Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].Cl[C:10]([O:12][CH3:13])=[O:11]>N1C=CC=CC=1>[C:10](=[O:11])([O:12][CH3:13])[O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)CCCO
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)OCCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
A 100 ml 3-neck round bottom flask, fitted with a magnetic stir bar, rubber septum and hose adapter, was flushed with dry nitrogen and was charged via syringe with 17.53 g (0.127 mol) 3-(methylsulfonyl)-1-propanol and 19 ml anhydrous pyridine. The resulting mixture was cooled in an ice-water bath. Methyl chloroformate (13.3 g; 0.141 mol) was added dropwise to the mixture via syringe over 45 minutes. The ice-water bath was then removed, and the mixture was allowed to stir at room temperature. After 3.5 hours, the resulting white opaque mixture was poured into 120 ml of ice cold 10% aqueous HCl in a separatory funnel, and the resulting solution was extracted four times with 50 ml aliquots of CH2Cl2. The resulting organic extracts were combined and dried over Na2SO4. Solvent removal under reduced pressure on a rotary evaporator left a clear pale yellow liquid, which solidified as it cooled. The resulting solid was purified by recrystallization from t-butyl methyl ether to give 17.6 g of white needles, m.p. 55-56.5° C., and a filtrate that was then concentrated to provide a second batch of crystals (1.9 g), m.p. =55-57° C., to yield a total of 19.5 g (78% yield) of 3-(methylsulfonyl) propyl methyl carbonate.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].Br[C:23]1[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]([C:23]2[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNC(=O)Nc1ccc(-c2ncc(C(=O)OC)s2)cn1

Procedure:
N-Ethyl-N′-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]urea (Intermediate 1, 0.20 g, 0.69 mmol), methyl 2-bromo-1,3-thiazole-5-carboxylate (0.152 g, 0.69 mmol), tetrakis triphenyl phosphine palladium (0.08 g, 0.069 mmol), and cesium carbonate (0.245 mg, 0.754 mmol) were taken in a microwave vial and degassed with argon. Then dioxane:water (4:1, 3 mL) was added to it and microwaved at 110° C. for half an hour. The reaction mixture was partitioned between water and EtOAc and layers separated. The organic layer was washed with sat. sodium bicarbonate solution, water, brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by flash chromatography eluting with 2% MeOH in DCM to 3% MeOH in DCM. MS (ESP): 307 (M+H+) for C13H14N4O3S; NMR: 1.09 (t, 3H), 3.16-3.22 (m, 2H), 3.86 (s, 3H), 7.60 (d, 1H), 7.79 (t, 1H), 8.27 (dd, 1H), 8.49 (s, 1H), 8.83 (s, 1H), 9.56 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Cl>[OH-].[Na+]>[C:25]1([CH2:24][O:23][C:21]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1CCc1ccccc1C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccccc1CCc1ccccc1C(=O)O)OCc1ccccc1
Yield: 53.3 %

Procedure:
A suspension of 2-[2-(2-aminophenyl)ethyl]benzoic acid hydrochloride (339 mg, 1 mmol) in aqueous sodium hydroxide (1N, 2 mL) was stirred vigorously and treated simultaneously with benzyl chloroformate (170 mg, 1 mmol) and aqueous sodium hydroxide (1N, 1 mL). The reaction mixture was stirred for 16 h, acidified with dilute hydrochloric acid and filtered. The solid was washed with water and hexane, dissolved with methylene chloride, and the organic phase was washed with water, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with ether to give 2-[2-(2-(phenylmethoxy-carbonylamino)phenyl)ethyl]benzoic acid (0.2 g, 53%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:29][CH2:28]5)=[N:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(Cl)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(Cl)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 92.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (130 mg. 0.197 mmol) was alkylated using (S)-2-methyloxirane (34 mg, 0.59 mmol), DIPEA (73 mg, 0.59 mmol) and ethanol (5 mL) to get 124 mg (92.3% yield) of the titled compound.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]/[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.O.BrN1C(=[O:30])CCC1=O>C(COC)OC>[CH3:20][C:19]([CH:18]([OH:30])[CH2:17][CH2:16]/[C:15](/[CH3:22])=[CH:14]/[CH2:13][CH2:12]/[C:2](/[CH3:1])=[CH:3]\[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[CH2:21]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: COCCOC
Solvent: O
Product: C=C(C)C(O)CC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g (0.0065 mol) of tetrahydro-2-[[(2Z,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran dissolved in 13 ml of monoglyme and 2.6 ml of water is treated portionwise at -10° with 1.3 g of N-bromosuccinimide. The mixture is subsequently stirred at 0° for 1/4 hour and at room temperature for 2 hours. The reaction solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing tetrahydro-2-[[(2Z,6E)-10-bromo-11-hydroxy-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran, is dissolved in 18 ml of methanol and treated with 600 mg of potassium carbonate. The suspension is stirred at room temperature for 1.5 hours under argon. After removing the methanol on a rotary evaporator the residue is treated 500 ml of ether and 200 ml of water. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing (6E,10Z)-2,3-epoxy-2,6,10-trimethyl-12 -[(tetrahydro-2H-pyran-2-yl)oxy]-6,10-dodecadiene, is dissolved in 30 ml of toluene and treated with 1.35 g of aluminum isopropylate. The reaction mixture is boiled at reflux for 17 hours and, after cooling to room temperature, poured into 200 ml of an ice-water mixture. After acidification with 1N hydrochloric acid the mixture is extracted with 3×150 ml of hexane. The organic phase is washed with 500 ml of saturated sodium chloride solution. After drying and removing the solvent the residue is chromatographed on silica gel with a 1:2 ether-hexane mixture which additionally contains 0.1% triethylamine. There is obtained (6E,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol which has the following bands in the IR spectrum: 3445 cm-1, 1648 cm-1, 1441 cm-1, 1375 cm-1, 901 cm-1.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C([O-])([O-])=O.[Na+].[Na+].O.Cl>O1CCOCC1>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
(−)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.00 g, 2.6 mmol, prepared in example 1a), 4-carboxybenzene boronic acid (485 mg, 2.9 mmol), Na2CO3/H2O (4.4 mL, excess), tetrakis(triphenyl phosphine)palladium(0) (206 mg, 0.2 mmol) and dioxane (20 mL) were mixed together in a 50 mL single neck flask and stirred at 80° C. for 4 hours. The reaction was cooled to room temperature and poured into 1N HCl and the desired product was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 871 mg as a foam. This material was purified via silica gel chromatography employing the chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/methanol 9:1 to yield the title compound (500 mg, 51%) as a tan solid. Ion spray M.S. 378.1 (M*−1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].I.CS[C:33]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)=[NH:34]>C(O)C.C(OCC)C.[Pd]>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:33]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[NH:34])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4cccs4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (150 mg, 0.378 mmol) was dissolved in anhydrous ethanol (10 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon, (40.3 mg, 0.0378 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) showed complete conversion to 8a 1-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-1H-benzoimidazol-5-ylamine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (10 mL) and the ethanolic solution of the amine 8a is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide 9a (140 mg, 0.491 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 67 hours. The solution was diluted with diethyl ether (80 ml) and cooled in and ice bath resulting in the formation of an off-white precipitate that was collected on a sintered glass funnel and washed with ether. The hygroscopic solid was solubilized on the funnel in methanol and the solvent collected and evaporated to yield crude solid. The solid was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 8. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford yellow residue 10 N-[1-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-1H-benzo-imidazol-5-yl]-thiophene-2-carboxamidine. Yield: 94 mg (52.2%). 1H NMR (DMSO) δ: 0.82 (t, 6H, J=7.1), 1.29 (t, 3H, J=7.0), 2.45 (q, 4H, J=7.0), 2.45-2.50 (m, 2H), 3.98 (q, 2H, J=7.0), 4.07-4.13 (m, 2H), 4.22 (s, 2H), 6.31 (br s, 2H), 6.72 (d, 1H, J=7.7), 6.88 (d, 2H, J=8.7), 6.99 (s, 1H), 7.08-7.11 (m, 1H), 7.17 (d, 2H, J=8.4), 7.35 (d, 1H, J=8.4), 7.59 (d, 1H, J=5.1), 7.72 (d, 1H, J=3.4); MS (ESI): 476 (MH+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:4]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccnc(-c2cccc(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)aniline (130 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (216 mg) and diisopropylethyl-amine (0.26 ml) in dichloromethane (6.5 ml) was added 1-methyl-2-chloropyridinium iodide (216 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=4:1) to give N,N′-bis (tert-butoxycarbonyl) -N″- (3- (4-methoxypyridin-2-yl) phenyl) guanidine (240 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[F:12][C:13]1[CH:19]=[C:18]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])(=[O:22])=[O:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([S:20]([C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])(=[O:22])=[O:21])[CH:17]=[CH:16][C:14]=1[N:15]=[C:1]=[O:2]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)C(F)F)cc1F
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(S(=O)(=O)C(F)(F)C(F)F)cc1F

Procedure:
To 4% phosgen-toluene solution was added 4.0 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)aniline, followed by heating under reflux for 3 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give 2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)phenyl isocyanate as an oily material. In 50 ml of xylene was dissolved the oily material, and 1.5 of 2.6-difluorobenzamide was added to the solution, followed by heating under reflux for 20 hours. After the completion of the reaction, the reaction mixture was cooled to 0° C., and the crystals which separated out was recovered by filtration and recrystallized from acetone to give N-(2,6-difluorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)phenyl]urea (Compound No. 5) as crystals having a melting point of 186°-187° C. The melting point of the crystals did not descend in a mixed examination with the product of Example 4.
Reaction SMILES: N[C@H](C=O)CCSC.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[CH3:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:20]2=[O:34].[NH4+].[Cl-]>O1CCCC1>[CH3:26][C:25]1[CH:24]=[C:23]2[C:19](=[CH:18][C:17]=1[CH3:16])[C:20](=[O:34])[N:21]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:22]2([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[OH:27]
Reactant: Cc1cc2c(cc1C)C(=O)N(c1cccnc1)C2=O
Reactant: CCCCCCBr
Agent: CSCC[C@H](N)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCC1(O)c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.5 %

Procedure:
Metal magnesium (0.14 g, 5.6 mmol) and 1-bromohexane (0.78 ml, 5.6 mmol) were stirred with heating at 65° C. in anhydrous tetrahydrofuran (24 ml) under an argon atmosphere for 2 hrs, and 5,6-dimethyl-2-(3-pyridyl)isoindolin-1,3-dione (0.40 g, 1.6 mmol) was added thereto, followed by stirring at 25° C. for 15 minutes. The reaction solution was poured into saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 0.23 g of 5,6-dimethyl-3-hexyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([OH:29])[CH2:14][N:15]2[CH2:20][CH2:19][N:18](C3C=CC(OC)=CC=3)[CH2:17][CH2:16]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:30]1([O:40][CH2:41]C2OC2)[C:39]2CCCC[C:34]=2[CH:33]=[CH:32][CH:31]=1.COC1C=CC=CC=1N1CCNCC1>>[C:1]1([O:11][CH2:12][CH:13]([OH:29])[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:39][C:30]=3[O:40][CH3:41])[CH2:19][CH2:20]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(N2CCN(CC(O)COc3cccc4c3CCCC4)CC2)cc1
Reactant: c1cc2c(c(OCC3CO3)c1)CCCC2
Agent: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3c2CCCC3)CC1

Procedure:
1-[3-(5,6,7,8-tetrahydronaphth-1-yloxy)-2-hydroxyprop-1-yl]-4-(4-methoxyphenyl)-piperazine from 1-(5,6,7,8-tetrahydronaphth-1-yloxy)-2,3-epoxypropane and 1-(4-(methoxyphenyl)-piperazine; yield 72% of theory; m.p. 83°-84°C. (recrystallized from isopropanol); m.p. of the dihydrochloride 230°-231°C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[Cl:19][C:20]1[CH:21]=[N:22][C:23]([CH3:29])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:25]([C:24]2[C:23]([CH3:29])=[N:22][CH:21]=[C:20]([Cl:19])[CH:28]=2)=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(Cl)cnc2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-4-Amino-cyclohexanecarboxylic acid methyl ester (2.14 g, 11.05 mmol) is suspended in THF (50 mL) and Et3N (2.79 g, 27.6 mmol) and cooled to 0° C. 5-chloro-2-methylnicotinoyl chloride (step 1) (2.20 g, 11.05 mmol) is slowly added portionwise and the RM is stirred at r.t. for 2 hours. LCMS showed mainly product. The reaction mixture is partitioned between EtOAc and 1M HCl. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo to afford the title product which is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 7.42 (1H, 5), 7.80 (1H, d), 3.70 (1H, m), 3.60 (3H, s), 2.49 (3H, s), 2.29 (1H, m), 1.95 (4H, m), 1.42 (2H, m), 1.29 (2H, m); [MH]+311.26.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:39][C:40]([F:52])([F:51])[C:41]1[N:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[S:47]([C:44]3[CH:45]=[N:46][C:41]([C:40]([F:52])([F:39])[F:51])=[CH:42][CH:43]=3)(=[O:49])=[O:48])=[CH:16][CH:15]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)nc1)N(Cc1ccc(F)cc1)Cc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(4-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (47 mg, 0.10 mmol) in CH2Cl2 (1 mL) were added 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (25 mg, 0.10 mmol, Aldrich) and diisopropylethylamine (0.042 mL, 0.30 mmol). The reaction mixture was stirred at rt for 2 h, and then concentrated. The residue was dissolved in methanol and purified by prep HPLC to give the title compound (24.0 mg, 57%) as a white solid. 1H NMR (DMSO-d6) δ 11.17 (br s, 1H), 9.15 (s, 1H), 8.50 (d, 1H, J=8.1 Hz), 8.11 (d, 1H, J=8.1 Hz), 7.83 (d, 2H, J=2.3 Hz), 7.56 (d, 1H, J=2.3 Hz), 7.17-6.97 (m, 12H), 4.40 (s, 2H), 4.39 (s, 2H), 4.37 (s, 2H), 4.34 (s, 2H); MS (ESI): 786.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:17])([F:18])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Br)c2)=NO1
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CNCc3ccccn3)c(Br)c2)=NO1
Yield: 52.9 %

Procedure:
A solution of 3-[3-bromo-4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.8 g), 2-aminomethylpyridine (0.38 g) and potassium carbonate (0.97 g) in acetonitrile (20 mL) was heated to reflux for 3 hours. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to yield 1-{2-bromo-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}-N-(pyridin-2-ylmethyl)methanamine (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:14])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Br)cc2CO1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a solution of (2-amino-5-bromophenyl)methanol (772 mg, 3.8 mmol) in 15 ml THF was added triphosgene (1.03 g, 3.8 mmol) under nitrogen. After precipitation of a colorless solid, stirring was continued for 20 min before water was added. The solution was extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 6-bromo-1H-benzo[d][1,3]oxazin-2(4H)-one (830 mg, 3.64 mmol, 96%) as colorless solid.