Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:8]([NH:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:33][CH2:34]2)[S:27][CH:28]=1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 47.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (212 mg, 0.782 mmol), 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 136 mg (47.4%) of the desired product as a solid.
Reaction SMILES: C([Li])CCC.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([OH:10])=O.N1C=CC=CC=1C1C=CC=CN=1.[F:27][C:28]1[C:36]([O:37][CH3:38])=[C:35]([F:39])[C:34]([F:40])=[CH:33][C:29]=1C(Cl)=O>O1CCCC1.C(OCC)(=O)C>[OH:10]/[C:8](/[C:29]1[CH:33]=[C:34]([F:40])[C:35]([F:39])=[C:36]([O:37][CH3:38])[C:28]=1[F:27])=[CH:7]\[C:6]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1c(F)c(F)cc(C(=O)Cl)c1F
Reactant: CCOC(=O)CC(=O)O
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\O)c1cc(F)c(F)c(OC)c1F
Temperature: 25 °C

Procedure:
Compound B is prepared using the general method of Wierenga and Skulnick (Wierenga, W.; Skulnick, H. I. J. Org. Chem. (1979) 44: 310-311). n-Butyllithium (1.6 M in hexanes) is added to a cooled (−78° C.) solution of tetrahydrofuran (10 mL) containing ethyl hydrogen malonate (180 μL, 1.50 mmol) and 2,2′-bipyridyl (˜1 mg as indicator). The temperature of the reaction mixture is allowed to rise to ca. −5° C. during the addition of n-butyllithium. Sufficient n-butyllithium (2.8 mL, 4.48 mmol) is added until a pink color persists at −5° C. for 5-10 min. A solution of 2,4,5-trifluoro-3-methoxybenzoyl chloride (0.75 mmol, vide supra) in tetrahydrofuran (˜3 mL) is added in one portion to the reaction mixture that had been recooled to −78° C. The resulting mixture is allowed to warm to room temperature, diluted with ethyl acetate (50 mL), and quenched with a 1 M aqueous solution of hydrochloric acid. The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2×30 mL), followed by brine (2×50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 20% v/v ethyl acetate in hexanes) to give pure B as a white solid. 1H NMR (300 MHz, CDCl3): (enol, predominant tautomer, ≧90%) 81.32 (t, JH-H=7.0 Hz, 3H, CO2CH2CH3), 4.02 (apparent t, JH-F=1.0 Hz, 3H, OCH3), 4.25 (q, JH-H=7.0 Hz, 2H, CO2CH2CH3), 5.79 (s, 1H, CH3C(OH)═CH—CO2CH2CH3), 7.39 (ddd, JH-F=11.0 Hz, 8.5 Hz, 6.5 Hz, 1H, aromatic), 12.68 (s, 1H, OH). 19F{1H} NMR (282 MHz, CDCl3): δ−146.8 (dd, JF-F=21.5 Hz, 10.5 Hz, 1F), −140.2 (dd, JF-F=21.5 Hz, 13.5 Hz, 1F), −131.3 (dd, JF-F=13.5 Hz, 10.5 Hz, 1F).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH3:13][NH2:14]>C1COCC1.CCOC(C)=O>[CH3:13][NH:14][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: CN
Reactant: CCOC(=O)c1csc(CBr)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(CNC)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of ethyl 2-bromomethylthiazole-4-carboxylate (4.25 g, 17 mmol) in THF (50 ml) was added to a solution of methylamine in THF (2M, 30 ml, 60 mmol) drop-wise while cooling to −10° C. The mixture was allowed to warm to room temperature and stirred for a further 30 min. The mixture was diluted with EtOAc and washed with 0.3N potassium hydrogen sulphate solution and brine. The organic phase was dried and reduced to yield ethyl 2-(methylaminomethyl)thiazole-4-carboxylate (3.06 g, 70%) as an orange oil which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[NH:14][CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Cl)Cl.[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[N:14]([C:20](=[O:21])[CH:19]([Cl:23])[Cl:18])[CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(C2NCCO2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCOC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Five and eight tenths (5.8) grams of 2-m-nitrophenyl oxazolidine was dissolved in 50 ml. methylene chloride containing 3.5 g. of triethylamine. Dichloroacetyl chloride 4.4 g. was added dropwise with stirring to the reaction flask and cooled in a water bath at room temperature. When addition was complete, the mixture was stirred at room temperature for about 30 minutes, washed with water, separated and dried over anhydrous magnesium sulfate. The solvent was stripped off under vacuum. There was obtained a yield of 8.6 g. of the title compound, ND30 =1.5590.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]([CH3:27])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.OS(O)(=O)=O>C(O)(=O)C.O.C(Cl)Cl>[Cl:26][C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[N:6][N:5]([CH:4]([CH3:27])[CH:3]=[O:2])[C:9]=3[CH:10]=2)[CH:20]=[C:19]([F:21])[C:18]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COC(OC)C(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 70 °C

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (20 g, 0.046 mole) in acetic acid is treated with 47 ml of 2.5N H2SO4, heated for 12 hours at 70° C., cooled and diluted with water and methylene chloride. The phases are separated and the aqueous phase is extracted with methylene chloride. The combined organic phases are dried (MgSO4), filtered through a pad of Al2O3, and concentrated in vacuo to afford the title compound as a solid, mp 107°-108° C., characterized by elemental and NMR analyses.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][NH2:24].CCN(C(C)C)C(C)C>>[OH:20][CH2:21][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][NH:24][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCC(CO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCC(CO)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 3-hydroxy-2-phenyl-propylamine and DIEA to give 2-(3-hydroxy-2-phenyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[NH:19][CH3:20]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:19]([CH3:20])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:21]=[CH:22][CH:23]=1
Reactant: CNc1cccc(OC)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)c1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with 3-methoxy-N-methylaniline (933 mg, 6.8 mmol) using method A to give 4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as an off white solid. Yield: 398 mg (55%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 6.88 (ddd, J=8.5, 2.5, 1.0 Hz, 1H), 6.67-6.64 (m, 2H), 3.69 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]N(C=O)C.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a 500 ml flask under nitrogen atmosphere was charged 3-fluoro-4-nitro benzoic acid (10 g, 0.054 mol, 1 eq) and 250 ml of Toluene followed by DMF (210 ul, 3.7 mmol, 0.05 eq) and was heated to 70° C. At 40° C. thionyl chloride (8.0 ml, 0.11 mol, 2.0 eq) was added and the reaction was allowed to stir at 70° C. for 16 hours. The reaction was removed from the heat and placed in an ambient temperature bath. 100 ml of anhydrous methanol was added and then concentrated on rotary evaporator under reduced pressure, and bath temp of 45° C. The final volume was reduced to ˜70 ml and slowly add hexane 100 ml with stiring to yield a light yellow solid, yield 97%. 1H NMR (Solvent CDCl3), Singlet, 3 H, 3.99 ppm, Doublet of Doublets, 2H, 7.95 ppm, Triplet, 1H, 8.15 ppm. Thin Layer Chromatography elution 5% methanol/dichloromethane, Rf=0.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH:20]1[C:25]([CH:26]=O)=[CH:24][C:23]2[O:28][CH2:29][O:30][C:22]=2[CH:21]=1>>[O:30]1[C:22]2[CH:21]=[CH:20][C:25]([CH2:26][N:17]3[CH2:18][CH2:19][CH:14]([NH:13][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=5)[O:8][C:7](=[O:12])[CH:6]=4)[CH2:15][CH2:16]3)=[CH:24][C:23]=2[O:28][CH2:29]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)ccc2o1
Yield: 39 %

Procedure:
According to Procedure A above, 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one and piperonal (0.032 g, 0.216 mmol) were allowed to react to give the title compound (0.0123 g, 39%, mono-TFA salt) as an off-white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.12 (br s, 1H), 7.61 (d, J=8, 1H), 7.33 (d, J=8, 1H), 7.00 (m, 2H), 6.93 (dd, J=4, 8, 1H), 6.03 (s, 2H), 5.44 (s, 1H), 4.26 (s, 2H), 3.79-3.90 (m, 1H), 3.62-3.56 (m, 2H), 3.11-3.22 (m, 2H), 2.29-2.40 (m, 2H), 1.85-1.99 (m, 2H); MS (ESI+Q1MS) m/z 413 [M]+
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH:6]([OH:8])=[O:7].CC([N:12](C)C)=O>>[CH:6]([O:8][NH2:12])=[O:7].[CH3:1][S:2]([O-:5])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O
Reactant: O=CO
Reactant: CC(=O)N(C)C
Product: CS(=O)(=O)[O-]
Product: NOC=O
Reaction time: 16 h

Procedure:
A solution of 0.25 mmol (1 equivalent) of the corresponding methanesulfonic acid in 0.7 ml dry DMA was treated with a solution of 0.5 mmol (2 equivalents) of the corresponding secondary amine in 0.15 ml dry DMA at room temperature. After 16 h, 2 equivalents of secondary amine were added again to the solution. The reaction mixture was allowed to stand over night at room temperature, treated with 0.2 ml formic acid and purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water (0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation, the product was obtained as a mixture of amino formate and methanesulfonate.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:12].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:18][O:17][C:15]([CH2:14][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:12])=[O:16]
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: COC(=O)CBr
Product: COC(=O)Cn1c2c(ccc1=O)C(=O)CCC2

Procedure:
Prepared analogously to Example 29 from 7,8-dihydro- 2,5(1H,6H)-quinolinedione and methyl bromoacetate.
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C:21]3[CH:26]=[CH:25][C:24]([O:27]CC4C=CC=CC=4)=[CH:23][C:22]=3[Cl:35])=[CH:15][CH:14]=2)=[O:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCCCC1>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[Cl:35])=[CH:15][CH:14]=2)=[O:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(OCc4ccccc4)cc3Cl)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCCCC1
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(O)cc3Cl)cc2)cc1
Yield: 80 %

Procedure:
2.5 g (4.7 mmol) of 4-benzyloxy-2-chloro-benzoic acid 4-(4-pentyl-phenoxycarbonyl)-phenyl ester, 20 mL of cyclohexane and 0.13 g of palladium hydroxide/carbon were added to 25 mL of dehydrated ethanol and refluxed for 12 hours in the presence of argon. The resulting reaction mixture was filtered and the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate to obtain 1.65 g of a white solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CC1(C)[O:15][C:14](=O)[CH2:13][C:12](=[O:17])[O:11]1>C(OCC)(=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[CH2:13][C:12]([OH:17])=[O:11])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccc(I)cc1
Solvent: CCOC(C)=O
Product: O=C(O)CC(=O)Nc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture containing 4-iodoaniline (400 g, 1.83 mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (263 g, 1.83 mol) was stirred at 80° C. After 2 hours, the mixture was cooled to 23° C. and then ethyl acetate (5 L) was added. The mixture was extracted with aqueous sodium hydroxide solution (110 g of sodium hydroxide dissolved in 5 L of water). The basic aqueous layer was washed with ethyl acetate (3 L). The washed layer was brought to pH 2 with 6 M aqueous hydrochloric acid solution. The acidic aqueous solution was extracted with ethyl acetate (3×3 L). The organic layers were combined and the combined solution was dried with magnesium sulfate. The dried solution was filtered and the filtrate was concentrated to afford the title compound as a yellow solid.
Reaction SMILES: [O:1]1C=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9].Cl.[C:19]([O-:22])([O-])=[O:20].[Na+].[Na+].[CH2:25](O)[CH3:26]>>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][CH2:6][C:2](=[O:1])[CH2:3][CH2:4][C:19]([O:22][CH2:25][CH3:26])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)C=Cc2ccco2)cc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)CCC(=O)CCC(=O)c1ccc(OC)cc1
Yield: 49 %

Procedure:
To a solution of compound 3-(furan-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (8.0 g, 35.1 mmol) in ethanol (150 mL) was added conc. HCl (38.0 mL). The resulting mixture was refluxed for 14 h. Then the solution was neutralized with 10% Na2CO3 solution. The volatile was removed. The residue was diluted with DCM (750 mL), washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=8:1˜4:1) to give ethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C) as a yellow solid (5.10 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 60 h
Yield: 84.4 %

Procedure:
Methyl 5-fluoro-2-hydroxybenzoate (2.65 g, 15.6 mmo.) and 1-fluoro-2-nitrobenzene (2.02 g, 14.2 mmol) were dissolved in acetonitrile (30 mL) and cesium carbonate (6.10 g, 18.7 mmol) was added. The reaction mixture was stirred at 80° C. for 60 hours. The mixture was cooled down to room temperature and poured into ethyl acetate. This organic mixture was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography with 10-20% ethyl acetate in hexanes and triturated in ethanol to afford the title compound 18 (3.49 g, 84%) as white solid. LRMS (ESI): (calc) 291.05 (found) 292.2 (MS)+.
Reaction SMILES: [OH:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:14]1([S:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C>CC(N(C)C)=O>[C:14]1([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:27][C:7]([C:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])=[CH:28][CH:29]=2)(=[O:21])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1(O)CCCC1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: C
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C1(O)CCCC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 1-hydroxycyclopentanecarboxylic acid (0.76 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto water, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water, and brine. After drying (Na2SO4) the ethyl acetate was removed by evaporation. Crystallization from ethyl acetate/hexane yielded the title tertiary carbinol (0.70 g, 47%) as a white solid; mp=214.0°-216.0° C. 1H--NMR (300 MHz, d6 --DMSO): 1.73 (m, 6 H, CH2), 1.97 (m, 2H, CH2), 5.67 (s, 1H, OH), 7.64 (m, 3H, ArH), 7.94 (m, 6H, ArH), 10.13 (s, 1H, NH). MS (CI, CH4): 346(M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: NCCOCCO
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Yield: 63 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (72 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (92 mg), 2-(2-aminoethoxy)-ethanol (30 mg), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 446.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.47 (t, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.84-7.58 (m, 2H), 7.48 (d, 1H), 7.40 (d, 1H), 4.63 (t, 1H), 3.64 (s, 3H), 3.56 (t, 2H), 3.51 (t, 2H), 3.49-3.41 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: CCCCCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOC(=O)c1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
17.2 g (0.1 mol) of 3-amino-4-chlorobenzoic acid was added to 50 ml of dimethylsulfoxide.. Then 13.8 g (0.1 mol) of potassium carbonate was added to the solution obtained above, and the resulting mixture was stirred in the temperature range of from 20 to 30° C. for 30 min. 22.5 g (0.11 mol) of dodecyl chloride was poured into the solution thus obtained, and the resulting solution was heated to 100° C., and allowed to react at the temperature for 1 hour. After completing the reaction, 50 ml of ethyl acetate, and 50 ml of water were added to the reaction mixture, and the organic layer obtained was separated, concentrated, diluted with 100 ml of methanol, and then cooled to precipitate crystals. The crystals were separated by filtration, and then dried to obtain 32.3 g (yield 95%) of the desired product. Purity 99% or higher. Melting point 58.0-59.2° C. A result of the elemental analysis of this sample was as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([OH:26])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22]C(=O)C)[CH2:8]2)=[CH:4][CH:3]=1.[ClH:29].CO>C(OCC)C>[ClH:1].[ClH:29].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH:13]([OH:26])[CH2:12][N:9]1[CH2:10][CH2:11][CH:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8]1
Reactant: CC(=O)Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Temperature: 102.5 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide (0.95 g, 2.34 mmol) and concentrated hydrochloric acid (25 mL) was heated (100-105° C.) for 3 hours then allowed to stand at room temperature overnight. The mixture was concentrated at reduced pressure to a third of its volume basified with saturated sodium hydrogen carbonate. The resulting suspension was extracted twice with ethyl acetate. The organic extracts were dried, the solvent was evaporated at reduced pressure to give a pale brown oil. This oil was dissolved in a to minimum amount of methanol, diluted with ethyl ether and the product precipitated by addition of HCl-saturated ethyl ether. The product was filtered to afford the subtitle product (0.93 g, 91.2%).