Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10]([C:12]1[CH:21]=[C:20]([OH:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:23][CH3:24])[C:13]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])[CH3:8].Cl[C:30]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:33]=[N:32][N:31]=1>CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1[CH:21]=[C:20]([O:22][C:30]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]=[N:32][N:31]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:23][CH3:24])[C:13]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])[CH3:8]
Reactant: CCCCc1c(C(=O)OCC)cc(O)c2c(OC)cccc12
Reactant: Clc1nnnn1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1c(C(=O)OCC)cc(Oc2nnnn2-c2ccccc2)c2c(OC)cccc12
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 60.7 %

Procedure:
Potassium t-butoxide (1.03 g) was added to a solution of 1-butyl-4-hydroxy-5-methoxy-2-naphthalenecarboxylic acid ethyl ester (2.4 g) and 5-chloro-1-phenyl-1H-tetrazole (1.55 g) in dimethylformamide (20 mL) and the reaction was stirred at room temperature for 1.25 hours. After the solvent was removed in vacuo, the residual material was partitioned between dichloromethane (150 mL) and water (75 mL). The separated aqueous layer was re-extracted with dichloromethane, and after each organic extract was washed with water, they were combined, dried (Na2SO4) and evaporated. Crystallization of the crude product from diethyl ether-hexane gave 2.15 g of 1-butyl-5-methoxy-4-[(1-phenyl-1H-tetrazole-5-yl)oxy]-2-naphthalenecarboxylic acid ethyl ester, mp 144°-146° C. A portion was recrystallized from the same solvents to provide the analytical sample, mp 145°-146° C. Anal. Calcd for C25H26N4O4 : C, 67.25; H, 5.87; N, 12.55 Found: C, 67.07; H, 5.99; N, 12.51
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:30][CH2:29][C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1C1CCC(=O)CC1
Reactant: NCc1ccc(F)cc1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccc(F)cc2)CC1

Procedure:
from 4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-cyclohexanone and 4-fluorobenzylamine. Colourless oil. Rf value: 0.43 (alumina, petroleum ether/ethyl acetate=5:1, v:v).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:8][C:7]([SiH:21]([CH3:23])[CH3:22])=[CH:6]1)(=O)C>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[C:12]([O:11][C@@H:10]1[C@@H:9]([CH2:15][O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[O:8][C:7]([SiH:21]([CH3:22])[CH3:23])=[CH:6][C@H:5]1[OH:4])(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)C=C([SiH](C)C)O[C@@H]1COC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)O[C@H]1[C@H](O)C=C([SiH](C)C)O[C@@H]1COC(C)(C)C
Yield: 82 %

Procedure:
1.03 g (3 mmol) of 3,4-di-O-acetyl-6-O-tert.butyldimethylsilyl-glucal in 10 ml of 0.1M potassium phosphate buffer (pH=7) are stirred with 0.5-1.0 g of lipase P or lipase Fp (Amano), immobilized on SiO2, at room temperature. After the reaction is complete (5-8 h), the immobilized reusable enzyme is separated off. The desired 4-O-acetyl-6-O-tert.butyldimethylsilyl-glucal is obtained either by extraction of the aqueous solution with chloroform or ethyl acetate or after freeze-drying and subsequent chromatography on silica gel (ether/hexane 1:2) in 82% yield.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1.[OH-].[Na+].Cl>O>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1OCOCO1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 12.5 °C
Reaction time: 0.25 h

Procedure:
To 800 ml of fuming sulfuric acid, containing about 27% of SO3, 260 g (1.56 m) of terephthalic acid are added, under stirring, in 15 minutes without exceeding the temperature of 25° C. By maintaining the stirring, 60 g (0.665 m) of 1,3,5-trioxane are added portionwise to the thick suspension thus obtained, whereby the temperature rises to bout 25° C. The mixture is cooled to 10-15° C. in 30 minutes, then a further 60 g (0.665 m) of 1,3,5-trioxane is added thereinto. The mixture is heated and it is observed that at 90° C. the mass becomes clear. The temperature is brought to 120° C. and the mixture is kept 10-15 minutes under these conditions, whereby the temperature may rise to 135-140° C. If no exothermia is observed, the mixture is nevertheless heated to 130-135° C. and kept 4 hours under these conditions. The cooled mixture is poured, in about 1 hour and without exceeding the temperature of 25-35° C., into 3000 g of crushed ice. To the mixture thus obtained, 8000-8500 ml of a 15% w/w solution of sodium hydroxide are added to a pH=5-6, by letting the temperature to rise to 35-40° C. and by keeping it at these values by a water-cooling. Then, at 35-40° C., 300 ml of 5% w/w solution of sodium hydroxide are added to the mixture to a pH≅8. The solid is removed by filtration on a Dicalite® bed in a buchner and washed with water. To the solution thus obtained, 2000 ml of 35% hydrochloric acid are added to a pH≅1 and the suspension thus obtained is heated to 35° C. The solid is filtered, washed 3 times with 500 ml of deionized water at 40° C. The wet product is treated with 4000 ml of warm deionized water (about 45° C.) and the suspension is heated 30 minutes under stirring at 45° C. Without cooling, the product is filtered, washed with deionized water and dried in vacuo at 50° C. to constant weight. Thus, 215-225 g of light-brown coloured 5-carboxyphthalide with a purity (HPLC) >95% are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:3]=1.[OH-].[Na+]>Cl>[CH:22]1([C:19]2[CH:18]=[CH:17][C:16]([C:4]3[CH:3]=[C:2]([NH2:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=4)[N:5]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(=O)Nc1ccc2nc(-c3ccc(C4CCCCC4)cc3)cc(N)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2nc(-c3ccc(C4CCCCC4)cc3)cc(N)c2c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
N-[4-Amino-2-(4-cyclohexylphenyl)-quinolin-6-yl]-acetamide (22 g) was placed in a 1 L flask to which 500 mL of 6 N HCl was added and the mixture heated with stirring to 95° C. for 18 hrs. After this time, the solution was cooled in ice and was then cautiously neutralized with concentrated NaOH solution, followed by adjustment to pH 9.5. The solution was then poured into a 2 L separatory funnel and extracted with ethyl acetate. The organic layer was then dried over Na2SO4, filtered and concentrated to give 17 g of the desired product. Repeated crystallization using methanol, methylene chloride and hexane provided 9.0 g (41%) of the pure title compound.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[CH:16]([C:33](=C)[CH2:34][Cl:35])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:38]=[O+][O-]>C(Cl)Cl.CO>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[C:16](=[C:33]([OH:38])[CH2:34][Cl:35])[C:17]([O:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: C=C(CCl)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: CO
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(O)CCl)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dry ice acetone cooled solution of diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-chloro-2-propen-2-yl)acetate (160 mg) in a mixture of methylene chloride (3.2 ml) and methanol (0.3 ml) is introduced ozone until the reaction mixture shows blue color. Then excess ozone is purged with oxygen, mixed with an aqueous solution of 95% sodium hydrogen sulfite (100 mg), warmed to room temperature to decompose the ozonide. After 1.5 hours, the solution is washed with 5% sodium hydrogen carbonate and water, dried, and concentrated to remove methylene chloride. The resultant oil (132 mg) is purified over thin-layer chromatographic plate (Merck 60F-254) using a mixture of benzene and ethyl acetate (1:1) as developing solvent to give diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]-hept-2-en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate (44 mg) as glass.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][C:13]2[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:12]=2[S:11][CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH3:20][O:19][C:15]1[C:13]2[CH2:14][CH:9]([NH2:8])[CH2:10][S:11][C:12]=2[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2c1CC(NC(=O)OC(C)(C)C)CS2
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1CC(N)CS2

Procedure:
A solution of 10 g of N-t-butoxycarbonyl-3,4-dihydro-5-methoxy-2H-[1]-benzothiopyran-3-amine in 30 ml of trifluoroacetic acid is kept at room temperature for 1 hour. The solvent is removed in vacuo, the residue is treated with 1N NaOH and the product is extracted with ether. After drying over magnesium sulfate, the solvent is removed in vacuo to afford 3,4-dihydro-5-methoxy-2H-[1]-benzothiopyran-3-amine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.O[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: O=C1CCCN1CCO
Product: O=C1CCCN1CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIb was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 1-(2-hydroxyethyl)pyrrolidin-2-one following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:7]=1[C:8]([NH:10][C:11]1[C:19]2[O:18][C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:9].O>C(O)(=O)C>[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:7]=1[C:8]([NH:10][C:11]1[C:19]2[O:18][C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:14]=[CH:13][C:12]=1[N+:1]([O-:4])=[O:2])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1cccc2c3c(oc12)CCCC3)c1c(Cl)cccc1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1c([N+](=O)[O-])ccc2c3c(oc12)CCCC3)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Nitric acid (d; 1.5, 0.033 ml) was added to a solution of 6-(2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (200 mg) in acetic acid at 4° C. The mixture was stirred at ambient temperature for 5 hours and poured into cold water. The separated solid was collected and washed with isopropyl alcohol to give 6-(2,6-dichlorobenzoylamino)-7-nitro-1,2,3,4-tetrahydrodibenzofuran (17 mg).
Reaction SMILES: B.O1CCCC1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](O)=[O:14])([O-:9])=[O:8]>O1CCCC1>[N+:7]([C:10]1[CH:11]=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])([O-:9])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 800 mL, 800 mmol) was added at −20° C. over 45 min to a solution of 3,4-dinitrobenzoic acid (93.5 g, 441 mmol) in tetrahydrofuran (300 mL). The resulting mixture was stirred at −20° C. for 1 h and then warmed to room temperature and stirred overnight. It was quenched by the addition of 32 mL of 1:1 acetic acid/water. Solvents were removed in vacuo and the residue was poured into an ice-cold 1000 mL of sat. sodium bicarbonate with vigorous stirring over 15 min. The mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with sat. sodium bicarbonate, brine and dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a light yellow solid (100%). 1H-NMR (CDCl3, 500 MHz) δ 7.91(d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.71 (dd, J=8.5, 1.0 Hz, 1H), 4.87 (s, 2H), 2.30 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])=O.[NH4+]>CCO.[Pd]>[N:1]1([CH:6]2[CH:11]3[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]3)[CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C1=C(n2ccnc2)C2CCN1CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1cn(C2CN3CCC2CC3)cn1
Temperature: 110 °C
Yield: 52.2 %

Procedure:
To a mixture of 3-imidazol-1-yl-1-azabicyclo[2.2.2]oct-2-ene (1a) (356 mg, 2.03 mmol) and ammonium formate (2.6 g, 40.6 mmol) in absolute EtOH (6 mL) was added 10% Pd/C (178 mg, 50% w/w). The sealed reaction vessel was heated to 110° C. for 13 hrs before cooling to ambient temperature. The mixture was filtered through diatomaceous earth (0.75″ by 2″ diameter), washed liberally with EtOH and concentrated to a white-yellow tacky residue which was subsequently purified by flash chromatography (SiO2—40 grams; gradient elution: 5-30% 3N NH3/MeOH—EtOAc at 60 mL/min over 25 min) to yield the title compound (188 mg, 52%). Mass spectrum (ES+): M+1: 178 (100%); 1H NMR (300 MHz, CDCl3) δ 1.50 (m, 1H), 1.64 (m, 1H), 1.77 (m, 2H), 2.09 (app q, J=3 Hz, 1H), 2.81-3.05 (m, 4H), 3.15 (dd, J=14.5, 4.4 Hz, 1H), 3.47 (ddd, J=14.5, 9.7, 1.8 Hz, 1H), 4.26 (m, 1H), 7.05 (s, 1H), 7.08 (s, 1H), 7.62 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[CH3:12][S:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:16][CH:15]=1
Reactant: CSc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: CSc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-methylmercaptoaniline to yield 2-[(4-methylmercaptophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:26][CH:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH:14]2[CH2:13]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH2:13][CH:14]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH:15]3[CH2:26]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(c1nc(Cl)ncc1Cl)C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.85 g, 10.1 mmol) and tert-butyl 5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.66 g, 15.2 mmol) in EtOH (20 mL) was added Et3N (2.08 g, 20.6 mmol). After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/12) to give the title compound as yellow oil (987.8 mg, 25.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:14][N:15]1[C:23]2[C:18](=[C:19]([O:24][CH2:25][CH2:26]Br)[CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:28]([O:30][CH3:31])=[O:29].[I-].[K+]>C(#N)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:14][N:15]1[C:23]2[C:18](=[C:19]([O:24][CH2:25][CH2:26][N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]3)[CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: OCCN1CCNCC1
Reactant: COC(=O)c1cc2c(OCCBr)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc2c(OCCN3CCN(CCO)CC3)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
1-(2-Hydroxyethyl)piperazine (175 mg) was added to a stirred solution of methyl N-(3,4-dichlorobenzyl)-4-(bromoethyloxy)indole-2-carboxylate (278 mg) and potassium iodide (10 mg) in acetonitrile (15 ml). The reaction was heated at 80° C. for 16 hours. The reaction was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water, saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed in vacuo to give the product as a colourless oil (215 mg, 70%); NMR d (CD3SOCD3) 2.31-2.57 (m, 10H), 2.78 (t, 2H), 3.47 (dd, 2H), 3.80 (s, 3H), 4.20 (t, 2H), 4.30 (t, 1H), 5.79 (s, 2H), 6.61 (d, 1H), 6.88 (dd, 1H), 7.13 (d, 1H), 7.22 (t, 1H), 7.29-7.32 (m, 2H), 7.51 (d, 1H); M/z (+) 506 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=O.[NH3:14]>>[NH2:13][C:7]1[N:6]=[C:5]([C:3]([NH2:14])=[O:2])[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=1
Reactant: N
Reactant: COC(=O)c1cc(SC)cc(N)n1
Product: CSc1cc(N)nc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.099 g 6-amino-4-methylsulfanyl-pyridine-2-carboxylic acid methyl ester in 4 ml 25% aqueous ammonia was stirred at room temperature for 24 h. The solid was collected by filtration washed with water and dried to constant weight to yield 0.070 g of the title compound as white crystals melting at 158-159° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([OH:20])[CH:13]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:20])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C)CC2)cc1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(CN(C(=O)Cc2ccc(O)c(O)c2)C2CCN(C)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
N-((4-methylphenyl)methyl)-N-(1-methylpiperidine-4-yl)-2-(3-hydroxy-4-methoxyphenyl)acetamide (57MBT12B) (52 mg, 0.136 mmol) was dissolved in CH2Cl2 (1 mL) and cooled to −78° C. Boron tribromide (1M in CH2Cl2, 204 μl, 0.204 mmol) was added dropwise and the cooling bath was removed. After stirring for 2 h, methanol (2 mL) was added and the mixture was evaporated. The resulting oil was purified by preparative HPLC to give 24 mg (48%) of the title compound as a white solid. HPLC-MS (method A) showed MH+=369. UV/MS (%)=100/97. 1H-NMR (400 MHz, CD3OD, Rotamers 33:67):δ 7.19-6.47 (m, 7H), 4.54 and 4.53 (2s, 2H), 4.23 (m, 1H), 3.83 and 3.58 (2s, 2H), 3.46 and 3.40 (2br d, J=12 Hz, 2H), 3.02 and 2.95 (2br t, J=12 Hz, 2H), 2.79 (s, 3H), 2.33 and 2.28 (2s, 3H), 2.17 and 1.84 (2dq, J=4, 12 Hz, 2H), 1.87 and 1.48 (2br d, J=12 Hz, 2H)
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[C:15]([F:22])=[C:16]([NH2:21])[CH:17]=[CH:18][C:19]=2[F:20])=[N:4]1)[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[C:15]([F:22])=[C:16]([NH:21][S:31]([C:25]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=3[F:23])(=[O:33])=[O:32])[CH:17]=[CH:18][C:19]=2[F:20])=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N)c2F)n1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenylamine (1.146 g, 3.816 mmol) was dissolved in anhydrous pyridine (30 M) under nitrogen atmosphere and cooled to 0° C. 2,5-Difluoro-benzenesulfonyl chloride (0.513 mL, 3.816 mmol, 1 eq) was added and the mixture was allowed to stir at the same temperature. Further additions of sulfonyl chloride (for a total amount of 0.650 mL) were needed to drive the reaction to completion. The reaction mixture was kept at 0° C. overnight and then it was allowed to reach room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with NaHCO3 saturated aqueous solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was slurried in methanol at 50° C. for 10 minutes and the solid was filtered and washed with ethyl ether. After drying at 40° C. for 5 hours 1.13 g of the title compound were obtained as a white solid (62% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6]([C:9]1[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([CH3:22])[CH:10]=1)(=[O:8])=[O:7]>CN(C=O)C>[CH3:5][S:6]([C:9]1[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[C:11]([CH3:22])[CH:10]=1)(=[O:8])=[O:7]
Reactant: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)Cl

Procedure:
15 l of thionyl chloride are initially introduced at 40°, and 50 ml of DMF are added. 3.8 kg of 4,5-bismethanesulfonyl-2-methylbenzoic acid are slowly introduced with stirring, and the mixture is then stirred at the boiling point for 1 hour. After cooling, the excess SOCl2 is removed, and the residue is codistilled a number of times with 5 l of toluene, giving 4, 5-bismethanesulfonyl-2-methylbenzoyl chloride, which is reacted further as the crude product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Pd].CO>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=1[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 12.5 h

Procedure:
A mixture of t-butyl N-(5-benzyloxy-2-nitrophenyl)-N-methylcarbamate (15 g), palladium on carbon (3 g, 10%), toluene (150 ml) and methanol (150 ml) was stirred under a hydrogen atmosphere at room temperature for 12.5 hours. The palladium on carbon was filtered and the filtrate was concentrated to afford the title compound (12.3 g, brown oil, Rf=0.15: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=4 : 1 as the eluant).