Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:38])[C:5]([CH3:37])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:33]C(=O)C)=[C:17]([CH:32]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[CH:30][NH:29][N:28]=3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.ClCCl.O>[CH3:1][O:2][C:3]1[C:4](=[O:38])[C:5]([CH3:37])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:33])=[C:17]([CH:32]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[CH:30][NH:29][N:28]=3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(-c4cc[nH]n4)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(-c4cc[nH]n4)cc3)c2)=C(C)C1=O
Yield: 59.4 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-(1H-pyrazol-3-yl)aniline (0.090 g, 0.175 mmol) was dissolved in a mixed solvent of methanol (2 ml) and dichloromethane (1 ml), and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (1:1) to obtain the titled compound (0.049 g, 0.104 mmol, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Br:10][CH2:11][C:12](Br)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(OCC)(=O)C>[Br:10][CH2:11][C:12]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([Cl:9])=[CH:5][C:6]=1[Cl:8])=[O:13]
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1c(Cl)cc(Cl)cc1Cl
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of 1,3,5-trichlorobenzene (10.0 g, 55.1 mmol), 2-bromoacetyl bromide (5.0 mL, 57.8 mmol, 1.05 eq), and aluminum chloride (7.7 g, 57.8 mmol, 1.05 eq) was heated neat at 80° C. under argon for 17 h until a black precipitate is formed. The reaction was cooled to room temperature, and the resultant black mass was dissolved in ethyl acetate (500 mL). Water (200 mL) was added slowly at 0° C. to quench the reaction, and the biphasic layers were separated. The organic layer was then washed with water (2×150 mL) and brine (1×150 mL), dried (MgSO4), filtered, and evaporated in vacuo. Recrystallization from hexane gave 11.5 g (69.3%) of 2-bromo-1-(2,4,6-trichlorophenyl)ethanone as a fluffy white solid. 1H-NMR (DMSO-d6) δ 7.86 (s, 2H), 4.78 (s, 2H); Rf=0.28, 2% ethyl acetate-hexane.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9](=[O:14])[CH2:8][CH2:7]2>C(O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([OH:14])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(F)ccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC1CCc2cc(F)ccc2C1
Yield: 80 %

Procedure:
Sodium borohydride (1.67 g) was added in portions to a solution of 6-fluoro-2-tetralone (6.56 g) in dry ethanol (30 ml) with stirring, keeping the temperature below 25° C. The mixture was then stirred at room temperature for 3 hours. The mixture was then diluted with a little ethyl acetate and concentrated to an oily residue. Dilute sulphuric acid was added dropwise until effervescence no longer occurred. The mixture was extracted with ether and the extract washed, dried, and concentrated to give an oil. This was distilled (b.p. 75-77/0.1 Torr) to give 6-fluorotetralin-2-ol (5.31 g) containing a trace of the tetralone starting material.
Reaction SMILES: [CH2:1]([N:7]([CH:21]([CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:22][CH2:23][CH2:24][CH3:25])[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:38]>C(O)C>[NH2:38][CH2:26][CH:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:9])=[O:10])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: N
Reactant: CCCCCCN(C(CCCC)COS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Solvent: CCO
Product: CCCCCCN(C(CN)CCCC)S(=O)(=O)c1cccc2cnccc12
Temperature: 100 °C

Procedure:
To 2.37 g of the thus obtained N-hexyl-N-(1-p-toluenesulfonyloxymethylpentyl)-5-isoquinolinesulfonamide was added 40 ml of an ethanol solution containing 4 g of ammonia, and the mixture was heated in a pressure vessel at 100° C. for 13 hours. Then, the solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: a 5% methanol solution in chloroform) to obtain 0.70 g of N-(1-aminomethylpentyl)-N-hexyl-5-isoquinolinesulfonamide [Compound (19)]. Compound (19) was analyzed to give the following data.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:7][CH2:6]1)=O.[CH3:21]C(C)([O-])C.[K+].O>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:4]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:7][CH2:6]1)[CH2:3][CH:1]=[CH2:21]
Reactant: O=CCC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reaction time: 0.5 h

Procedure:
7.0 g of 1-((trans-4-(2-formylethyl)cyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 30 mL of THF, and 10.6 g of methyl triphenylphosphonium bromide was added thereto. To this solution, the THF (15 mL) solution containing 3.3 g of potassium-t-butoxide was added dropwise at an internal temperature of 5 to 20° C., and the solution was stirred for 30 min. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and subjected to column chromatography. The solvent was evaporated under reduced pressure, to thereby obtain 3.0 g of 1-((trans-4-(3-butenyl)cyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: C(O[CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C.C1C=CC([Se])=CC=1>C(Cl)Cl.B(F)(F)F.CCOCC.C(OCC)(=O)C>[O:13]([CH2:12][C:11]([NH:10][C@H:6]1[CH2:5][NH:8][C:7]1=[O:9])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC1NC(=O)[C@H]1NC(=O)COc1ccccc1
Agent: FB(F)F
Agent: [Se]c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)N[C@H]1CNC1=O

Procedure:
Under a nitrogen atmosphere, 4-(R,S)-acetoxy-3-(S)-(phenoxyacetamido)azetidinone (1.32 g, 4.74 mmol) was dissolved in methylene chloride (9 ml). To this solution was added phenylselenol (1.5 ml, approximately 9.8 mmol), then boron trifluoride-etherate (10 drops). The resultant solution was stirred at room temperature for 20 minutes. The solution was diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate solution (2×). The solution was dried over magnesium sulfate, filtered and concentrated in vacuo. The concentrate was absorbed onto silica gel (7 g) and then chromatographed over an additional amount of silica gel (15 g) using a gradient elution of toluene to ethyl acetate. The product-containing fractions gave 4-(R,S)-phenylselenyl)-3-(S)-(phenoxyacetamido)azetidinone.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC=C)(=O)[CH3:11].C([O-])(=O)C.[K+]>C(OC=C)(=O)CC.[Cu](Br)Br.O1CCCC1>[C:1]([O:9][CH:10]=[CH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C=COC(C)=O
Agent: Br[Cu]Br
Agent: C=COC(=O)CC
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: C=COC(=O)c1ccccc1
Temperature: 70 °C

Procedure:
A solution consisting of 4.88 g of benzoic acid, 24.8 of vinyl acetate, 0.4 g of potassium acetate, 89.4 mg of copper(II) bromide and 20 ml of tetrahydrofuran was mixed with 1.34 g of the solid catalyst prepared in Example 9. The resulting mixture was heated at 70° C. for 24 hours in the same manner as in Example 9, to form 4.80 g of vinyl benzoate and recover 1.94 g of acetic acid as the byproduct.
Reaction SMILES: O=O.[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14](\[CH3:17])/[CH2:15][OH:16])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C1(C)C=CC=CC=1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: C/C(=C\c1ccc(C(C)(C)C)cc1)CO
Agent: O=O
Solvent: Cc1ccccc1
Product: C[C@@H](CO)Cc1ccc(C(C)(C)C)cc1
Yield: 98.3 %

Procedure:
A 500 ml autoclave was charged in a glove box (O2 content <1 ppm) with 16.11 g (78.85 mmol) of (E)-3-(4-tert.butylphenyl)-2-methylprop-2-en-1-ol, 145 ml of toluene and 5 ml of catalyst solution (in accordance with a)). This mixture was hydrogenated at 100°, a constant pressure of 60 bar H2 and while stirring intensively. The conversion was >99% after 22 hours. The pale yellow hydrogenation solution was rinsed from the autoclave and evaporated on a rotary evaporator at 60°/17 mbar. The residue was distilled at 140°/0.01 mbar. There were obtained 16.0 g (99.0%) of (R)-3-(4-tert.butylphenyl)-2-methylpropan-1-ol as a colourless oil with an enantiomeric purity of 91.3% e.e.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[C:35]([C:49]2([OH:52])[CH2:51][CH2:50]2)[CH:36]=[C:37]([F:48])[C:38]=1B1OC(C)(C)C(C)(C)O1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[C:37]([F:48])=[CH:36][C:35]([C:49]4([OH:52])[CH2:50][CH2:51]4)=[CH:34][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CC3)cc2F)OC1(C)C
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cc(C4(O)CC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanol (see US2012/225062) gave 225. LCMS (ES+) m/z 508 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1>O>[CH:10](=[N:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(N=Cc2ccccc2)c(F)c1
Yield: 95.2 %

Procedure:
322.8 g (2.5 mol) of 2,4-difluoroaniline, 265.3 g (2.5 mol) of benzaldehyde and 1000 ml of toluene are heated to reflux, and the water formed is removed for 5 hours at 90°-105° C. using a water separator. The toluene is removed by distillation on a vacuum rotary evaporator, and the product is recrystallized from hexane, to give 516.9 g (92.5 % of theory) of N-benzal-2,4-difluoroaniline, which melts at 51°-52° C.
Reaction SMILES: C([Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CO>O1CCCC1>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([S:35]([CH:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][OH:18])[CH2:27][CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])(=[O:36])=[O:37])=[CH:39][CH:40]=1
Reactant: CC(C)(C)[Si](OCc1ccccc1C(CCCCS(C)(=O)=O)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)CCCCC(c1ccccc1CO)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
In tetrahydrofuran (5 ml) was dissolved t-butyl [[2-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzyl]oxy]diphenylsilane (175 mg, 0.261 mmol). Under ice cooling, a tetrahydrofuran solution (1.0M, 0.6 ml, 0.6 mmol) of tetrabutylammonium fluoride was added dropwise to the resulting solution. The resulting mixture was then stirred at room temperature for 1 hour. After addition of water (0.5 ml), the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure, whereby the title compound (87 mg, 0.20 mmol, 61%) was obtained as a pale yellowish brown oil.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][CH2:24][CH2:25]O)(=[O:16])=[O:15])=[C:9]([CH3:27])[CH:8]=1.O>CN(C=O)C>[Br:2][CH2:25][CH2:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[S:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([O:6][CH3:5])=[CH:8][C:9]=1[CH3:27])(=[O:16])=[O:15]
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCO)c(C)c1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCBr)c(C)c1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
PBr3 (2.64 mmol, 1.5 eq) was added to a solution of 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propan-1-ol (1.76 mmol, 1 eq) in DMF (6 ml) at 0° C. and the mixture was stirred for 30 min. Water (20 ml) was subsequently added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel). Yield: 25%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([NH:11][C:12](=[CH:17][C:18]([O:20]C)=O)[C:13]([O:15][CH3:16])=[O:14])[C:7](=[O:22])[C:6]=2[CH:23]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]3[C:18](=[O:20])[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:8]=3[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: COC(=O)C=C(Nc1coc2ccc(Cl)cc2c1=O)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2[nH]1
Yield: 79.3 %

Procedure:
Dimethyl 2-[(6-chloro-4-oxo-4H-1-benzopyran-3-yl)amino]-2-butenedioate (1.0 g, 0.0033 mole) was added to diphenyl ether (25 ml) at 200°. The reaction mixture was refluxed for 10 min. (bath temperature 260°-280°). The product, which crystallized out on cooling, was filtered off and washed with ether. Recrystallization from DMF gave white crystals (0.8 g, 88%), m.p. 300°-305°.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][NH2:13]>C1COCC1>[CH3:12][NH:13][CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: BrCc1nc2ccccc2s1
Solvent: C1CCOC1
Product: CNCc1nc2ccccc2s1
Reaction time: 8 h
Yield: 115.4 %

Procedure:
To a stirred solution of 2-bromomethylbenzothiazole (0.4 g. 1.75 mmol) in THF (4 mL) was added 40% aqueous methylamine (0.30 g, 8.77 mmol). Stirring was continued overnight, then the mixture was concentrated. The residue was taken up in H2O, neutralized with 2.5 N NaOH, and extracted with CH2Cl2. The organic extracts were dried (MgSO4) and concentrated to give the title compound (0.36 g, 80%) as a brown oil: 1H NMR (250 MHz, DMSO-d6): δ 2.70 (s, 3H), 4.71 (s, 2H), 7.55 (m, 2H), 8.0 (d, J=7.9 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].CCCCCC>O1CCCC1.CO.C(OCC)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:29][CH:30]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(N2CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)cc1
Reaction time: 8 h
Yield: 54.9 %

Procedure:
4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (117 mg) was dissolved in tetrahydrofuran (3 ml)-methanol (3 ml), and then 10% palladium carbon (61 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with ethanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then suspended in diethyl ether (2 ml)-hexane (2 ml). The solid was filtered and dried under aeration to provide the titled compound (59.5 mg, 54.7%).
Reaction SMILES: [C:1](O)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:22]([O:23][C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[O:25])[C:21]4[S:32][CH2:33][CH2:34][S:35][C:20]=4[C:19]3=[O:36])=[N:15]2)=[CH:10][CH:9]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([O:23][CH:22]2[N:18]([C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[N:17][C:8]([Cl:7])=[CH:9][CH:10]=4)[N:15]=3)[C:19](=[O:36])[C:20]3[S:35][CH2:34][CH2:33][S:32][C:21]2=3)=[O:25])[CH2:31][CH2:30]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: O=C(OC1C2=C(SCCS2)C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(=O)N1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Butyric acid (0.71 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-(piperazin-1-yl)carbonyloxy-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (2.50 g.) and N,N'-dicyclohexyl-carbodiimide (1.67 g.) in anhydrous methylene chloride (50 cc.) and the mixture is stirred for 1 hour at 20° C. After filtering off the dicyclohexylurea formed, washing with methylene chloride (15 cc.) and evaporating the solvent, the residue obtained (3.8 g.) is washed with boiling ethanol (35 cc.) and then recrystallised from a mixture of acetonitrile (110 cc.) and ethanol (11 cc.). 5-(4-Butyrylpiperazin-1-yl)carbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (1.95 g.), which melts at 248° C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([F:54])=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][OH:53])[CH:47]=2)[CH:45]=1.C(N(CC)CC)C>C(Cl)Cl>[F:54][C:43]1[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][OH:53])[CH:47]=2)=[CH:45][C:40]([CH2:39][NH:38][C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])=[CH:41][CH:42]=1
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reaction time: 8 h

Procedure:
To 3-[(methyloxy)carbonyl]benzoic acid (0.18 g, 1 mmol) in CH2Cl2 (25 mL) was added HBTU (0.379 g, 1 mmol), followed by [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (0.231 g, 1 mmol), and triethylamine (0.278 mL, 2 mmol). The mixture was stirred under argon overnight. The reaction mixture was then concentrated to dryness, and taken up in EtOAc and H2O. The organic phase was washed 2× with H2O, 1× with brine, dried and concentrated. The residue was absorbed on Isolute® Sorbent, and CombiFlashed on a 12 g column eluted with 0-100% EtOAc/hexane to afford the title compound as a white solid. LC-MS m/z 393.8 (M+H)+, 1.98 min (ret time); analytical HPLC shows 97.2% purity, (ret time 7.205 min).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].[CH2:5]([Mg]Br)[CH:6]=[CH2:7].[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13](/[CH:17]=[N:18]/[S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH:12]=1>C1COCC1.C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C@@H:17]([NH:18][S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:7][CH:6]=[CH2:5])[CH:12]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc(Cl)ccn1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [In+3]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.1 %

Procedure:
To a cooled (0-5° C.) mixture of indium(III) chloride (13.56 g, 61.3 mmol) in THF (170 mL) was added allylmagnesium bromide (1M in diethylether) (62 mL, 61.3 mmol) dropwise over 30 min. The reaction was allowed to warm to rt. After 1 h at rt, a solution of 45A (10 g, 40.9 mmol) in ethanol (170 mL) was added. After 2-3 h, the reaction was concentrated under vacuum at 50-55° C. The crude material was partitioned between ethyl acetate (200 ml) and water (1×50 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 ml). The organic layers were combined and washed with brine (1×100 ml), dried over sodium sulfate, filtered and concentrated to give 45B (13.5 g, 106%) as a yellow oil. MS (ESI) m/z: 287.2 (M+H)+. This material was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([Cl:21])(=[O:20])=[O:19])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([Cl:21])(=[O:19])=[O:20])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][C:11]=2[N+:27]([O-:29])=[O:28])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2ccccc2c1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc2c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
An ice-cold, stirred solution of 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonyl chloride (17.66 g, 45.1 mmol) in trifluoroacetic acid (150 mL) was treated with 96% sulfuric acid (12.5 mL, 225 mmol) and with 90% nitric acid (2.65 mL, 56.4 mmol) added dropwise over 3 minutes. The reaction mixture was removed from the ice bath, stirred at room temperature for 15 minutes, re-cooled in an ice bath, and treated with water (850 mL) added dropwise. The resulting mixture was filtered through a celite pad to collect the solid which was washed with water (100 mL) and dissolved in methylene chloride (350 mL). The methylene chloride solution was washed with water (500 mL) containing brine (100 mL), dried over magnesium sulfate, and evaporated under vacuum to an oil (21.23 g). This material was shown to be a 42:58 mixture of the 5-NO2 to 8-NO2 products by 1H NMR). The crude product was mixed with ethyl acetate (20 mL) and sonicated to provide a crystalline precipitate. This material was collected, washed with ethyl acetate, and dried under vacuum to afford the title compound (8.11 g) as an off-white solid. The mother liquors yielded an additional 1.47 g of the title compound following flash chromatography on silica gel (eluting with 30-35% ethyl acetate in hexane) and crystallization from diethyl ether.