Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH2:1](=[O:3])[OH:2].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:16]=[C:17]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18]([CH:17]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[CH2:16][PH:1](=[O:2])[OH:3])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[PH2]O
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
Dry phosphinic acid (100 g, 1.52 mol) was dissolved in 100 mL of chloroform and treated with triethylamine (155 g, 1.52 mol). The mixture was evaporated and transferred to a three liter flask containing 750 mL of chloroform. The solution was stirred by means of a mechanical stirrer and the flask cooled to 0° C. The clear solution was treated with triethylamine (277 g, 2.72 mol) followed by trimethylsilyl chloride (281 g, 2.58 mol). Once addition of trimethylsilyl chloride was complete dibenzyl 2-methylenepentanedioate (2) in 150 mL of chloroform was added dropwise over 20 minutes. The low temperature bath was removed and the mixture warmed to room temperature. After 6 hours the thick slurry was filtered and the filtrate cooled to 0° C. The filtrate was then quenched with 5% hydrochloric acid and the organic layer removed. The aqueous layer was extracted with chloroform, the organics combined, dried (MgSO4) and evaporated under reduced pressure to give 55 g or 2,4-di(benzyloxycarbonyl)butylphosphinic acid (6) as a light yellow liquid. The liquid was purified by flash chromatography and eluted using 3:1 hexanes/ethyl acetate containing 5% trifluoroacetic acid to give 40 g (7%) of the desired product. Rf 0.28 (3:1 Hexane/EtOAc 5% TFA).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15]CC)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].IC>CS(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH3:15])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCSc1cc2c(cc1Br)N(C(C)=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CSc1cc2c(cc1Br)N(C(C)=O)CC2
Yield: 92.1 %

Procedure:
The thiol (D79) (0.35 g, 1.29 mmol) was treated with K2CO3 (0.20 g, 1.45 mmol) and iodomethane (0.24 ml, 3.85 mmol) in DMSO (15 ml) at 50° C. as in the method of Description 80 to afford the title compound (0.34 g, 92%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:27]=[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:11]([O:18][C:19]1[CH:27]=[C:22]2[CH2:23][N:24]([C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[O:7])[CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(COc2cc3n(n2)CCNC3)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCn2nc(OCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
4-Fluorobenzoyl chloride (0.36 mL, 3.04 mmol) was added to a stirred solution of 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.71 g, 2.53 mmol) and triethylamine (0.65 mL, 3.8 mmol) in DCM (25 mL) under nitrogen at 0° C. The mixture was stirred at room temperature for 16 hours, diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 2-(benzyloxy)-5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.73 g, 83% yield) as a white solid. C20H18FN3O2. 1H NMR (400 MHz, CDCl3) δ ppm 4.10 (br. s., 4H), 4.73 (br. s., 2 H), 5.18 (s, 2 H), 5.50 (br. s., 1 H), 7.10-7.19 (m, 2 H), 7.29-7.35 (m, 1 H), 7.35-7.41 (m, 2 H), 7.41-7.46 (m, 2 H), 7.46-7.51 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2[O:24]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][C:12]=2[OH:24])=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(O)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of N-[(4-chlorophenyl)-methyl]-2-methoxy-6-methyl-4-morpholin-4-yl-benzamide (synthesized according to the methods described in sections a) to f) of example 10) (0.25 g, 0.67 mmol) in dichloromethane (10 ml) is added neat boron tribromide (0.095 ml, 1.0 mmol) at −78° C. The temperature is slowly raised to RT over a period of 30 min and stirred for 1 h at RT. The reaction mixture is poured onto cold water and extracted with dichloromethane (3×30 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude material is purified by column chromatography (silica gel, 40% ethyl acetate/hexane) affording N-[(4-chlorophenyl)-methyl]-2-hydroxy-6-methyl-4-morpholin-4-yl-benzamide (0.11 g, 0.30 mmol, 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[CH2:15][C:16](=[O:21])C(OC)=O)([O-:3])=[O:2].OO.[O-:24]S([O-])=O.[Na+].[Na+]>CC(O)=O>[N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:12])([F:13])[F:14])[C:5]=1[CH2:15][C:16]([OH:21])=[O:24])([O-:3])=[O:2]
Reactant: O=S([O-])[O-]
Reactant: COC(=O)C(=O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
To crude methyl 3-[2-nitro-4-iodo-6-(trifluoromethyl)phenyl]-2-oxo-propanoate prepared above (40.98 g) in AcOH (750 mL) was added aqueous 30% H2O2 solution (266 mL) followed by 70% HClO4 (41 mL). The resulting mixture was stirred at 50° C. (bath temperature) for 4.5 hours. The solution was cooled and solid Na2SO3 (100 g) was added. The solvent was then removed in vacuo. The resulting orange solid was suspended in EtOAc (500 mL) and washed with H2O (300 mL). The organic phase was then extracted with aqueous saturated NaHCO3:aqueous 2N NaOH (6:1, 600 mL) followed by aqueous saturated NaHCO3 (200 mL). The aqueous extracts were combined and cooled in an ice-water bath. The solution was then acidified with aqueous 35% HCl. The resulting solid was isolated by filtration and dried to give the title compound as a yellow solid (7.086 g). The organic phase was then re-extracted with aqueous saturated NaHCO3 (6×50 mL). The extracts were combined and cooled in an ice-water bath, and then acidified with aqueous 35% HCl. The resulting solid was isolated by filtration and dried to give the title compound as a yellow solid (6.896 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N:21]1C2C(=CC=CC=2)C=C[CH:22]=1>CN(C)C=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([F:20])([F:19])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:22]#[N:21])([F:18])[F:17])=[CH:2][CH:7]=1
Reactant: c1ccc2ncccc2c1
Reactant: Fc1ccc(C(F)(F)C(F)(F)c2ccccc2)c(Br)c1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C(F)(F)C(F)(F)c1ccc(F)cc1

Procedure:
A mixture of 8.5 g. (0.024 mole) of 2-bromo-4,α,α,α',α'-pentafluorobibenzyl, 6.4 g. of cuprous cyanide, 75 ml. of dry quinoline and 7.5 ml. of dry dimethylformamide is stirred and heated to refluxing for 34 hours. The precipitate is removed from the cooled mixture by filtration and washed with a mixture of benzene and ether. Solvents are evaporated from the filtrate under reduced pressure leaving the product as an oily black solid. Sublimation at 80°C. and 0.05 mm. yields light brown solid, m.p. 90°-93°C. Purification is effected by column chromatography on 300 g. of silica, the product being eluted with benzene-hexane (1:1). The fractions that show one spot of rf 0.85 on a fluorescent silica thin layer plate developed with benzene are combined. Evaporation of the solvent under reduced pressure leaves white crystals, m.p. 96.5°-97.5°C. A sample for analysis is sublimed.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][NH2:38].CO>C(O)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([NH:38][CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CN
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(Cl)nc2ccccc2c1-c1ccccc1
Solvent: CO
Solvent: CCO
Product: CNc1nc2ccccc2c(-c2ccccc2)c1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
To a solution of the compound obtained in Example 269 (100 mg) in ethanol (4 ml) was added 40% MeNH2 -methanol (12 ml), and the mixture was stirred for 4 hours with heating under reflux. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to yield the title compound as colorless crystals (65 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.S(Cl)([Cl:14])(=O)=O>C(O)(=O)C>[Cl:14][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:2]=1[CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc2cccnc2[nH]1
Solvent: CC(=O)O
Product: Cc1[nH]c2ncccc2c1Cl
Yield: 51 %

Procedure:
To a solution of 0,7 g (5.3 mmol) of 2-methylpyrrolo[2,3-b]pyridine in 2,5 ml glacial acetic acid was added dropwise 0,8 g (5.9 mmol) of sulfuryl chloride at room temperature and with stirring. The reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was crystallized from ether: ethyl acetate, 5:1 to give 0,45 g (51%) of the title compound.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[C:26]([Si:23]([O:4][CH2:3][CH2:2][I:1])([CH3:25])[CH3:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCI
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCI
Reaction time: 8 h

Procedure:
To 2-iodoethanol (20 gm, 116 mmol) suspended in methylene chloride (500 mL) was added dimethylaminopyridine (100 mg) followed by diisopropylethylamine (30 mL, 174 mmol) and tert-butyldimethylsilyl chloride (19 gm, 128 mmol). The reaction was stirred overnight and the solvent was removed in vacuo and the residue was passed through a short column of silica gel and eluted with 95:5 methylene chloride: methanol. The desired fractions were combined and the solvent was removed in vacuo to give the desired product.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20](Cl)(=[O:22])=[O:21])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1>C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:39][S:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:12]=2)(=[O:22])=[O:21])[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1
Reactant: COc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3)c3ccccc23)c1
Yield: 47.2 %

Procedure:
To a solution of 4-benzoylamino-naphthalene-1-sulfonyl chloride (320 mg, 0.93 mmol) in CH2Cl2 (20 mL) was added triethylamine (0.26 mL, 1.85 mmol) and m-anisidine (137 mg, 1.11 mmol). The resultant solution was stirred at 25° C. overnight. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated to provide the crude product as yellow viscous oil. HPLC purification of the residue gave the title compound (190 mg) as a pale white solid. 1H NMR (300 MHz, DMSO) δ 8.72 (d, 1H), 8.26 (d, 1H), 8.15 (d, 1H), 8.02 (d, 2H), 7.78 (d, 1H), 7.60 (m, 5H), 7.00 (t, 1H), 6.55 (m, 2H), 6.46 (d, 1H), 3.56 (s, 3H); LC/MS m/z 433 (M+H)+.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][CH2:15][C:16](=[O:19])[CH2:17]I.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](=[O:27])[NH:25][CH:26]=1>>[Cl:14][CH2:15][C:16](=[O:19])[CH2:17][O:27][C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=1
Reactant: O=C(CCl)CI
Reactant: O=c1ccc(Cl)c[nH]1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(CCl)COc1ccc(Cl)cn1

Procedure:
A protected ketone derivative wherein R2 is a 5-chloro-2-pyridyl radical, for use as a starting material in the process of the invention, may be obtained by reacting epichlorhydrin with hydriodic acid and sodium iodide to give 1-chloro-3-iodopropan-2-ol, which is oxidised by Jones' reagent to the ketone, 1-chloro-3-iodopropan-2-one. The ketone is reacted with 5-chloropyrid-2-one to give 1-chloro-3-(5-chloropyrid-2-yloxy)propan-2-one, which is converted to the protected ketone derivative, ClCH2.CR3.CH2OR2 wherein R2 is a 5-chloro-2-pyridyl radical, which in turn is reacted with a trialkyl phosphite to give the required protected ketone starting material, (R1O)2.PO.CH2.CR3.CH2OR2.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.[N+]([C:17]1[O:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=1)([O-])=O>CS(C)=O>[CH2:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:17]2[O:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:11]([CH3:12])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2ccc(CC(C)=O)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.1 g of an 80% dispersion in oil) was added, with vigorous stirring to a solution of (4-hydroxyphenyl)propan-2-one, ethylene ketal (6.8 g) in dimethylsulphoxide (50 ml). After 30 minutes, methyl 5 nitrofuran-2-carboxylate (5 g) was added and the resulting mixture was stirred and heated at 80°-90° C. for 10 hr. The cooled reaction mixture was poured into ice-water and extracted into diethylether. The organic layer was washed with 5% potassium hydroxide solution and water, dried (MgSO4) and evaporated to an oil which was chromatographed on silica gel. Elution with chloroform gave methyl 5-[4-acetonylphenoxy]-furan-2-carboxylate, ethylene ketal (3.3 g) which was taken up in a 1:1 mixture of methanol and 2N hydrochloric acid and stirred at ambient temperature for 4 hr. Evaporation of the methanol and extraction of the aqueous residue into dichloromethane gave an oil which was chromatographed on silica gel. Elution with chloroform gave methyl 5-[4-acetonylphenoxy]furan-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])[CH:7]=1.[C:29]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:28][CH2:29][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]4[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[C:9]3=[O:27])[C:6]=2[CH:7]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc(Br)ccc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1ccc(Br)cc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 5-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one was obtained (78%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.36-7.27 (m, 2H), 7.17-6.98 (m, 3H), 6.8 (d, J=8.6 Hz, 1H), 6.78-6.72 (m, 2H), 6.39 (d, J=3.4 Hz, 1H), 5.07-5.87 (m, 3H), 4.69 (d, J=9.1 Hz, 1H); MS (ES+) m/z 463.9 (M+1), 465.9 (M+1).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][S:17][CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:12])=[C:6]([C:30]2[CH:35]=[C:34]([C:36](=[O:49])[NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=3)[CH:33]=[CH:32][N:31]=2)[CH:5]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][S:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12])=[C:6]([C:30]2[CH:35]=[C:34]([C:36](=[O:49])[NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:47])([F:48])[F:46])[CH:40]=3)[CH:33]=[CH:32][N:31]=2)[CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCSc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-(4-(ethylthio)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzylthio)propanoate (200 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (0.2 g) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained 40.4 mg (21%) of a light yellow solid. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 12.85 (s, 1H), 12.28 (s, 1H), 9.60-9.57 (m, 1H), 9.01-8.99 (m, 1H), 8.55-8.53 (m, 1H), 8.39 (s, 1H), 7.96-7.51 (m, 11H), 4.65-4.64 (d, J=5.2 Hz, 2H), 3.90 (s, 2H), 3.08-3.03 (m, 2H), 2.63-2.59 (t, J=5.1 Hz, 2H), 1.28-1.24 (t, J=5.7 Hz, 3H). MS (ES, m/z): 654 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][CH:13]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].CCN(C(C)C)C(C)C.[CH2:30](Cl)[O:31][CH2:32][CH2:33][O:34][CH3:35]>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:8]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][CH:13]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCCl
Reactant: Cc1onc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Yield: 60.5 %

Procedure:
The title compound was prepared by the method of Example 4(A) using N-(4-chloro-5-methyl-3-isoxazolyl)thieno[2,3-b]pyridine-3-sulfonamide (0.30 g, 0.91 mmoles), EtOAc (30 ml), DIEA (0.24 ml, 1.4 mmoles) and MEM-Cl (0.11 ml, 1.0 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.23 g (59%) of the title compound as a light yellow oil.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].ClCl.[I:12]Cl.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([I:12])=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: ClI
Reactant: O=Cc1ccccc1O
Agent: ClCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cc(I)ccc1O
Reaction time: 14 h

Procedure:
To a solution of salicylaldehyde (10 g, 82 mmol) in 50 mL of CH2 Cl2 is added 22 mL of a 1M ICl solution in CH2Cl2. The solution is stirred for 14 h. After this time, a saturated solution of sodium sulfite is added until the color is discharged. The solution is diluted with CH2Cl2. The layers are separated. The organic layer is washed with water. The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude material is recrystallized from cyclohexane to give the title compound (7.2 g, 32 mmol) as white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1>CCO.CCOC(C)=O.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])=[O:17])=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCCO
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(CC(=O)NCCCO)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
A slurry of N-(3-hydroxy-propyl)-2-(4-nitro-phenyl)-acetamide (as prepared in the previous step, 183 mg, 0.768 mmol) and 5% Pd—C (130 mg) in EtOH-EtOAc (5 mL, 4:1 v/v) was stirred under 1 atm H2 for 2 h. The reaction was filtered and concentrated to afford 152 mg (95%) of the title compound. 1H-NMR (DMSO-d6; 400 MHz): δ 7.78 (br s, 1H), 6.88 (d, 2H, J=8.3 Hz), 6.47 (d, 2H, J=8.3 Hz), 4.88 (br s, 2H), 4.39 (t, 1H, J=5.2 Hz), 3.43-3.34 (m, 2H), 3.16 (s, 2H), 3.08-3.03 (m, 2H), 1.55-1.48 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12](=[O:21])[CH:13]=[CH:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1[CH3:20].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26]>>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1[CH3:20]
Reactant: Cc1[nH]cnc1C=CC(=O)c1cccc2c(F)cccc12
Agent: O=C(O)/C=C\C(=O)O
Product: Cc1[nH]cnc1CCC(=O)c1cccc2c(F)cccc12
Yield: 64.1 %

Procedure:
The filtrate from the hydrogenation of 1-(5-fluoro-1-naphthalenyl)-3-(5-methyl-1H-imidazol-4-yl)-2-propen-1-one (1.01 g) was treated with maleic acid (418 mg) and the resultant solution was evaporated to dryness to give a solid. This was recrystallised from methanol/ethyl acetate to give the title compound (920 mg), m.p. 138°-140°.