Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].CN(CCN(C)C)C.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CCCCCC>[CH:22]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: BrC1CCCC1
Agent: CN(C)CCN(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FC(F)(F)c1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a 10 L jacketed reactor was added dry THF (2.4 L) and magnesium turnings (81.0 g, 3.33 mol, 1.5 eq.) under N2. In a separate flask FeCl3 (36 g, 0.22 mol, 0.1 eq.) was dissolved in THF (150 mL) (caution, exothermic) under N2. This dark brown solution was allowed to cool to ambient temperature and then added over 10 min to the reactor content under N2 at an internal temperature of about 10° C. TMEDA (402 mL) was added to this yellow/green mixture keeping the internal temperature below about 20° C. (slightly exothermic). The resulting rust brown mixture was stirred at ambient temperature for 1 h under N2 then 1 h at 45° C. The reactor contents were allowed to cool below about 20° C. and a mixture of 1-bromo-2-(trifluoromethyl)benzene (500 g, 2.22 mol) and bromocyclopentane (397 g, 2.66 mol, 1.2 eq.) added dropwise under N2 at a rate as to maintain the internal temperature between about 25-30° C. After the addition, the reaction mixture was stirred at about 25° C. under N2 overnight, allowed to cool to an internal temperature of about 0° C. and quenched with 6 N HCl (2 L) at a rate as to maintain the internal temperature below about 15° C. (caution, exothermic). [Note: 1PC's after completing the addition and stirring overnight were similar indicating that the reaction may have been completed much sooner.] After the quench, hexane (3 L) was added and the reactor contents were stirred at ambient temperature for 1 h. The phases were separated and the aqueous layer back extracted with hexane (1 L). The combined organic layers were dried (Na2SO4), slurried with silica (750 g) and filtered washing the solids with hexane (1 L). The filtrate was concentrated under reduced pressure (100 torr at 37° C.) to give an amber oil (317 g, 97.3 Area % by HPLC, 87.7 wt % by HPLC (contained residual hexane by NMR), corrected yield 58%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc(F)cc1CO
Temperature: 20 °C
Reaction time: 72 h
Yield: 100.3 %

Procedure:
Dissolve 5-fluoro-2-nitrobenzoic acid (15 g, 81.08 mmol) in anhydrous tetrahydrofuran (200 mL) and add dropwise with stirring at 20° C. a 1 molar solution of borane in tetrahydrofuran (243 ml, 243 mmol). Stir the mixture at 20° C. for 72 hours then add methanol (200 ml). Concentrate under reduced pressure and purify the residue by flash column chromatography (silica gel, 10-30% ethyl acetate/hexane) to obtain 13.92 g (100%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([OH:13])=O)=[N:5]1)([CH3:3])[CH3:2].[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([NH:40][CH2:39][CH2:38][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2ccn(C(C)C)n2)CC1
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)NCCN2CCCC2)c2ccn(C(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
(±)-3-(1-Isopropyl-1H-pyrazol-3-yl)-3-[4-(7-methoxyquinolin-8-yl)-1,4-diazepan-1-yl]propanoic acid (220 mg, 0.50 mmol) and 2-(pyrrolidin-1-yl)ethanamine (114 mg, 1.0 mmol) were suspended in anhydrous DMF (6 mL). N,N-Diisopropylethylamine (0.2 mL, 1.2 mmol) was added and the mixture was stirred at ambient temperature for 5 min followed by addition of HATU (300 mg, 0.79 mmol). After 1 h at ambient temperature, LC-MS and TLC indicated completion of reaction (LC/MS [M+H]+ 534.6). Water (5 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (3×30 mL) and concentrated. The residue was purified by silica gel chromatography using 2 to 5% MeOH in CH2Cl2 containing 0.5% aqueous NH4OH to afford the title compound (230 mg, 86%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.20 (br, 1H), 8.81 (d, 1H, J=2.8 Hz), 8.03 (d, 1H, J=8.4 Hz), 7.51 (d, 1H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.0 and 8.0 Hz), 6.16 (s, 1H), 4.52 (septet, 1H, J=6.8 Hz), 4.34 (br, 1H), 3.90 (s, 3H), 3.58 (m, 2H), 3.52-3.40 (m, 4H), 3.20-2.80 (m, 4H), 2.63 (t, 2H, J=6.8 Hz), 2.54 (br s, 4H), 2.20 (br s, 2H), 2.02 (m, 2H), 1.78 (br s, 4H), 1.47 (d, 6H, J=6.8 Hz). MS (ES) m/z 534.6 (M+H+).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:15])([CH3:14])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=12.[C:16]([N:18]=[C:19]1[NH:23][CH2:22][CH2:21][S:20]1)#[N:17]>C(N(CC)CC)C>[C:16]([N:18]=[C:19]1[N:23]([C@@H:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH3:15])([CH3:14])[C@H:2]2[OH:1])[CH2:22][CH2:21][S:20]1)#[N:17]
Reactant: N#CN=C1NCCS1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
A mixture of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.51 g), 2-cyanoiminothiazolidine (0.64 g), and triethylamine (4.1 ml) was heated at 100° C. for 5 hours. Triethylamine was removed under reduced pressure. To the residue was added a mixture of ethyl acetate (15 ml) and water (15 ml), and the mixture was stirred for 30 minutes. The precipitate was collected by filtration and washed with ethyl acetate to give trans-4-(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.60 g).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C([Cl:19])(=O)C>C(Cl)(Cl)Cl>[Cl-:19].[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Agent: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Solvent: ClC(Cl)Cl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Acetylgalactosamine 41 [3.0 g (13.56 mmol)] was suspended in acetyl chloride (6 ml), and stirred at room temperature overnight. The reaction mixture was diluted with chloroform (24 ml), poured into ice-water, and the chloroform layer was washed with saturated sodium bicarbonate. The organic layer dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo to give an N-acetylgalactosamine chloride 43 (4.35 g). To a mixture of dexamethasone 6 [5.95 g (15.17 mmol)], the N-acetylgalactosamine chloride 43 [5.55 g (15.17 m mol)], trityl chloride [4.23 g (15.17 mmol)] and zinc chloride [2.07 g (15.17 mmol)] was added nitromethane (130 ml), and the resulting mixture was stirred under an argon atmosphere at room temperature overnight. The reaction solution was diluted with chloroform, and filtered to remove insoluble materials. The filtrate was washed successively with saturated solutions of sodium bicarbonate and sodium chloride. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off in vacuo, and the residue thus obtained was purified by silica gel column chromatography (acetone:toluene =2:3) to give fractions containing the desired product (950.8 mg). This fraction was further purified by HPLC using a reversed phase partition column (acetonitrile-water) to give α-anomer 44α [98.0 mg (yield 0.9%)] and β-anomer 44β [569.5 mg (yield 5.2%)], respectively, both as white powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:14][CH2:13][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=1)[C:15]([F:16])([F:17])[F:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reaction time: 14 h
Yield: 55.9 %

Procedure:
Under a nitrogen atmosphere, 132 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry DMF. A solution of 0.77 g of 2-(4-ethoxyphenyl)-3,3,3-triflouropropanol and 0.69 g of 3-phenoxybenzyl bromide in 5 ml of dry DMF was then added at room temperature, and the reaction solution was stirred at that temperature for 14 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1 ) mixture] to obtain 0.61 g of the desired compound.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=1>CN(C=O)C>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)=[C:6]([F:12])[CH:5]=1
Reactant: Nc1cc(F)c(O)cc1F
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of potassium hydride (30-35% dispersion in mineral oil, 1.9 g, 13.9 mmol) in DMF (30 mL) was added 4-amino-2,5-difluorophenol (1.7 g, 11.6 mmol) as a solution in DMF (5 mL). After one hour of stirring at ambient temperature, 4-chloropicolinamide (1.8 g, 11.6 mmol) was added and the reaction mixture was heated to 100° C. for 135 h. The mixture was cooled to room temperature, quenched with 10% aqueous lithium chloride and then extracted three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was partitioned between chloroform and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to a solid (3.0 g, 98%). 1H NMR (DMSO-d6) δ 8.51-8.57 (m, 1H), 8.14 (br s, 1H), 7.74 (br s, 1H), 7.37-7.38 (m, 1H), 7.17-7.30 (m, 2H), 6.74-6.80 (m, 1H), 5.62 (s, 2H); MS(ESI+) m/z 266 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18](OC)=[O:19])[CH:12]=[CH:11]2>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH2:18][OH:19])[CH:12]=[CH:11]2
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2cc(Br)ccc2c1
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a three-necked flask (5 L) cooled with an ice-bath was added lithium aluminum hydride (40 g, 1.05 mol), and anhydrous THF (500 mL) under nitrogen protection. To this suspension, Methyl 6-bromo-2-naphthoate (141 g, 0.534 mol) dissolved in anhydrous THF (1200 mL) was added dropwise slowly through a dropping funnel. Cooling bath was removed and the reaction mixture was kept under stirring for additional 2 hours. The reaction mixture was cooled with an ice-bath again, and to it was added methanol (150 mL) dropwise carefully until there was no gas release. The mixture was kept under stirring for half an hour and then was acidified with concentrated hydrochloric acid to a PH of about 4. The resulting solid was removed by filtering under reduced pressure and the filtrate was concentrated, and then poured into deionized water (2 L). The resulting precipitate was collected by suction filter, and washed with deionized water, followed by a little ethanol, and dried in vacuum to afford (6-bromonaphthalen-2-yl)methanol (95.4 g).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:10])[CH2:7][CH2:8][OH:9]>>[N:6]([CH2:7][CH2:8][O:9][CH2:3][CH2:2][C:1]#[N:4])([CH3:10])[CH3:5]
Reactant: C=CC#N
Reactant: CN(C)CCO
Product: CN(C)CCOCCC#N

Procedure:
244 g of acrylonitrile are added dropwise to 356.5 g of 2-dimethylaminoethanol and 5 ml of Triton B in the course of 15 minutes. In the course of the ensuing exothermic reaction the mixture warms from room temperature to 75° C. While adding a further 5 ml of Triton B, the mixture is heated for 8 hours to 95° C. and then distilled. Yield: 451.4 g (79.4%) of analytically pure product (analysis by gas chromatography); b.p. 102° C./8 torr.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:21])[C:4]1([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1.Cl>O>[CH3:2][N:3]([CH3:21])[C:4]1([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: Cc1cccc(C2(N(C)C)CCC3(CC2)OCCO3)c1
Agent: Cl
Solvent: O
Product: Cc1cccc(C2(N(C)C)CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 76 h

Procedure:
Dimethyl-(8-m-tolyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (2.76 g, 10 mmole) was dissolved in water (4.2 ml), conc. hydrochloric acid (6.15 ml) was added and the mixture was stirred for 76 hours at RT.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH2:2][CH2:3][CH3:4].[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Br)(Br)Br>>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccccc1O
Reactant: CCOC(=O)NC
Agent: BrP(Br)Br
Product: CCCCc1ccccc1OC(=O)NC
Temperature: 140 °C

Procedure:
To a solution of 2-sec butylphenol (1.5 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) was added phosphorus tribromide (2.7 g, 0.01 mole) and the contents were heated at 140° C. for 15 hours. The reaction mixture was worked up as described earlier to give 2-sec butylphenyl N-methylcarbamate, identified by spectral data.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH:9](Br)Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:13](#[N:18])/[CH:14]=[CH:15]/[C:16]#[N:17].[I-].[Na+]>CN(C)C=O>[C:16]([C:15]1[C:14]([C:13]#[N:18])=[CH:9][C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]=1)#[N:17]
Reactant: BrC(Br)c1ccccc1C(Br)Br
Reactant: N#C/C=C/C#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2ccccc2cc1C#N

Procedure:
That is, α,α,α',α'-tetrabromo-o-xylene [the formula (V)] in an amount of 0.1 mol and fumaronitrile in an amount of 0.178 mol are reacted at 75° C. for 7 hours in the presence of 0.67 mol of sodium iodide in anhydrous N,N-dimethylformamide to yield 2,3-dicyanonaphthalene of the formula (VI). Subsequently, 57.3 mmol of the 2,3-dicyanonaphthalene is reacted with ammonia in the presence of sodium methoxide in methanol with heating for 3 hours to yield 1,3-diiminobenzo(f)isoindoline of the formula (VII). Further, 30.6 mmol of the 1,3-diiminobenzo(f)isoindoline was reacted with 47.1 mmol of silicon tetrachloride in anhydrous tetralin and anhydrous tri-n-butyl-amine under reflux for about 3 hours to give dichlorosilicon naphthalocyanine [SiNoX2 (X=Cl)] which can be represented by the formula (II) except that the two OHs are replaced by two Cl's. Then, this compound is treated with concentrated sulfuric acid and then concentrated ammonia water to give dihydroxysilicon naphthalocyanine [SiNcX2 (X=OH)] of the formula (II).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[Cl:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 95.9 %

Procedure:
A mixture of 6.59 g (0.025 moles) of the 4-benzyloxy-3-chloro nitrobenzene (example 4), 4.19 g (0.075 moles) of iron powder, and 12.04 g (0.225 moles) of ammonium chloride in 100 ml of ethanol and 25 ml of water was stirred mechanically and refluxed for half an hour. The reaction was allowed to cool and stir for 1 hour. The mixture was filtered and solids were washed with ethanol. The combined filtrates were taken to dryness in vacuo. This solid was dissolved in methylene chloride and passed through Magnesol. Removal of the solvent from the filtrate in vacuo gave 5.60 g of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:35]([C:32]1[CH:33]=[CH:34][C:29]([F:28])=[C:30]([N+:39]([O-:41])=[O:40])[CH:31]=1)(=[O:36])=[O:37]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c([N+](=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 100-mL round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE A, 1.478 g, 5.88 mmol) and THF (10 mL) to give a clear, light-yellow solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (5.88 mL, 5.88 mmol) was added dropwise over 2 min. The cooling bath was removed for 5 minutes, then re-cooled for 5 min. A solution of 4-fluoro-3-nitrobenzene-1-sulfonyl chloride (1.281 g, 5.35 mmol) in THF (3 mL with a 1 mL flask/syringe wash) was added dropwise over 2 minutes. The cooling bath was removed and the reaction was warmed to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was concentrated from EtOAc (2×), then taken up in EtOAc, sonicated for 1 min, and filtered through a membrane filter. The resulting solid was transferred to a sonication vial, then put under high vacuum at 60° C. for 10 min to give N-(2,4-dimethoxybenzyl)-4-fluoro-3-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (INTERMEDIATE S) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.24 (s, 1 H), 8.18 (dd, J=2.4, 6.7 Hz, 1 H), 7.99 (ddd, J=2.4, 3.9, 8.8 Hz, 1H), 7.33-7.28 (m, 1 H), 7.09 (d, J=8.4 Hz, 1 H), 6.32 (dd, J=2.3, 8.4 Hz, 1 H), 6.21 (d, J=2.4 Hz, 1 H), 5.37 (s, 2 H), 3.76 (s, 3 H), 3.63 (s, 3 H). m/z (ESI) 477.0 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])O[C:10]=1[C:17]([OH:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:23]([CH:20]2[CH2:22][CH2:21]2)[C:10]=1[C:17]([OH:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Solvent: O
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C1CC1
Yield: 93 %

Procedure:
To a suspension of 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.0 g, 7.685 mmol) in H2O (10 ml) in a reaction tube with a stirrer, was added cyclopropylamine (2.13 ml, 30.74 mmol). A clear light yellow solution was formed. The reaction mixture was heated for ca. 19 h in a sealed tube. The reaction mixture then worked up as described in Procedure II. Thus, the title compound (2.14 g, 93%) was obtained as an off white solid.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Br:30])[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)[C:15](O)=[O:16].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Br:30])[C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)[C:15]([NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
To a stirred mixture of benzenesulphonamide (0.89 mmol), dichloromethane (1 mL) and dimethylformamide (one drop), a solution of 3,5-dibromo-4-(3-bromo-benzyloxy)benzoic acid (0.17 mmol) and N,N-diisopropylethylamine (0.86 mmol) in dichloromethane (1 mL) was added. After 15 minutes bromotripyrrolidino phosphoniumhexafluoro phosphate (0.21 mmol) and 1-hydroxybenzotriazole hydrate (0.045 mmol) were added. The reaction mixture was stirred at room temperature over night. Dichloromethane was added (3 mL) and the mixture was washed with an aqueous solution of citric acid (10%, 3×3 mL). The organic layer was washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified on column (silica gel, chloroform/methanol 19:1) and further purified on semi-preparative HPLC (column and eluents as described for Examples 27, 28 an 30) to give 16 mg (16%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]benzene-sulphonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:13][CH2:14][C:15]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2ccc(O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCl)Nc1cccc2ccc(O)cc12

Procedure:
The coupling component used in this Example was prepared by chloroacetylating 8-amino-2-naphthol in glacial acetic acid with chloroacetic acid chloride by using sodium acetate as an acid binding agent, to obtain 8-chloroacetylamino-2-naphthol, dissolving isolated 8-chloroacetylamino-2-naphthol in acetone, and then blowing gaseous trimethylamine into the solution.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C1(OC2C=CC=CC=2)C=CC=CC=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1Nc1ccccc1C(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Temperature: 175 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
The 2-(2-amino-4-chlorophenylamino)benzoic acid (2.00 g, 7.63 mmol) was mixed with diphenyl ether (5 mL). The reaction mixture was stirred at 175° C. for 2 hours. The mixture was cooled down to room temperature and put directly to the column eluting with 10% to 50% ethyl acetate in hexanes to afford the title compound 9 (1.42 g, 76%) as a purple solid.