)CN2CC[NH2+]C3(CCCC3)C2)ccc2c1COC2=O
Product: [Cl-]
Reaction time: 3 h

Procedure:
A suspension of tert-butyl 9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-6,9-diazaspiro[4.5]decane-6-carboxylate (80 mg, 0.20 mmol) in dioxane (200 L) was treated with a solution of hydrochloric acid in dioxane (4.0 M, 200 L). After shaking for 3 hours, the solution was treated with additional hydrochloric acid in dioxane (4.0 M, 100 L). After shaking an additional sixteen hours, the solvents were removed in vacuo to provide 9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-9-aza-6-azoniaspiro[4.5]decane chloride which was carried on without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[S:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[S:20]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O:23][CH3:24])(=[O:22])=[O:21]>>[S:20]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O-:23])(=[O:22])=[O:21].[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[S:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:24]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc2ccc(-c3nc4ccccc4s3)cc2s1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1sc2cc(-c3nc4ccccc4s3)ccc2[n+]1C
Temperature: 25 °C

Procedure:
2-methyl-6-(benzothiazol-2-yl)-benzothiazole (44 mg, 0.156 mmol) was stirred for 5 h at 90° C. in melted methyl tosylate (660 mg, 3.5 mmol). After being allowed to cool to room temperature, the product was precipitated by addition of acetone and collected by filtration. The precipitate was washed with acetone and allowed to dry over night. This gave the product as green crystals. Yield: 51 mg, 70%. 1H NMR (DMSO): δ 2.28 (s, 3H, —CH3), 3.20 (s, 3H, CH3), 4.24 (s, 3H, —CH3), 7.11 (d, J=7.2, 2H, ArH), 7.46 (d, J=7.2, 2H, ArH), 7.55 (t, J=7.6, 1H, ArH), 7.62 (t, J=7.6, 1H, ArH), 8.14 (d, J=8, 1H, ArH), 8.25 (d, J=8, 1H, ArH), 8.45 (d, J=8.8, 1H, ArH), 8.59 (d, J=8.8, 1H, ArH), 9.24 (s, 1H, ArH). HR-FAB-MS m/z Found: 297.067 C16H13N2S2 (M+): requires M, 297.052.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].F[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29].Cl>CN(C=O)C.O>[C:11]([O:10][C:8]([NH:1][C@@H:2]([CH2:3][O:4][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])[C:5]([OH:7])=[O:6])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1c([N+](=O)[O-])cccc1C(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of BOC-Ser-OH (981 mg, 4.78 mmol) in DMF (5.00 mL) was added to a suspension of NaH (60% in mineral oil, 402 mg, 10.0 mmol) in DMF (5 mL). The mixture was stirred at 0° C. for 1 h and a solution of 2-fluoro-1-nitro-3-(trifluoromethyl)benzene (1 g, 4.78 mmol) in DMF (5 mL) was added. After 2 h the mixture was diluted with H2O and acidified to pH 3 with 1 N HCl. The mixture was extracted with EtOAc, the combined extracts dried over MgSO4, filtered and the filtrate concentrated to give a residue that was purified by silica gel chromatography to afford (S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-6-(trifluoromethyl)phenoxy)propanoic acid (1.53 g, 81%) as a light yellow solid. MS m/z 417 (M+Na)′
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[CH:2]=[CH2:3].[S:10]1C=CC=C1.O1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:3]12[S:10][CH:17]([CH:18]=[CH:19]1)[CH2:16][CH:2]2[C:1]([O:5][CH2:6][CH2:7][CH2:8][OH:9])=[O:4]
Reactant: C1CCOC1
Reactant: C=CC(=O)OCCCO
Reactant: c1ccsc1
Product: O=C(OCCCO)C1CC2C=CC1S2
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Tetrahydrofuran solvent (500 g), 3-hydroxypropyl acrylate (1.2 mole) of Chemical Formula 3b below, and thiophene (1.0 mole) are introduced to a 2-liter flask, and the mixture is stirred at 70° C. for 24 hours. After the reaction is completed, the solvent and excess amount of 3-hydroxypropyl acrylate were removed by using a rotary evaporator. The residue is distilled in vacuo to obtain pure 3-hydroxypropyl 7-thiabicyclo[2.2.1]hept-5-ene-2-carboxylate represented by Chemical Formula 109 (yield: 80%).