Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([O:6][C:7]1[C:8]([S:21][CH3:22])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)(=[O:5])=[O:4].[OH:25]O>C(O)(=O)C>[F:24][C:2]([F:1])([F:23])[S:3]([O:6][C:7]1[C:8]([S:21]([CH3:22])=[O:25])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)(=[O:5])=[O:4]
Reactant: CCCC(C)n1ccc2c(SC)c(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OO
Solvent: CC(=O)O
Product: CCCC(C)n1ccc2c(S(C)=O)c(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 4-(methylthio)-1-(pentan-2-yl)-1H-indol-5-yltrifluoromethanesulfonate (13) (1.3 g, 3.4 mmol) in acetic acid (CH3COOH, 5.0 mL) at around 5° C. was added hydrogen peroxide (H2O2, 30%, 0.42 ml, 3.7 mmol). The mixture was allowed to warm to room temperature, stirred overnight, and then concentrated to dryness in vacuo to give 4-(methylsulfinyl)-1-(pentan-2-yl)-1H-indol-5-yl trifluoromethanesulfonate (17) (1.32 g, 100%). 1H NMR (500 MHz, CD2Cl2): δ 7.58 (d, J=9.0, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.35 (m, 1H), 7.13 (d, J=9.0, 1H), 4.57 (m, 1H), 3.07 (d, 3H), 1.87 (m, 2H), 1.55 (m, 3H), 1.26 (m, 2H), 0.92 (m, 3H). Mass (ESI, M+H): 398.4. See also Bronner, S. M.; Bahnck K. B.; Garg, N. K.; Org. Lett., 11: 1007 (2009).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:6]=1.[OH-].[Na+]>CO>[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[O:24][CH2:23][CH2:22][N:12]([CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[CH:9][CH:8]=1)[S:13]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15]
Reactant: COC(=O)Cc1cccc(CN(CCOc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(CN(CCOc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)c1
Yield: 81.9 %

Procedure:
A solution of the compound of Example 2, Step A (0.025 g, 0.053 mmol), in 2 mL MeOH and 0.5 mL 2N NaOH was stirred at room temperature overnight. The mixture was quenched with 2N HCl and was diluted with CH2Cl2. The organic layer was washed with 1N HCl and water, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) to afford the title compound (20 mg). 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.77 (d, 1H), 8.11 (d, 1H), 7.43 (m, 1H), 7.08-7.27 (m, 5H), 6.89 (d, 1H), 6.62 (s, 1H), 6.55 (d, 1H), 4.51 (s, 2H), 3.95 (t, 2H), 3.59 (s, 4H); MS 495 (M−2).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[O:10][CH:11]=[C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=23)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOC1.[Br:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](Cl)(=[O:45])=[O:44]>C1COCC1>[Br:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43]([N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:12]2=[CH:11][O:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[C:13]12)(=[O:45])=[O:44]
Reactant: c1ccc(-c2occ3c2[nH]c2ccccc23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1Br)n1c2ccccc2c2coc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g (52.5 mmol) of NaH (60% in mineral oil) are dissolved in 500 ml of THF under a protective-gas atmosphere. 11.5 g (50 mmol) of 3-phenyl-4H-furo[3,4-b]indole and 11.5 g (52.5 mmol) of 15-crown-5 dissolved in 200 ml of THF are added. After 1 h at room temperature, a solution of 12.7 g (55 mmol) of 2-bromobenzenesulfonyl chloride in 250 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 18 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene and recrystallised from toluene/n-heptane. The yield is 16 g (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:35][NH:36][C:37](=O)[CH2:38][NH:39]C(=O)OC(C)(C)C)=[N:10][N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.ClC(Cl)(Br)C(Cl)(Cl)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.C(O)(C(F)(F)F)=O>CCOC(C)=O.C(Cl)Cl.CO.C(Cl)Cl.C(#N)C>[NH2:39][CH2:38][C:37]1[N:10]2[N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]2=[N:35][N:36]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CN)n21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33.8 %

Procedure:
To a round bottom flask was added tert-butyl 2-(2-(4-(4-chlorophenyl) -5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)hydrazinyl)-2-oxoethylcarbamate (54 mg, 0.0808 mmol), acetonitrile (3 ml), and tetra-chloro-1,2-dibromo-ethane (58 mg, 0.178 mmol). The reaction was cooled to 0° C. Triphenylphosphine (47 mg, 0.178 mmol) was then added and the reaction was stirred at 0° C. for 5 min. After this time, Et3N (0.05 ml, 0.356 mmol) was added to the reaction. The reaction was slowly warmed up to rt and stirred for 16 hrs. After this time, the reaction was diluted with EtOAc (25 ml). The resulting solution was washed with water (2×20 ml) and saturated NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (8 gm silica gel) eluting with a gradient of 20%-80% EtOAc/Hex to give the cyclized intermediate. This material was then dissolved in CH2Cl2(1 ml) and TFA (1 ml) was added. The reaction was stirred at rt for 1 hr. After this time, the solvent was removed. The residue was diluted with EtOAc (20 ml). The resulting solution was washed with saturated NaHCO3(20 ml), water (10 ml) and saturated NaCl (10 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel) eluting with a gradient of 100% EtOAc and then 5% MeOH/CH2Cl2 to give product as a white solid (15 mg, 34% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: Brc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 58 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (10.0 g, 69.9 mmol, 1 eq) and 4-bromopyridine HBr (16.2 g, 83.7 mmol, 1.2 eq) were dissolved in n-butanol (120 ml) and DIPEA (23 ml, 139.8 mmol, 2.0 eq) and refluxed for 14 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 3% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 58% (9.0 g, 40.9 mmol).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+]>CO>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCOC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)O

Procedure:
Boc-Leu-Ala-Gly-OEt (4.5g, 0.012 mol) was dissolved in methanol (20 ml), and treated with sodium hydroxide in the manner similar to that of Example 1, paragraph 4).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][C@H:17]2[CH2:30][O:29][C:20]3[CH:21]=[CH:22][C:23]4[NH:24][C:25](=[O:28])[O:26][C:27]=4[C:19]=3[O:18]2)(=O)=O)=CC=1>CN(C)C=O>[N:1]([CH2:16][CH:17]1[CH2:30][O:29][C:20]2[CH:21]=[CH:22][C:23]3[NH:24][C:25](=[O:28])[O:26][C:27]=3[C:19]=2[O:18]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(=O)oc4c3O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1COc2ccc3[nH]c(=O)oc3c2O1
Temperature: 70 °C
Yield: 88.6 %

Procedure:
Sodium azide (0.86 g, 13.2 mmole) was added to a solution of [(8R)-2-oxo-2,3,7,8-tetrahydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzene-sulfonate (5.0 g, 13 mmole) in dimethylformamide (250 mL). The solution was heated at 70° C. for 9 hours. The solvent was then removed in vacuum and replaced with 300 mL of methylene chloride. The mixture was washed with 300 mL portions of water and saturated brine, dried over magnesium sulfate, filtered and evaporated in vacuum to a yellow solid. The crude solid was column chromatographed on silica gel with 3% methanol in methylene chloride to yield the (S)-enantiomer of the title compound as a white solid (2.86 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[O:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([C:21]2[O:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Yield: 50.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(oxazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5.47 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.3 g, 51%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]3[S:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[CH2:6]1.[CH2:22]([N:25]1C(=O)O[C:28](=[O:29])[C:27]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:26]12)[CH2:23][CH3:24]>>[O:10]=[C:8]1[N:7]([C:11]2[CH:12]=[CH:13][C:14]3[S:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[CH2:6][C@@H:5]([CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=2[NH:25][CH2:22][CH2:23][CH3:24])[O:9]1
Reactant: CCCn1c(=O)oc(=O)c2ccccc21
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: CCCNc1ccccc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 67 %

Procedure:
Starting from 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and N-propylisatoic anhydride and using Procedure A, the title compound was obtained as a beige solid (77 mg; 67% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:21][CH2:20]4)=[C:10]([O:34][CH3:35])[CH:9]=2)[O:6][CH:7]=1)[CH3:2].[Li+].[OH-]>C1COCC1.O.CCO>[CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:20]4)=[C:10]([O:34][CH3:35])[CH:9]=2)[O:6][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(CC)co4)cc3OC)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1coc(-c2ccc(OCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[4-(4-ethyl-1,3-oxazol-2-yl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (52.2 mg, 0.109 mmol) (Example 173) in THF/water/EtOH (1:2:1, 4 mL) was added LiOH (5.2 mg, 0.218 mmol). The solution was stirred at rt for 3 h and concentrated under reduced pressure. The residue was diluted with water and acidified using HCl (2 N aqueous solution), resulting in precipitation of a white solid. The solid was collected by filtration and dried to give 38.0 mg (77%) of the title compound. 1H NMR (400 MHz, CD2Cl2): δ 7.82 (s, 1H), 7.66 (d, 1H), 7.47 (s, 1H), 7.07 (d, 1H), 6.98 (d, 1H), 6.79 (s, 1H), 6.70 (d. 1H), 4.28 (t, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.51 (m, 1H), 2.91 (m, 2H), 2.75 (m, 3H), 2.50 (m, 1H), 2.40 (m, 1H), 2.30 (m, 2H), 1.79 (m, 1H), 1.34 (t, 3H); LC-MS: RT=3.31 min, (M+H)+ 452.1.
Reaction SMILES: [Li+].[OH-:2].Cl.[CH2:4]1[CH2:8][O:7][CH2:6][CH2:5]1>CO>[C:4]1(=[CH:5][C:6]([OH:2])=[O:7])[CH2:8][CH2:6][CH2:5][CH2:4][CH2:8]1
Reactant: [OH-]
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Solvent: CO
Product: O=C(O)C=C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude intermediate 23 was dissolved in 15 mL THF and 15 mL methanol. 30 mL aqueous 1N LiOH solution was added, and it was stirred at ambient temperature overnight. The next day, pH of the reaction system was adjusted to 1 with 6N hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times, and the ethyl acetate layers were combined and washed with water once, saturated aqueous NaCl solution once, dried over anhydrous MgSO4 for 2 hours, filtrated, and the filtrate was dried under vacuum to give 0.796 g of oily crude title product.
Reaction SMILES: C[O-].[Na+].[C:4]1(=[O:13])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH2:6][O:5]1.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.C(OCC)(=O)CC>CO>[NH:14]1[CH:19]=[CH:18][C:17](=[C:20]2[C:6](=[O:5])[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:4]2=[O:13])[CH:16]=[CH:15]1
Reactant: O=Cc1ccncc1
Reactant: O=C1OCC2=C1CCCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(=O)CC
Product: O=C1C2=C(CCCC2)C(=O)C1=C1C=CNC=C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Four portions each of 0.99 ml 5.4 M methanolic sodium methylate solution (21.4 mmol) are stirred into a solution of 2.957 g (21.4 mmol) 4,5,6,7-tetrahydro-1(3H)-isobenzofuranone (for preparation see J. Am. Chem. Soc. 118, 1-12 [1996]), 2.02 ml (21.4 mmol) pyridine-4-carbaldehyde, and 10.7 ml (93.2 mmol) ethyl propionate in 17.4 ml methanol at intervals of 5 min respectively and at 0° C. The reaction mixture is stirred for 20 min at RT, heated for 2 h under reflux, and then evaporated under vacuum. Stirring of the residue in 5 ml water, filtration, washing of the filter residue with water, and drying under HV (8 h, 100° C.) yields the title compound; m.p. 258-261° C.; ESI-MS: (M+H)+=228. A further, slightly impure batch of title compound may be obtained by extracting the aqueous filtrate with diethylether, adjusting the aqueous phase to pH 7 with glacial acetic acid, filtering, and washing the filter residue with water.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9]2(=[O:11])=[O:10])[CH:6]=[CH:5]C=CC=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.[H-].[Na+].[CH2:34]([O:41][C:42]1[CH:53]=[CH:52][C:45]([O:46]CCCCBr)=[CH:44][CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([O:41][C:42]1[CH:43]=[CH:44][C:45]([O:46][CH2:5][CH2:6][CH2:1][CH2:7][N:8]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9]2(=[O:10])=[O:11])=[CH:52][CH:53]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1Cc1ccccc1
Reactant: BrCCCCOc1ccc(OCc2ccccc2)cc1
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccc(OCc2ccccc2)cc1
Yield: 66 %

Procedure:
The synthesis was carried out analogous to the preparation of 83.1 using 82 (0.307 g, 1.5 mmol), NaH (0.036 g, 1.5 mmol) and 4-(4-benzyloxy-phenoxy)-butyl bromide (0.2 g, 0.6 mmol) in DMF (5 mL). Purification by flash column chromatography on silica gel gave 83.3 (0.150 g, 66% yield) as a white solid (m p 82-84° C.).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Yield: 58 %

Procedure:
First, 53.2 g of benzyl chloride, 69.2 g of 4-bromophenol, 110.4 g of potassium carbonate, and 800 ml of methyl ethyl ketone were put in a 2 flask, and stirred under reflux for 30 minutes. After the reaction, insoluble material was filtered off, and the solvent was distilled off from the filtrate. Ether and a 2% sodium hydroxide aqueous solution were added to the residue to separate an organic layer. The organic layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was distilled (b.p. 131° C. to 140° C./0.08 mmHg), to obtain 61.0 g (Y: 58.07%) of 4-bromo-1-benzyloxybenzene. The purity of the resultant compound was 99.0% as measured by GC.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH2:8]([C@@:11]1([CH3:32])[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C@H:14]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[O:13][C:12]1=[O:31])[CH:9]=[CH2:10]>C(OCC)(=O)C>[Cl:23][C:19]1[CH:18]=[C:17]([C@H:15]([C@H:14]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[OH:13])[CH2:16][C@:11]([CH3:32])([CH2:8][CH:9]=[CH2:10])[C:12]([NH:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4])=[O:31])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)[C@H](N)CO
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@H](CO)C(C)C
Temperature: 100 °C

Procedure:
A mixture of (S)-2-amino-3-methylbutan-1-ol (550 mg, 5.33 mmol) and (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (Example 261, Step H, 2nd compound, 500 mg, 1.332 mmol) was heated to 100° C. for 24 h. After cooling to room temperature, the residue was dissolved in ethyl acetate and washed 3× with 1N HCl (5 mL) followed by sat. aq. NaCl solution (5 mL). The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [C:1]([C:3](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:4]([NH:6][C:7](OCC)=[O:8])=[O:5])#[N:2]>ClC1C=CC=CC=1Cl>[C:1]([C:3]1[C:4](=[O:5])[NH:6][C:7](=[O:8])[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:12]=1)#[N:2]
Reactant: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(Cl)cc1
Solvent: Clc1ccccc1Cl
Product: N#Cc1cn(-c2ccc(Cl)cc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8.8 g (0.03 mol) of α-cyano-β-(4-chloroanilino)-N-ethoxycarbonylacrylamide and 40 ml of ortho-dichlorobenzene is heated at reflux. After about 2 hours, crystals appear and the mixture is allowed to cool to room temperature. The mixture is filtered to yield 5-cyano-1-(4-chlorophenyl)uracil, m.p. 236°-239°.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])C.[OH-].[Na+]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:15]([C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([F:13])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:27])=[O:3])=[O:26])=[C:19]([F:25])[CH:20]=1
Reactant: CCOC(=O)COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)NCc2ccc(Br)cc2F)c(OCC(=O)O)cc1F
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A stirring solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.72 g, 1.62 mmol) in ethanol (8.1 mL, 0.2 M) was placed in an ice bath and treated with aq NaOH (1.25 M, 7.8 mL, 9.73 mmol). The mixture was gradually allowed to warm to room temperature and after two hours the mixture was concentrated under reduced pressure, diluted with ethyl acetate, and treated with 2 N HCl (10 mL). The separated organic layer was washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to afford [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid (0.66 g, 98%) as a white solid: mp 169° C.; Rf 0.22 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 0.300 MHz) δ 9.00 (bd t, J=5.3 Hz, 1 H), 7.76 (d, J=9.6 Hz, 1 H), 7.49 (d, J=9.6 Hz, 1 H), 7.39–7.33 (m, 2 H), 7.04 (dd, J1=11.4 Hz, J2=1.4 Hz, 1 H), 4.84 (d, J=1.8 Hz, 2 H), 4.48 (bd 8, 2 H), 2.17 (s, 3 H); ESI-LC/MS m/z calcd for C17H14BrF2NO4: 413.0; found 412 (M−1)−. Anal. calcd for C17H14BrF2NO4: C, 49.30; H, 3.41; N, 3.38. Found C, 49.32; H, 3.43; Br, 3.32.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[CH:13]=[C:12](C(=O)N(C4C=CC(Cl)=CC=4Cl)C)[S:11][C:10]=3[C:9]=2[CH:30]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(O)C>[S:11]1[C:10]2[C:9]3[CH:30]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12]1
Reactant: COC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(Cl)cc3Cl)cc1CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)-c1sccc1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid methyl ester (700 mg) in THF (8 mL) and ethanol (4 mL) was added sodium hydroxide solution (121 mg in 4 mL of water) and the reaction stirred at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and the resulting solid was filtered and air-dried to give 2-(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:24])([F:23])[C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)[O:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.C1(C)C=CC=CC=1.[F:32][C:33]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:34]=1[NH2:35]>C(Cl)Cl.C(N(CC)CC)C>[F:32][C:33]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:34]=1[NH:35][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[N:19][C:11]=1[O:10][C:9]1[CH:20]=[CH:21][CH:22]=[C:7]([C:6]([F:5])([F:24])[F:23])[CH:8]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1F)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reaction time: 18 h

Procedure:
A mixture of thionyl chloride (465 ml) and 2-(3-trifluoromethylphenoxy)nicotinic acid [930 L g; described by F. J. Villani et al, J. Med. Chem. 18, 1 (1975)] was allowed to stand at ambient temperature for 18 hours and was then heated at reflux for 1 hour. Toluene (1 liter) was then added and the solution was evaporated under reduced pressure. The residue thus obtained was dissolved in methylene chloride (3 liters) and treated, with stirring, with triethylamine (453 ml) at ambient temperature. 2,4-Difluoroaniline (422 g) was then added over 1 hour while maintaining the temperature at 10° to 15° C. and the mixture was then heated at reflux for 2 hours. The methylene chloride was removed by distillation and the residue was treated with water (4 liters). A solid of spongy texture was obtained which was filtered off, dried at 50° C. and recrystallised from a mixture of toluene and hexane (2:3; 15 liters), to give N-(2,4-difluorophenyl)-2-(3-trifluoromethylphenoxy)nicotinamide (720 g), m.p. 160°-161° C. as a colourless crystalline solid.