Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[C@H:10]([OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[NH2:15][CH2:14][C@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][C@H:10]1[OH:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN2C(=O)c3ccccc3C2=O)[C@H](O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@H](O)C1
Yield: 110.8 %

Procedure:
To a solution of cis-l-tert-butoxycarbonyl-4-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)methyl-3-hydroxypiperidine (2.4 g) in ethanol (35 ml) was added hydrazine monohydrate (0.48 ml), and the resulting mixture was stirred at refluxing temperature for 1 hr. The resulting crystals were filtered off and the solvent was evaporated under reduced pressure to give 1.7 g of cis-4-aminomethyl-1-tert-butoxycarbonyl-3-hydroxypiperidine.
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[NH:23]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2B(O)O)=[N:26][N:25]=[N:24]1.[OH-].[Na+]>CO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][CH2:18][CH2:17][CH2:16][C:15]([N:7]([C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:22][CH:21]=1)=[O:20]
Reactant: CCCCC(=O)N(Cc1ccc(I)cc1)[C@H](C(=O)O)C(C)C
Reactant: OB(O)c1ccccc1-c1nnn[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: 70 °C
Yield: 85.1 %

Procedure:
Nitrogen is bubbled for 5 min. To a mixture made up of 0.20 g (0.48 mmol) of N-(4-iodobenzyl)-N-valeryl-L-valine, 0.115 g (0.61 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.017 g (0.024 mmol) of bis(triphenylphosphine)palladium chloride and 0.115 g (2.87 mmol) of NaOH in 2.4 mL of methanol and 0.7 mL of water are added. The reaction is heated to 70° C. under nitrogen atmosphere. Once 3 h has elapsed the reaction is considered to be completed and the methanol is distilled. The crude product is treated with 25 mL of HCl 1N and 25 mL of AcOEt. The AcOEt phase is dried with anhydrous sodium sulphate and after distilling the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 1.5:5:0.2) to provide 0.178 g (85%) of Valsartan.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cccc(F)c1
Product: COC(=O)c1c(O)c2ccc(-c3cccc(F)c3)cc2sc1=O

Procedure:
7-(3-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 3-fluorophenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.41 (d, 1H), 7.625-7.114 (m, 6H), 4.02 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:9](=[O:18])[C:8]=2[CH:19]=1.Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[N:24]([CH3:29])[C:23](=[O:30])[CH:22]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:12][CH2:13][N:14]([C:21]4[N:26]([CH3:27])[C:25](=[O:28])[N:24]([CH3:29])[C:23](=[O:30])[CH:22]=4)[CH2:15][CH2:16]3)[CH2:10][C:9](=[O:18])[C:8]=2[CH:19]=1
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Reactant: COc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2c(c1)C(=O)CC1(CCN(c3cc(=O)n(C)c(=O)n3C)CC1)O2
Yield: 61 %

Procedure:
A solution of 3,4-dihydro-6-methoxyspiro-[(2H)-1-benzopyran-2,4'-piperidin]-4-one hydrochloride (0.568 g, 2 mmol), 6-chloro-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione (0.349 g, 2 mmol) and sodium bicarbonate (0.42 g, 5 mmol) in acetonitrile was heated at reflux for 42 hours. After cooling, the reaction mixture was concentrated in vacuo to dryness. The residue was partitioned between chloroform and water. The chloroform solution was washed twice with water and once with saturated brine solution and then dried over sodium sulfate and concentrated to dryness in vacuo. The solid residue was recrystallized from methanol/ethanol to give the title compound (0.47 g, 61% yield) mp 202°-203° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[NH:4][CH2:5][CH3:6].Cl.[Cl:13][CH2:14][C:15](O)=O.N>>[CH2:5]([N:4]1[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[N:1]=[C:15]1[CH2:14][Cl:13])[CH3:6]
Reactant: CCNc1ccc(C)cc1N
Reactant: O=C(O)CCl
Agent: Cl
Agent: N
Product: CCn1c(CCl)nc2cc(C)ccc21
Yield: 27.9 %

Procedure:
2-amino-4-methyl-N-ethylaniline (2.15 g, 14 mmol), which is a known compound, hydrochloric acid (4N, 15 ml) and monochloroacetic acid (2 g, 21 mmol) were refluxed for 2.5 hours. After cooling, the reactant was neutralized with ammonia. The occurred oily substance was extracted with ethyl acetate and the product was treated as in a usual process to obtain the title intermediate (1.0 g, 3.9 mmol).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20]C)=[CH:15][CH:16]=2)[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:22]>C(O)(=O)C>[BrH:22].[CH2:2]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([OH:20])=[CH:15][CH:16]=2)[CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CC2
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CC(NCc1ccccc1)CC2
Reaction time: 2 h

Procedure:
A mixture of 2-benzylamino-7-methoxytetralin hydrochloride (25 g) described in Preparation I step (a), and 33% hydrobromic acid in acetic acid (215 ml) in the presence of 48% hydrobromic acid (36 ml) is refluxed, under stirring, for 2 hours. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is taken up in absolute ethanol (100 ml) and concentrated to dryness. The step of taking up in absolute ethanol and concentrating to dryness is repeated two other times and the thus obtained product is finally triturated with acetone (150 ml) and filtered yielding 2-benzylamino-7-hydroxytetralin hydrobromide (25.3 g). M.p. 198°-200° C. This product is then dissolved in hot water (1300 ml), the solution is cooled and concentrated ammonium hydroxide is then added thereto. The free base is extracted with ethyl acetate, the organic solution is dried and the solvent is evaporated off yielding a solid which is crystallized from toluene (250 ml). 2-Benzylamino-7-hydroxytetralin free base (14 g) is thus obtained . M.p. 161°-163° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([O:12][C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([O:28][CH3:29])[N:19]3C3CCCCO3)=[C:15]([NH2:30])[N:14]=2)[CH2:11][CH2:10][CH2:9]1>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([O:12][C:13]2[NH:14][C:15]([NH2:30])=[C:16]3[C:20]([N:21]=2)=[N:19][C:18]([O:28][CH3:29])=[N:17]3)[CH2:9][CH2:10][CH2:11]1
Reactant: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2nc(OC3CCC3)[nH]c(N)c-2n1
Temperature: 20 °C
Reaction time: 21 h
Yield: 78.6 %

Procedure:
Trifluoroacetic acid (3 ml, 38.9 mmol) was added to a solution of 2-(cyclobutyloxy)-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.27 g, 3.98 mmol) in methanol (50 ml) and the mixture stirred at 20° C. under an atmosphere of nitrogen for 21 hours. The solvent was removed in vacuo, and the residual solid was triturated with 1,1-dimethylethyl methyl ether and then collected by filtration and dried in vacuo to give the title compound as a cream solid (1.0922 g).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>>[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Reactant: Fc1ccccc1CBr
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1ccccc1F

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 using 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole and using 2-fluorobenzyl bromide instead of benzyl bromide.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:21][C:18]2[C:17]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:48])=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc4ccccc4c3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc3ccccc3c2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(naphthalen-2-yl)pyrazin-2-amine (7e) (500 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C., and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11e (460 mg, 681 μmol, 58.2%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 6H), 0.21 (s, 6H), 0.91 (s, 9H), 0.94 (s, 9H), 3.46 (s, 2H), 6.55-6.65 (AA′BB′, 2H), 6.91-6.97 (AA′BB′, 2H), 6.97-7.03 (AA′BB′, 2H), 7.47-7.58 (m, 2H), 7.75-8.00 (m, 4H), 8.08-8.14 (AA′BB′, 2H), 8.23 (s, 1H), 9.00 (s, 1H), 10.63 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.8, 17.9, 25.5 (6C), 119.4 (2C), 120.3 (2C), 125.5, 126.1, 126.6, 127.1, 127.2, 127.3, 127.5, 127.9, 128.2 (2C), 128.5, 130.2 (2C), 132.6, 132.8, 135.3, 137.6, 143.0, 147.5, 148.0, 153.7, 156.7, 169.4 (one carbon at the benzyl position was unobservable due to overlapping with the septet peak of DMSO); IR (KBr, cm−1) 478, 527, 687, 718, 746, 781, 804, 839, 914, 1009, 1082, 1103, 1128, 1169, 1261, 1362, 1415, 1445, 1472, 1508, 1605, 1670, 2857, 2886, 2928, 2955, 3057, 3221; HRMS (ESI+) m/z 698.3194 ([M+Na]+, C40H49N3NaO3Si2+ requires 698.3205).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])=[CH:5][CH:4]=1)#[N:2].[C:31](C1SC=C(CN2CC[C@H](NS(C3C=CC4C(=CC(OC)=CC=4)C=3)(=O)=O)C2=O)C=1)#N>>[C:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH3:31])[S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(C#N)s4)C3=O)cc2c1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccc(C#N)s4)C3=O)cc2c1

Procedure:
The title compound is prepared as in EXAMPLE 126, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as in EXAMPLE 148, Part A, in place of 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-])=O>[Pt].C(OCC)(=O)C.C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1

Procedure:
A mixture of 4-amino-N-(4-tert-butylphenyl)-3-nitrobenzamide from the previous step and 100 mg of 5% platinum on carbon in 50 mL of 1:1 ethyl acetate/ethanol was reduced under a hydrogen balloon. The reaction was filtered through Celite to remove catalyst and the solvent was removed under reduced pressure to afford 3,4-diamino-N-(4-tert-butylphenyl)-benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[CH3:41][S:42][C:43]1[N:48]=[C:47]([Sn](C)(C)C)[CH:46]=[CH:45][N:44]=1>>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][N:48]=[C:43]([S:42][CH3:41])[N:44]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: CSc1nccc([Sn](C)(C)C)n1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccnc(SC)n3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Yield: 97.5 %

Procedure:
Title compound was prepared according to a similar procedure described in Example 21, step 1 by reaction of 4-{2-(2-ethoxycarbonylethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (300 mg, 0.436 mmol) with 2-methylsulfanyl-4-trimethylstannanyl-pyrimidine (189 mg, 0.653 mmol) to afford 4-(2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-methanesulfonyl-5-(2-methylsulfanyl-pyrimidin-4-yl)-phenoxy]-hexyl}-phenoxy)-butyric acid ethyl ester (292 mg, 97% yield) as an oil. 1H NMR (CDCl3): □ 8.62 (d, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.55 (s, 1H), 7.42 (d, 1H), 7.09 (dd, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 4.17-4.07 (m, 6H), 3.99 (dd, 2H), 3.10 (s, 3H), 2.97 (dd, 2H), 2.66-2.61 (m, 5H), 2.56-2.46 (m, 4H), 2.17-0.89 (m, 16H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.Cl.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[OH:28].C(N(CC)CC)C>CN(C)C=O>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)=[CH:22][C:21]=1[OH:28]
Reactant: NCc1ccc(N)c(O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.6 %

Procedure:
To a suspension of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (1.0 g, 3.0 mmol) and 2-amino-5-(aminomethyl)phenol dihydrochloride (0.64 g, 3.0 mmol) in N,N-dimethylformamide (15 mL) is added triethylamine (1.2 mL, 9.0 mmol). The mixture is stirred at room temperature for 60 hours and then concentrated to dryness under reduced pressure. The residue is then triturated with water, and the solid is collected by filtration, washed successively with diethyl ether and acetonitrile, and dried under house vacuum to provide (4Z)-4-{[(4-amino-3-hydroxybenzyl)amino]methylene}-6-iodoisoquinoline-1,3(2H,4H)-dione as a golden powder (1.3 g, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH2:15](I)[CH3:16]>>[CH2:15]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[CH3:16]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(-c2ncc[nH]2)cc1
Product: CCn1ccnc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(imidazol-2-yl)-nitrobenzene and ethyl iodide
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([CH3:22])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:31].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:21])=[O:31])=[C:16]([CH3:22])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C2=C(c3cc(F)cc(F)c3)C(=O)C(C)(C)O2)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C2=C(c3cc(F)cc(F)c3)C(=O)C(C)(C)O2)ccc1S(C)=O
Temperature: 0 °C
Yield: 63.1 %

Procedure:
To 320 mg of 4-(3,5-difluorophenyl)-2,2-dimethyl-5-{3-methyl-4-(methylthio)phenyl}-3(2H)-furanone (Example 381) in 50 ml dichloromethane, was added 172 mg of 70% m-chloroperoxybenzoic acid. The mixture was stirred at 0° C. for an hour, which was followed by addition of 30 ml 5% aqueous sodium bicarbonate. The solution was stirred for another 10 minutes. Then the mixture was concentrated in vacuo, and was extracted with 50 ml water and dichloromethane (30 ml×3). Then the organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=1:1) to give 211 mg of 4-(3,5-difluorophenyl)-2,2-dimethyl-5-{3-methyl-4-(methylsulfinyl)phenyl}-3(2H)-furanone. NMR: δ1.57 (s, 6H), 2.36 (s, 3H), 2.73 (s, 3H), 6.77 (m, 1H), 6.86 (m, 2H), 7.50 (m, 1H), 7.66 (m, 1H), 7.99 (d, J=8.4 Hz, 1H). IR (cm−1): 1698,1624,1592,1384, 1310,1206,1072,915.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:15]([CH2:23][CH2:24][OH:25])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[C:6]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH:14]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH:15]([CH2:23][CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO)C(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Yield: 95.8 %

Procedure:
Methanesulfonyl chloride (64 μL, 0.83 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-2-(2-hydroxyethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (368 mg, 0.751 mmol) and triethylamine (15.4 mg, 209 μL, 1.52 mmol) in dichloromethane (2 mL) at room temperature under nitrogen. After stirring at room temperature for 1 h the crude mixture was partitioned between saturated aqueous citric acid solution (20 mL) and dichloromethane (20 mL). The phases were separated and the organic layer was evaporated to give the title compound (409 mg, 79%) as a yellow oil which was a mixture of diastereomers. LC/MS: 4.08 min; z/e 586, calcd (M+1) 586. 1H NMR (400 MHz: CDCl3): 7.50 (6H), 7.25 (4H), 7.15 (1H), 6.90 (2H), 4.50 (2H), 4.25 (2H), 3.80 (3H), 3.75 (1H), 2.95 (3H), 2.90-2.50 (3H), 2.05 (2H), 1.95-1.65 (2H), 1.55-1.35 (9H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:35])=[CH:28]\[CH2:29]OS(C)(=O)=O)[C:21]=1[CH3:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].O>CN(C)C=O>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:35])=[CH:28]\[CH2:29][N:41]2[C:37](=[O:47])[C:38]3=[CH:46][CH:45]=[CH:44][CH:43]=[C:39]3[C:40]2=[O:42])[C:21]=1[CH3:36])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C(=C/COS(C)(=O)=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(=C/CN1C(=O)c2ccccc2C1=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a solution of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-methanesulfonyloxy-1-methyl-1-propenyl)benzene (132 mg) in N,N-dimethylformamide was added potassium phthalimide (55 mg) at ambient temperature under nitrogen atmosphere, and the mixture was stirred at the same temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane:ethyl acetate =4:1, V/V) to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((z)-1-methyl-3-phthalimido-1-propenyl)benzene (99 mg) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[O:6][CH:7]=1.[OH:21][C:22]1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO>>[OH:1][C:2]1[C:3](=[O:20])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[O:6][C:7]=1[CH2:22][OH:21]
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(O)co2)c1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(O)c(CO)o2)c1
Yield: 45.34 %

Procedure:
N-(5-Hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (9-04) (7.5 g, 45.34%) was synthesized as a white solid from N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (8-04) (15.0 g, 50.84 mmol) following the procedure described for N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-01).