Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15].Br[CH2:18][C:19]([CH3:21])=[CH2:20]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[N:13]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A suspension of 2 g NaH (95% powder) in anhydrous DMF (100 mL) was cooled to −78° C., N-(2-bromo-5-nitrophenyl)acetamide (7 g, Step A) in dry DMF (50 mL) was added to the mixture under N2 atmosphere. After the mixture was warmed to 0° C., 3-bromo-2-methylpropene (7.3 g in 20 dry DMF) was added to the mixture. The mixture was stirred at RT overnight. Next morning, the mixture was poured into a container of ice and extracted between saturated NaHCO3 solution and EtOAc. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 7:2 hexane:EtOAc to afford the title compound as a yellow gum. MS: 314 (M+1). Calc'd. for C12H13BrN2O3—313.15.
Reaction SMILES: [P:1]([O-:21])([O-:20])([O:3][CH2:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:2].[CH2:22]([CH:24]1[O:26][CH2:25]1)[Cl:23].[OH-].[Na+:28]>>[P:1]([O-:20])([O:21][CH2:25][CH:24]([OH:26])[CH2:22][Cl:23])([O:3][CH2:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:2].[Na+:28]
Reactant: ClCC1CO1
Reactant: CCCCCCCCC(CCCCCC)COP(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCC(CCCCCC)COP(=O)([O-])OCC(O)CCl
Reaction time: 8 h
Yield: 82.3 %

Procedure:
20 g (0.057 moles) of mono2-hexyldecyl phosphate having a purity of 92% (AV1=167.2, AV2=329.8) was dispersed in 59.6 ml of 1N sodium hydroxide aqueous solution, at which the acid value of the reaction system was 39.5. While keeping the reaction system at 80° C., 16.5 g (0.178 moles) of epichlorohydrin was gradually added, followed by agitation at the temperature for 8 hours. The acid value of the reaction system was approximately zero, revealing that the conversion rate of the phosphoric monoester was almost 100%. The reaction solution was analyzed by HPLC. The chromatography showed peaks corresponding to hydrolysate or epichlorhidrine and a new reaction product. The resulting product was collected by HPLC and the solvent was distilled off under reduced pressure to obtain 20.5 g (yield 82.3%) of sodium 2-hexyldecyl 2-hydroxy-3-chloropropyl phosphate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH2:10][NH2:11])[CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([S:26](=[O:29])(=[O:28])[NH2:27])=[C:19]([CH3:30])[C:15]=1[C:16](Cl)=[O:17]>CC(CC)=O>[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH2:10][NH:11][C:16](=[O:17])[C:15]2[C:19]([CH3:30])=[C:20]([S:26](=[O:29])(=[O:28])[NH2:27])[CH:21]=[C:22]([CH:23]([CH3:25])[CH3:24])[C:14]=2[O:13][CH3:12])[CH2:2][CH2:3]1
Reactant: NCC1CCCN1CC1CC1
Reactant: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)Cl
Solvent: CCC(C)=O
Product: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)NCC1CCCN1CC1CC1
Temperature: 10 °C
Yield: 23.6 %

Procedure:
4.3 g of 1-cyclopropylmethyl-2-aminomethylpyrrolidine (0.028 mole) and 40 ml of methylethyl ketone are placed in 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The mixture is cooled to about 10° C. and a solution of 7.6 g of 2-methoxy-3-isopropyl-5-sulphamoyl-6-methyl benzoyl chloride (0.025 mole) in 50 ml of methyl-ethyl-ketone is poured in drop by drop. The mixture is reacted for 1 hour at room temperature then evaporated dry under vacuum, and the residue is dissolved in 100 ml of water and 10 ml of hydrochloric acid (density 1.18). The solution is sucked up under vacuum to eliminate the last traces of solvent, an insoluble component is filtered off and the filtrate is made alkaline with 15 ml of ammonia (density=0.91). The precipitate formed is filtered, washed with water and re-crystallised moist in 50 ml of ethyl acetate. 2.5 g (24%) of product is obtained, melting at about 125° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Yield: 100.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-fluorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4.4 g), the title compound (9 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][S:15][C:14](=[O:17])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:15][C:14]2=[O:17])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: COc1ccc(C2=NNC(=O)SC2)cc1OC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Product: COc1ccc(C2=NN(Cc3ccc([N+](=O)[O-])cc3)C(=O)SC2)cc1OC

Procedure:
In analogy to Example 1, the reaction of 5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one ("B") with 4-nitrobenzyl chloride gives 3-(4-nitrobenzyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 155°.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][C:22]([C:28]([O:30]C)=[O:29])=[CH:21][C:20]=3[CH:32]=2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH3:9])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:3]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][C:22]([C:28]([OH:30])=[O:29])=[CH:21][C:20]=3[CH:32]=2)=[CH:14][CH:15]=1)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g). To the solution was added 1N sodium hydroxide solution (7 ml), and the mixture was stirred at 60° C. for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.29 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][C:13]1[N:14]=[C:15]([Sn](CCCC)(CCCC)CCCC)[S:16][CH:17]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:13]1[N:14]=[C:15]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[S:16][CH:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2nc(C)cs2)c1
Temperature: 90 °C

Procedure:
A mixture of commercially available methyl 2-bromoisonicotinate (2.750 g; 12.70 mmol), 4-methyl-2-(tributylstannyl)thiazole (4.942 g; 12.70 mmol), copper iodide CuI (242 mg; 1.27 mmol), and Pd(PPh3)4 (1.471 g; 1.27 mmol) in anh. DMF (55 ml) was heated to 90° C., under nitrogen, for 18 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the separated solids were washed with AcOEt. The organic layer was washed with water and brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded methyl 2-(4-methylthiazol-2-yl)isonicotinate as a yellow solid. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 234.94 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:12][C:13]([O:15]CC)=[O:14])[OH:11])=[CH:4][CH:3]=1.[OH-].[Li+:19]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:12][C:13]([O-:15])=[O:14])[OH:11])=[CH:4][CH:3]=1.[Li+:19]
Reactant: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CC1(O)CCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
A mixture of ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (2.0 g, 8.4 mmol), 1N lithium hydroxide (8.4 mL) and absolute ethanol (13.0 mL) was stirred for 18 h at room temperature. The mixture was concentrated in vacuo, diluted with H2O and extracted with diethyl ether. The aqueous phase was concentrated in vacuo, diluted with toluene (100 mL) and concentrated in vacuo to give lithium 2-(6-fluoro-1-hydroxy-1-indanyl)acetate as a white solid (1.4 g, 77%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N:26]1([CH2:32][CH2:33][CH2:34][S:35]([NH2:38])(=[O:37])=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23]([NH:38][S:35]([CH2:34][CH2:33][CH2:32][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)(=[O:36])=[O:37])=[O:24])[O:20][C:21]=3[CH3:22])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Reactant: NS(=O)(=O)CCCN1CCOCC1
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)CCCN4CCOCC4)oc3C)cc2)cc1

Procedure:
Compound (59) was prepared from compounds (4) and (58) by adapting the procedure of Example 2A. LC/MS System D; Rt=4.97 mins, m/z (ES+)=529 (M+H for C27H32N2O7S).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: BrBr
Reactant: CCc1nc2ccccc2c(=O)[nH]1
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of 2-ethyl-3H-quinazolin-4-one (3.0 g, 17.22 mmol) in glacial acetic acid (50 ml) cooled in an ice bath was added dropwise a solution of bromine (2.75 g, 17.22 mmol) in glacial acetic acid (5 ml). After addition was complete, the reaction was heated to reflux for 18 hours. At which time it was allowed to cool to room temperature. Water was then added to the solution and the mixture was extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×30 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and was dried under reduced pressure to give 2-(1-Bromo-ethyl)-3H-quinazolin-4-one (Yield 3.02 g, 69.74%). 1H NMR (400 MHz, DMSO-d6): δ 2.22 (d, 3H, J=6.57 Hz), 5.09 (q, 1H, J=14.40, 6.57 Hz), 7.57 (m, 1H), 7.69 (d, 1H, J=8.08 Hz), 7.87-7.80 (m, 1H), 8.12 (d, 1H, J=6.82 Hz), 12.42 (s, 1H). MS m/z calc. 251.99, found (ESI); 253.0 (M+1)+. Retention time 2.60 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:13])=O.C([BH3-])#N.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:11]([CH3:13])[CH3:10])=[CH:4][N:3]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: CC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Nc1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
In a 100 mL flask containing 2,4-dichloropyrimidin-5-amine (1.0 g, 6.10 mmol) in 16.5 mL of dichloromethane was added acetone (1.062 g, 18.29 mmol). The solution was cooled to 0° C. then a solution of titanium tetrachloride (0.740 mL, 6.71 mmol) in 10 mL of dichloromethane was added slowly. The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (1.150 g, 18.29 mmol) was added in 4 equal portions over 10 minutes and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water (150 mL) and extracted with t-BuOMe twice. The organic layers were combined, dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in methanol and adsorbed onto silica. The residue was purified on silica gel using 0-10% methanol in dichloromethane as eluent. Relevant fractions were evaporated in vacuo to give 940 mg (74%) of 2,4-dichloro-N-isopropylpyrimidin-5-amine as a pale yellow oil. MS [M+H] Found 206.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.N1C=CC=CC=1.[C:39](Cl)(=[O:43])[CH2:40][CH2:41][CH3:42]>ClCCl>[C:39]([O:31][CH2:30][N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)[CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32])(=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Yield: 94.7 %

Procedure:
To a stirred suspension of Compound 2A (3 g, 6.27 mmol) in dichloromethane (30 mL) was added pyridine (2.54 mL, 31.35 mmol) followed by butyryl chloride (0.98 mL, 9.41 mmol) over 1-2 mins. The resultant solution was stirred at room temperature for 1 h 30 mins. The reaction was quenched with methanol (2 mL) and the mixture diluted with 1:1 NaHCO3 (aq)/brine (50 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (10 mL) and the combined organics dried over MgSO4. After filtration, the volatiles were removed and the residue azeotroped with toluene (3×10 mL). The crude material was purified by silica chromatography eluting 8% Methanol/(1:1 ethyl acetate/dichloromethane) to provide the desired product, Compound 2B (3.26 g, 5.94 mmol, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:42]2[CH2:41][CH2:40][N:39]([C:45]3[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=3)[CH2:44][CH2:43]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 77.2 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (424 mg, 1.84 mmol), a white solid required compound (542 mg, 1.42 mmol, 77%) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[CH2:24]1[O:36][C:27]([CH3:35])([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:26][CH2:25]1.[H-].[Na+]>O1CCCC1>[CH3:35][C:27]1([CH2:28][CH:29]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=2)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:26][CH2:25][CH2:24][O:36]1
Reactant: CCOC(=O)CCC1(C)OCCO1
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(CC2(C)OCCO2)C(=O)OCC)cc1
Reaction time: 18 h
Yield: 52.3 %

Procedure:
A mixture of about 33 g of 1-(bromomethyl)-4-(tetradecyloxy)benzene, about 16.2 g of ethyl levulinate ethylene ketal, about 4.54 g of about 50% sodium hydride and about 350 ml of tetrahydrofuran was refluxed with stirring, under argon for about 18 hours and then filtered through celite. The solvent was removed and the residue was dissolved in ether. The ether solution was washed with aqueous monobasic sodium phosphate, dried and the solvent removed. The residue was subjected to high performance liquid chromatography (HPLC), using the system hexane:ethyl acetate (about 9:1), giving about 22.1 g of the desired title compound as a light yellow oil).
Reaction SMILES: FC(F)(F)C(O)=O.CN(C)[CH:10]=[C:11]([N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[C:12](OCC)=[O:13].[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([NH:39][NH2:40])[N:36]=[CH:35][N:34]=3)[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH:23]1([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[N:34]=[CH:35][N:36]=[C:37]([N:39]4[C:12](=[O:13])[C:11]([N:17]5[CH:21]=[CH:20][N:19]=[N:18]5)=[CH:10][NH:40]4)[CH:38]=3)[CH2:31][CH2:32]2)[CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid are added to a mixture of 211 mg (1.0 mmol) of the compound from Example 8A and 250 mg (1.0 mmol) of the compound from Example 9A in 4 ml of ethyl acetate, and the mixture is stirred at 100° C. for 20 h. The reaction mixture is concentrated under reduced pressure, more ethyl acetate and trifluoroacetic acid (the same amounts as above) are added and the mixture is stirred at 100° C. for 3 d. The reaction mixture is cooled to RT, and the precipitated solid is filtered off and washed with diethyl ether. The residue is suspended in 2 ml of water, dissolved by adding aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 195 mg (51% of theory)
Reaction SMILES: O.[O:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:12][CH:13]([OH:16])[CH2:14][OH:15])[CH:6]=[CH:5][C:4]1=2>[Pd].COCCOCCOC>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH:13]([OH:16])[CH2:14][OH:15]
Reactant: O=C1CCCc2c1ccn2CC(O)CO
Agent: [Pd]
Solvent: COCCOCCOC
Solvent: O
Product: OCC(O)Cn1ccc2c(O)cccc21
Yield: 45.1 %

Procedure:
3.8 g of palladium on carbon at 5% by weight and containing 50% of water were introduced into a solution of 9.4 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β,γ-dihydroxypropyl)-indole, obtained in the preceding stage, in 50 cm3 of diglyme. The temperature of the reaction medium was raised to the reflux temperature of diglyme and the water was distilled off by azeotropy. After 23 hours of reaction, the catalyst was filtered off on celite and then the diglyme was evaporated off under vacuum. The crude product obtained was chromatographed on silica gel (ethyl acetate/heptane=9/1). 4.2 g of 4-hydroxy-1-N-(β,γ-dihydroxypropyl)indole were obtained in the form of a very viscous oil whose analysis by 1H and 13C nuclear magnetic resonance was in conformity with the expected product.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:8]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[CH:7]=1)=O.O[Li].O.Cl>CO.O>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:8]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[CH:7]=1
Reactant: CC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(=O)CCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-(3-oxobutyl)phenyl)acetamide (2 g, 4 mmol) in MeOH (15 mL) and water (15 mL) was added LiOH.H2O (0.93 g, 22 mmol). The mixture was stirred at r.t. overnight. The reaction mixture was concentrated, the residue was purified by pre-HPLC (column: Luna 300×50.0 mm, 10 um; liquid phase: [A-H2O+0.05% TFA; B-MeCN] B %: 12%-42%, 24 min), concentrated, acidified with HCl and freeze-dried to give 4-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(3-oxobutyl)benzenesulfonamide (650 mg, yield 40%) as HCl salt. 1H NMR: (400 MHz, DMSO-d6). δ 10.00 (s, 1H), 7.40 (d, 1H), 7.21 (d, 1H), 7.11 (d, 1H), 7.09 (d, 1H), 6.36-6.33 (m, 2H), 4.84 (s, 2H), 2.97 (t, 2H), 2.61 (t, 2H), 2.06 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:10]=[CH:9][N+:8]=2[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:22])=O>O>[Cl:22][C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc(-c2ccccc2)c1-c1ccccc1
Solvent: O
Product: Clc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To 922 mg of 2,3-diphenylpyridin-1-oxide, 3 ml of phosphorus oxychloride was added, followed by stirring at 100° C. for 15 minutes. The reaction solution was poured into iced water, extracted with ethyl acetate and then washed with an aqueous 5% potassium carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 428 mg of the desired compound as an oily substance.