Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22].S(=O)(=O)(O)O>CN(C)C=O.CCOCC>[Si:6]([O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1CCC[C@H]1CO
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC[C@H]1CO
Temperature: 24 °C
Reaction time: 22 h
Yield: 39.9 %

Procedure:
17.1 g of imidazole and 18.9 g of tert-butyldimethylsilyl chloride are added to a solution of 16 g of trans-1,2-dihydroxymethyl-cyclopentane in 146 ml of dimethylformamide at 0° C. and stirred for 22 hours at 24° C. It is diluted with 1.6 l of ether, shaken twice with 80 ml of 10% sulfuric acid each, washed neutral with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (9+1), 12 g of trans-1-(tert-butyldimethylsilyloxymethyl)-2-hydroxymethyl-cyclopentane is obtained as colorless liquid.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[H-].[Na+].C([Li])CCC.C1(S([Cl:38])(=O)=O)C=CC=CC=1>CCCCCC.C(O)(=O)C.O1CCCC1>[O:1]=[C:2]([CH:10]([Cl:38])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COP(=O)(CC(=O)CCCCCOC1CCCCO1)OC
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)C(Cl)CCCCOC1CCCCO1)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of nitrogen, a solution of 4.2 g. of dimethyl 2-oxo-7-(2-tetrahydropyranyloxy)-heptylphosphonate (prepared as described above) in 15 ml. of tetrahydrofuran was added to a suspension of 596 mg. of sodium hydride (63% content) in 20 ml. of tetrahydrofuran at room temperature, and the mixture was stirred at the same temperature for 30 minutes. After cooling to 0° C., 14 ml. of a 1.3M solution of n-butyllithium in n-hexane were added to the solution and the mixture was stirred at 0° C. for 30 minutes. After cooling the solution to -78° C., there was added a solution of 3.23 g. of benzenesulphonyl chloride in 10 ml. of tetrahydrofuran. The mixture was stirred at -78° C. for one hour and then at room temperature for one hour. The reaction mixture was acidified to pH 3 with acetic acid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and benzene (5:1) as eluent to give 2.97 g. of the title compound having the following physical characteristics:-
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][CH2:23]Cl.C(O)(=O)C>CN(C)C=O>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:21][O:22][CH3:23])[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COCN1C(=O)N([C@H](C)c2ccccc2)[C@H]2COC(=O)[C@H]21
Temperature: 5 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
4.0 g (93 mmol) sodium hydride (55 percent in oil) was added in 10 portions in 2 hours at -10° C. under argon to a solution of 19 g (77 mmol) of (3aS, 6aR)-[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]-imidazol-2,4-(3H, 3aH)-dione and 9.42 g (120 mmol) of chloromethyl methyl ether in 200 ml of dried N,N-dimethylformamide. The reaction mixture was stirred at 5° C. for 2 hours and then at room temperature for another 2 hours. Then 2 ml of acetic acid was added. Then the mixture was evaporated to dryness. Then the residue was taken up in 50 ml of water and 100 ml of dichloromethane, the phases were separated and the aqueous phase was extracted 2 times with 100 ml of dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. After chromatographing the oily residue over silica gel with 500 ml of dichloromethane/ethyl acetate and concentrations of the fractions, 4.0 g (18 percent) of the title product was obtained as white powder. Concerning the product: Melting point: 96°-98° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29]Br.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>C1COCC1.C1(C)C=CC=CC=1>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:29][NH:21][CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:22][CH3:23]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (94.1 mg, 0.291 mmol) was dissolved in THF (4 mL). 3,5-B is(trifluoromethyl)benzyl bromide (320 μL, 1.75 mmol) was added followed by potassium bis(trimethylsilyl)amide (2.33 mL of a 0.5 M solution in toluene, 1.164 mmol). The reaction was stirred at room temperature for 72 hours and then poured into H2O (30 mL). The mixture was extracted with EtOAc (75 mL). The organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0 to 15% EtOAc/hexanes, then a second column with 50% CH2Cl2, then a third column with 25% EtOAc/hexanes afforded [3,5-bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine as a light yellow oil. Rf=0.18 (40% CH2Cl2/hexanes). LCMS=550.3 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.75 (s, 1H), 7.74 (s, 1H), 7.70 (s, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.24 (dd, J=8.5, 2.2 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 3.68-3.76 (m, 4H), 3.68 (s, 3H), 2.88 (m, 1H), 1.22 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[C:12]2[C:11]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:5][CH:4]=1.[Na+].[OH-].[Na+].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25].Cl>O.CCOCC>[Na+:1].[Na+:1].[N+:24]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:2][C:3]2[C:12]3[C:11]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:5][CH:4]=2)=[O:32])=[CH:34][CH:35]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 25.0 g portion of 4-amino-1,5-naphthalenedisulfonic acid sodium salt is suspended in 100 ml of water and 80 ml of 1N sodium hydroxide is added, then 31.0 g of p-nitrobenzoylchloride is added all at once. The mixture is shaken for about 15 minutes and another 80 ml of 1N sodium hydroxide is added with additional shaking. The latter addition of sodium hydroxide and shaking is repeated three more times with the incorporation of 50 ml of water and 25 ml of ether. The final solution remains basic after about 30 minutes of shaking and is then acidified with 20 ml of concentrated hydrochloric acid (which is indicated by a deep blue color to Congo Red test paper). The solution is then diluted to one liter with water and is then extracted with 500 ml of ether. The emulsified ether phase is removed by vacuum siphoning. The ether extraction is repeated 8 additional times with 250 ml portions of ether. The aqueous phase is neutralized with 5N sodium hydroxide and the insoluble fraction is removed by filtration and is washed with 100 ml of 80% ethyl alcohol followed by 100 ml of absolute ethyl alcohol. The washes are combined with the filtrate obtained above and the combined solution is evaporated in vacuo at 55°-60° C. to about 500 ml. The solution is cooled to room temperature and the resultant crystalline material is collected by filtration and is washed consecutively with two 100 ml portions of 90% ethyl alcohol, 100 ml of absolute ethyl alcohol and two 100 ml portions of ether. The product of the example is then oven dried at 120° C. overnight.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[OH:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH:2]=[O:1]
Reactant: O=[N+]([O-])c1ccc(CO)c(O)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc([N+](=O)[O-])cc1O

Procedure:
6.0 g (35.5 mmol) of 2-(hydroxymethyl)-5-nitrophenol and 3.1 g (35.5 mmol) of activated manganese(IV) oxide in 100 ml of chloroform are heated under reflux for 20 h. The mixture is filtered through kieselguhr, concentrated and dried under high vacuum. The title compound is immediately reacted further.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].[CH:38]1([CH2:41][CH2:42]O)[CH2:40][CH2:39]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH:38]1([CH2:41][CH2:42][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]2[CH2:18][C@@H:17]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]2)=[O:11])[CH2:40][CH2:39]1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: OCCC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCC1CC1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reaction time: 17 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (257 mg), 2-cyclopropylethanol (86 mg) and triphenylphosphine (263 mg) in toluene (10 ml) was added diisopropyl azodicarboxylate (506 μl) at room temperature, and the mixture was stirred at the same temperature for 17 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(2-cyclopropylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate. The obtained tert-butyl (3S,5R)-3-[{[1-(2-cyclopropylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (220 mg).
Reaction SMILES: [NH2:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:9](Cl)(Cl)=O.S(=NC1C=CC=CC=1)=O.S(Cl)Cl>C(O)C.C1(C)C=CC=CC=1>[S:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:2]=[N:1]1
Reactant: O=S(Cl)Cl
Reactant: NNc1ccccc1
Agent: ClSCl
Agent: O=S=Nc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2snnc2c1

Procedure:
A dinitrobenzene (I) is reacted with, for example, ammonium chloride and iron or with hydrogen gas and palladium on activated carbon in a solvent such as ethanol or toluene and at elevated temperature to give the corresponding aminoaniline (VII). The aminoaniline (VII) is reacted with, for example, thionyl chloride, N-thionyl aniline or sulfur dichloride in a solvent such as toluene or ethanol and at elevated temperature to yield a benzothiadiazole of formula (A'").
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl[CH2:33][C@@H:34]([CH3:54])[CH2:35]/[C:36](=[CH:40]\[C:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]2)=[C:43]([F:53])[CH:42]=1)/[C:37]([OH:39])=O.Cl.[NH2:56][C@H:57]([C:61]1[CH:66]=[C:65]([F:67])[C:64]([F:68])=[C:63]([F:69])[CH:62]=1)[C@H:58]([OH:60])[CH3:59]>CN(C=O)C.C(OCC)(=O)C>[F:53][C:43]1[CH:42]=[C:41](/[CH:40]=[C:36]2/[C:37](=[O:39])[N:56]([C@H:57]([C:61]3[CH:62]=[C:63]([F:69])[C:64]([F:68])=[C:65]([F:67])[CH:66]=3)[C@H:58]([OH:60])[CH3:59])[CH2:33][C@@H:34]([CH3:54])[CH2:35]/2)[CH:46]=[CH:45][C:44]=1[N:47]1[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]1
Reactant: C[C@@H](O)[C@H](N)c1cc(F)c(F)c(F)c1
Reactant: Cc1cn(-c2ccc(/C=C(\C[C@H](C)CCl)C(=O)O)cc2F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(/C=C3\C[C@H](C)CN([C@H](c4cc(F)c(F)c(F)c4)[C@@H](C)O)C3=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
DIEA (0.47 mL), WSC (257 mg), and HOBT (181 mg) were added to a suspension of (E)-(S)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-4-methylvaleric acid hydrochloride (250 mg) and (1R,2R)-1-amino-1-(3,4,5-trifluorophenyl)propan-2-ol hydrochloride (243 mg) in DMF (5 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved DMF (8 mL). 60% sodium hydride (32 mg) was added at 0° C., and the reaction solution was stirred at 0° C. for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 176 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3[C:34]4([C:42]5[C:37](=[CH:38]C=CC=5)[NH:36][C:35]4=[O:43])COC3=CC=2ON=1.CC1C=CC(S(OC[C@@H]2CCC(=O)N2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:43]=[C:35]1[NH:36][C@H:37]([CH2:38][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[CH2:42][CH2:34]1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1CC[C@@H](CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)N1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (47%) as a colorless solid: mp 133-136° C.; 1H NMR (300 MHz, CDCl3) δ7.35-7.27 (m, 1H), 7.24-7.14 (m, 1H), 7.14-7.03 (m, 1H), 7.00-6.85 (m, 1H), 6.54-6.42 (m, 1H), 6.42-6.37 (m, 1H), 4.93 (t, J=9.3 Hz, 1H), 4.67 (dd, J=9.3, 3.0 Hz, 1H), 4.53 (t, J=8.5 Hz, 2H), 4.18-4.04 (m, 1H), 3.93 (dt, J=13.9, 4.6 Hz, 1H), 3.72 (dt, J=13.9, 4.6 Hz, 1H), 3.07-2.80 (m, 3H), 2.42-2.15 (m, 3H), 2.06-1.81 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.6, 178.5, 161.8 (2C), 161.3, 161.2, 142.2, 142.1, 132.6, 132.5, 129.0 (2C), 128.9, 128.8, 124.1, 123.6, 119.9 (3C), 119.7, 118.8, 108.3, 93.2, 93.1, 80.6, 80.5, 72.3, 57.5, 53.2, 53.1, 45.2 (2C), 29.6, 29.6, 28.9, 24.7 (2C); MS (ES+) m/z 377.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:15]([CH3:16])=[CH:14][CH:10]=[C:11]2[CH3:13])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cc(F)cc(F)c1

Procedure:
To the solution of 3,5-difluoroaniline (3.53 g, 26.8 mmol) in toluene/THF (1:1, 60 mL) is added acetonylacetone (3.24 mL, 26.8 mmol) and p-toluenesulfonic acid monohydrate (0.168 g). The reaction mixture is heated at reflux for 3 h, concentrated under reduced pressure, diluted with CH2Cl2 (60 mL), washed with water (3×10 mL) and saline (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge eluting with EtOAc/Hexanes (5/95-10/90) affords the title compound, mp 55-56° C.
Reaction SMILES: [S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6](O)=[O:7])([OH:4])(=[O:3])=[O:2].S(Cl)([Cl:20])=O.CN(C)C=O>CCOCC.CCCCCC>[S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([Cl:20])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: O=C(O)C(c1ccc2c(c1)CCO2)S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)C(c1ccc2c(c1)CCO2)S(=O)(=O)O
Temperature: 25 °C

Procedure:
Sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride is prepared according to the general procedure described in J. Med. Chem., 15, 1105 (1972). Sulfo(2,3-dihydro-5-benzofuranyl)acetic acid (20 mmole) is added slowly to a solution of ether (4 ml) and thionyl chloride (150 mmole). The mixture is stirred at room temperature until the gas evolution stopped. Then about 0.2 ml of dimethylformamide is added and the solution heated at 40° C. for 4 hours. The mixture is diluted with 30 ml of ether and 30 ml of hexane and then cooled to -25° C. Sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride is recovered from the mixture and used without further purification.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)O.O>C(O)C>[CH3:2][C:1]([O:4][C:12]1[CH:11]=[CH:10][CH:9]=[CH:7][C:6]=1[C:5]([OH:14])=[O:13])=[O:3]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 22.5 °C

Procedure:
To prepare a suspension, desalted egg phosphatides (Hepar) were dissolved in ethanol at a concentration of 250 mg/ml in a 1000 ml flask. To 400 mg of salicylic acid acetate, 1.6 ml of the above solution containing 400 mg of phosphatides was added and the solution adjusted with absolute ethanol to 4 ml. The final concentration of both ingredients in this pharmacological agent-lipid solution was 100 mg/ml. This procedure was performed at about 22.5° C.+/- about 2.5° C. and atmospheric pressure. Then 0.5 ml of the salicylic acid acetate-lipid solution was added to 9.5 ml of distilled water and briefly shaken by hand, at about 22.5° C.+/- about 2.5° C. and atmospheric pressure forming a suspension. The resulting suspension was milky in appearance and did not contain visable crystals or aggregates after a 30 minute period. Light microscopy of the suspension revealed aggregates, primarily with a diameter below 5 microns and no crystal characteristic for salicylic acid acetate. This suspension contained 0.5 mg salicylic acid acetate/ml.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([O:21][C:22]([N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>COCCOC.C(O)C>[C:17]([O:21][C:22]([N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc([N+](=O)[O-])c1
Yield: 51 %

Procedure:
A solution of 1-bromo-3-nitrobenzene (1.5 g 7.42 mmol) in anhydrous 1,2-dimethoxyethane (10 ml) was treated sequentially with 1,1-bistriphenylphosphine palladium II dichloride (260 mg, 0.371 mmol), 2M aqueous sodium carbonate (7.4 ml), and 1-(t-Butoxycarbonyl)pyrrole-2-boronic acid (1.88 g, 8.91 mmol) dissolved in ethanol (10 ml). The reaction was heated under reflux for 5 hours under argon. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of ether/hexane (5:95) to afford the title compound (1.09 g, 51%); MS (ES+) m/e 288 [M+H]+.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([S:19][CH2:20][C:21]([OH:23])=O)[N:13]=[C:12]([CH3:24])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=N[CH2:36][CH2:37][CH2:38][N:39](C)C.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1>C(Cl)Cl>[NH:1]([C:8]1[N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([S:19][CH2:20][C:21]([NH:39][CH:38]1[CH2:36][CH2:37]1)=[O:23])[N:13]=[C:12]([CH3:24])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc2c(c(SCC(=O)O)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc2c(c(SCC(=O)NC3CC3)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a mixture of [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (20 mg, 0.05 mmol), EDCI (18 mg, 0.10 mmol), HOBT (13 mg, 0.10 mmol) and cyclopropylamine (0.004 mL, 0.06 mmol) in CH2Cl2 (5 mL) was added TEA (0.02 mL, 0.14 mmol). The reaction solution was stirred at room temperature for 24 h before the mixture was diluted with CH2Cl2, washed with 0.5N HCl, saturated aqueous NaHCO3, brine and dried over Na2SO4. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide 2-[(2-anilino-7-methyl4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]-N-cyclopropylacetamide (13 mg, 59%): LCMS RT: 2.55 min, MH+: 457.1.