Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[NH:33][C:34]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21])=[O:35]
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1N
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 62 %

Procedure:
Using Method F2 with 8-(4-amino-3-(methylthio)phenoxy)pyrido[3,2-b]pyrazin-3(4H)-one and 2-fluoro-5-trifluoromethylphenyl isocyanate, the title compound (26 mg, 62%) was obtained as a powder.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=O)[C:12]=2[CH3:14])[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1)[CH3:2].[CH2:20]([N:22]1[C:26]([OH:27])=[CH:25][CH:24]=[N:23]1)[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:25]3[CH:24]=[N:23][N:22]([CH2:20][CH3:21])[C:26]=3[OH:27])=[O:17])[C:12]=2[CH3:14])[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCn1nccc1O
Reactant: CCSC1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCSC1CCS(=O)(=O)c2ccc(C(=O)c3cnn(CC)c3O)c(C)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
0.51 Gram (1.7 mmol) of 4-ethylthio-5-methyl-6-carboxythiochroman-1,1-dioxide was dissolved in 5 ml of t-amyl alcohol, and 0.22 g (2.0 mmol, 1.2 eq.) of 1-ethyl-5-hydroxypyrazole and 0.42 g (2.0 mmol, 1.2 eq.) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 3 hours, and then 0.18 g (1.3 mmol) of potassium carbonate was added. The mixture was heated at 80° C. for 8 hours. After the completion of the reaction, the solvent was distilled off. The remaining oil was dissolved in ethyl acetate and product was extracted with a 5 wt % sodium hydrogencarbonate aqueous solution. 2N Hydrochloric acid was added to the resultant aqueous solution to adjust a pH of 1, and the mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 0.5 g (75%) of 4-ethylthio-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH2:6]([S:8][CH:9]([CH2:14][CH3:15])[CH2:10][N+:11]([O-:13])=[O:12])[CH3:7].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:6]([S:8][C:9]([CH2:14][CH3:15])=[CH:10][N+:11]([O-:13])=[O:12])[CH3:7]
Reactant: CCSC(CC)C[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCSC(=C[N+](=O)[O-])CC
Reaction time: 0.25 h
Yield: 13 %

Procedure:
2-Ethylthio-1-nitrobutene was prepared by adding a solution of sulfuryl chloride (20.16 g., 0.149 mol) in methylene chloride (30 ml.) to a stirred solution of 2-ethylthio-1-nitrobutane (23.02 g., 0.141 mol) in methylene chloride (100 ml.) at 0° C. The resulting solution was stirred for 15 minutes after addition was complete, and the volatile components were removed under reduced pressure. The residue was dissolved in methylene chloride (100 ml.) and a solution of triethylamine (14.27 g., 0.141 mol) in methylene chloride (30 ml.) was added at 0C. Once addition was complete, the solution was stirred for 15 minutes, and then was poured into dilute aqueous hydrochloric acid solution (400 ml.). The organics were separated and washed with deionized water (2×75 ml.), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography(10:1 hexanes/ethyl acetate) yielded the product as a yellow oil, 2.85 g., 13% yield. 1H-NMR (CDCl3): δ 1.26, m, 3H, --CH3 ; 1.36, m, 3H, --CH3 ; 2.55, q, 2H, --CH2 --; 2.92, q, 2H, SCH2 --; 7.2, s, 1H, olefinic H.
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.[C:11]([O:15][CH3:16])(=[O:14])C=C.C1(C=CC(O)=CC=1)O>>[CH3:16][O:15][C:11]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:14]
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reactant: C=CC(=O)OC
Agent: Oc1ccc(O)cc1
Product: COC(=O)C12C=CC(CC1)C2
Temperature: 220 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
DCPD (Aldrich, 256.5 mL, 1.9 mol), methyl acrylate (Aldrich, 405 mL, 4.5 mol), and hydroquinone (3.2 g, 0.03 mol) were put in a 2 L autoclave. After heating to 220° C., reaction was carried out for 5 hours while stirring the autoclave at 300 rpm. After the reaction was completed, the reaction mixture was cooled down and transferred to a distillation unit. The reaction mixture was distilled at 1 torr using a vacuum pump at 50° C. to obtain the product (yield: 57.6%). The molar ratio (mol %) of exo/endo isomers of the product was 58.6:41.4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]=[N+]=[N-])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=N[C@H]1CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 62 %

Procedure:
The compound (3S)-1-benzyl-3-azidopyrrolidine (0.9 g, 4.5 mM) was dissolved in a mixture of tetrahydrofuran (36.0 ml) and water (7.0 ml). To it, triphenylphosphine (2.3 g, 8.9 mM) was added and the reaction mixture was refluxed for 7 hours. The reaction mixture was cooled to room temperature and tetrahydrofuran was evaporated under vacuum. The residue was taken in water (50.0 ml) and the pH was adjusted to about 2 and washed with chloroform. The pH of the aqueous solution was adjusted to about 12-13 with 1N sodium hydroxide and extracted with chloroform. The chloroform layer was washed with water and brine solution. It was further dried over anhydrous sodium sulphate and concentrated to give the title compound. Yield=62% (0.5 g, 2.8 mM).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@@H:10]([NH2:20])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>O1CCCC1>[NH2:20][C@@H:10]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][OH:8]
Reactant: COC(=O)[C@@H](N)CCOc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@H](CO)CCOc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (282 mg) in tetrahydrofuran (4 ml) was added a solution of (S)-2-amino-4-phenoxy-butyric acid methyl ester (778 mg) in tetrahydrofuran (3 ml) and the mixture was stirred for 2 hours at 50° C. Sodium hydroxide solution (4N) was added until gas evolution ceased and the suspension was filtered through Celite. The solvent was evaporated and the residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=98:2) to yield a colourless oil, (180 mg, 27%); MS (ISP): 182.3 ((M+H)+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[N:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[Br:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22]Br>>[Br:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][N:10]([C:11]1[C:16]([Cl:17])=[N:15][CH:14]=[CH:13][N:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Nc1nccnc1Cl
Reactant: BrC/C=C/CBr
Product: O=[N+]([O-])c1ccccc1N(C/C=C/CBr)c1nccnc1Cl

Procedure:
Similar to Production Example 132, 5.04 g of 2-[(2-nitrophenyl)amino]-3-chloropyrazine was treated with (E)-1,4-dibromo-2-butene to thereby give 0.34 g of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClC(Cl)C>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1
Reactant: c1ccc2c(c1)Oc1cc(-c3nnn[nH]3)ccc1N2C1CCNCC1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)Oc1cc(-c3nnn[nH]3)ccc1N2C1CCN(Cc2ncc[nH]2)CC1
Temperature: 80 °C
Yield: 6.5 %

Procedure:
To a solution of the TFA salt of 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a (40.7 mg; 0.091 mmol) and 1H-imidazole-2-carboxaldehyde (35 mg; 0.36 mmol) in dichloroethane (5 mL) was added tetramethylammonium triacetoxyborohydride (36 mg; 0.14 mmol). The mixture was heated to 80° C. for 15 hr in a sealed tube. The mixture was allowed to cool to rt, and the solvent was removed via evaporation. The residue was purified via reverse phase HPLC (eluent gradient: 15 to 40% acetonitrile in water containing 0.1% TFA) to yield 3.1 mg (6.5%) of 10-[1-(1H-imidazol-2-ylmethyl)-piperidin-4-yl]-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 7a as a TFA salt. MS m/z (MH+) 414.9.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[N:4][CH:3]=1.C(OCC)(=[O:12])C.O>Cl>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:12])[CH:5]=[N:4][CH:3]=1
Reactant: N#Cc1cncc(F)n1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Product: NC(=O)c1cncc(F)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In 10 mL of concentrated hydrochloric acid was dissolved 1.6 g of 6-fluoro-2-pyrazinecarbonitrile. The solution thus obtained was stirred at 40° C. for 2 hours. The reaction mixture was cooled to room temperature, a mixture of 25 mL of ethyl acetate and 10 mL of water was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were united, washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=1:1] to obtain 0.75 g of 6-fluoro-2-pyrazinecarboxamide as a light brown-colored solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:29][NH2:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:24](=[O:25])[NH:30][CH3:29])=[CH:27][CH:28]=4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Reactant: CN
Product: CNC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Yield: 67 %

Procedure:
The product of example 45 (50 mg, 0.128 mmol) in methylamine (40% in water, 3 mL) was heated in a sealed tube at 100° C. for two hours. The resulting precipitate was filtered and washed with small portions of ethyl acetate to afford the title compound (33 mg, 67% yield). 1H NMR (DMSO-d6) δ 13.22 (br s, 1H), 10.41 (s, 1H), 8.58 (m, 1H), 8.52 (s, 1H), 8.00 (m, 6H), 7.75 (d, 1H), 7.56 (d, 1H), 7.36 (t, 2H), 2.79 (m, 3H); ES-MS (m/z) 389[M+1]+.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:19])[C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)OC1.[ClH:21].Cl.[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH2:28])=[NH:27]>>[ClH:21].[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]([N:7]2[CH2:6][CH2:5][C:4]3([N:27]=[C:26]([NH2:28])[C:25]4[C:24](=[CH:32][CH:31]=[CH:30][C:29]=4[F:33])[NH:23]3)[CH2:9][CH2:8]2)=[O:19])=[CH:16][CH:15]=1)#[N:18]
Reactant: N=C(N)c1c(N)cccc1F
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)N=C(N)c2c(F)cccc2N3)cc1

Procedure:
This was prepared from 1-(4-cyanobenzoyl)-4-piperidone ethylene ketal (Example U(b)) and 2-amino-6-fluorobenzamidine dihydrochloride (Example C) by the method of Example 1, to give the title compound as pale yellow crystals, m.p. 299°-300° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[C:19]([O:23][C:24](=[O:39])[C:25]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1)([CH3:27])[CH3:26])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:39])[C:25]([CH3:26])([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](=[O:37])[NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=3)=[CH:5][CH:6]=2)=[CH:31][CH:30]=1)[CH3:27])([CH3:21])([CH3:20])[CH3:22]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1N
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC(=O)O)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1NC(=O)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1

Procedure:
A] In analogy to the procedures described in example 26B] and 124C], 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (example 125C]) was reacted with 2-(4-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (example 124A]) to give 2-methyl-2-(4-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as colorless solid.
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: COc1cc(N=C=S)ccc1-n1cnc(C)c1
Reactant: N
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
Step D (4): Methanolic ammonia (1.0 M, 100 mL, 100 mmol) was added to a flask charged with 1-(4-isothiocyanato-2-methoxyphenyl)-4-methyl-1H-imidazole (500 mg, 2.04 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated to dryness in vacuo. The resulting solid was dried under high vacuum to afford 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiourea (0.529 g, 100% yield) as a white solid. LC-MS (M+H)+ 263.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]=12.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][OH:27])=[CH:23][CH:22]=1>>[ClH:2].[Cl:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:7]1[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]2=[C:3]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][OH:27])=[CH:23][CH:22]=2)[CH:8]=1
Reactant: Clc1ccc(Cl)c(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3cc(Cl)ccc3Cl)nc3c2CCC3)cc1
Yield: 47.3 %

Procedure:
Following General Procedure A1, 4-chloro-2-(2,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 4-aminophenethyl alcohol (0.055 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.068 g, 68%) as a light tan solid. MW=435.77. 1H NMR (DMSO-d6, 300 MHz) δ 14.23 (s, 1H), 9.76 (s, 1H), 7.80-7.78 (m, 1H), 7.71-7.63 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 4.66 (s, 1H), 3.63 (t, J=6.9 Hz, 2H), 3.1 (t, J=7.6 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.73 (t, J=6.9 Hz, 2H), 2.30-2.14 (m, 2H); APCI MS m/z 399 [M+H]+.
Reaction SMILES: C([C@H]1C[C@H](O)CCO1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:21]([C@H:34]1[CH2:39][C@H:38]([O:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36][O:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:21]([C@H:34]1[CH2:39][C@@H:38]([O:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36][O:35]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Product: CS(=O)(=O)O[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Yield: 49 %

Procedure:
Cis-2-diphenylmethyl-4-hydroxy-pyran 3b (0.3 g, 1.12 mmol) was reacted with methanesulfonyl chloride (0.26 g, 2.24 mmol) (Procedure A) to give compound 4b (0.38 g, 98%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C1C(=O)N(Cc2ccccc2)c2ccc(O)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of N-benzyl-5-methoxyisatin (3.0 g, 11.2 mmol) in dichloromethane (60 mL), aluminum chloride (3.7 g, 28.1 mmol) was added, and the resulting mixture was stirred at 100° C. for 1 hour. Water was added thereto, and the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated sodium hydrogencarbonate aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the aimed product (yield: 78%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)C(CC=Cc1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1ccccc1)c1ccccc1

Procedure:
A sodium hydroxide solution (2.5 ml., 20%) is added to a solution of p-chlorobenzaldehyde (7.0 g., 0.05 mole) and 3,6-diphenyl-5-hexen-2-one (12.5 g., 0.05 mole) in ethanol (125 ml.) with stirring. The yellowish solid that separates on continued stirring is filtered, washed with cold ethanol, and air-dried, 14.35 g., m.p. 92°-95°C. Recrystallization from hexane gives material with m.p. 95°-96.5°C.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C@H:8]([C@H:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:12])[CH3:10])[C@@H:7]([C@H:19]([OH:21])[CH3:20])[C:6]1=[O:22])([OH:3])=[O:2].[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].[I-].[Na+].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:13]1([C:11]([C@@H:9]([C@H:8]2[N:5]([CH2:4][C:1]([O:3][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:2])[C:6](=[O:22])[C@@H:7]2[C@H:19]([OH:21])[CH3:20])[CH3:10])=[S:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N(CC(=O)O)[C@@H]1[C@@H](C)C(=S)c1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)OCOC(=O)C(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccccc1
Reaction time: 6 h

Procedure:
At room temperature (25° C.), 1.35 g (4.0 mmol) of (3S,4S)-1-carboxymethyl-4-[(1R)-1-(phenylthiocarbonyl)ethyl]-3-[(1R)-1-hydroxyethyl]-2-azetidinone was dissolved in 8 ml of dimethylformamide, and 1.20 (8.0 mmol) of-pivaloyloxymethyl chloride and 1.20 g (8.0 mmol) of sodium iodide were sequentially added thereto. Subsequently, 0.68 g (5.3 mmol) of diisopropylethylamine was added dropwise thereto, and stirring was performed at the same temperature for 6 hours. The reaction solution was diluted with 40 ml of ethyl acetate, and washing was performed several times using 5% aqueous sodium bicarbonate and water. The resulting ethyl acetate solution was dried over sodium sulfate, and then the solvent was removed by distillation. Thereby, 1.88 g of the target compound was produced.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([CH3:23])[CH3:22])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:30].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([CH3:23])[CH3:22])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)=[O:30])[CH3:2]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OC(C)C)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OC(C)C)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (60 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (235 mg, 1.70 mmol) and 2-iodopropane (0.085 mL, 0.85 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil. The crude product was used without further purification. To a stirred solution of 1-(3-ethoxy-benzyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde in acetic acid (2 mL) was added selenium dioxide (189 mg, 1.70 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde as a major product (31 mg, 46% yield).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([OH:17])=[O:16].[CH3:18]O>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)cc1F

Procedure:
Sulfuric acid (3.35 mL) was added to a stirred solution of 2,4-difluorophenylacetic acid ([CAS 81228-09-3], 3.5 g, 20.33 mmol) in MeOH (70 mL) at RT. The mixture was stirred at reflux for 18 h. The methanol was removed in vacuo. The residue was diluted with EtOAc and washed successively with H2O, sat. aq. NaHCO3 and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield I-24 (3.34 g, 88%) as a light yellow oil.