Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:15]1[N:20]2[C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:11][S:8]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][C:15]2[N:20]3[C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH2:3][CH2:4]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cnc2cccc(Cl)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCC(Oc2cccc3ncc([N+](=O)[O-])n23)CC1
Yield: 54.7 %

Procedure:
To a solution of 4-hydroxy-1-methylsulfonylpiperidine (2.15 g, 12 mmoles) in dimethylformamide (3 ml) was added 60% sodium hydride in oil (0.48 g, 12 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 5-chloro-3-nitroimidazo[1,2-a]pyridine (1.976 g, 10 mmoles) with stirring under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The precipitate was filtered off, washed with water and dried to obtain 1.862 g of the desired product (54.7%, yellow solid). The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solventy was distilled off, the crude crystlals thus obtained were recrystallized from methylene-n-hexane to obtain 460 mg of the desired product (460 mg, tan solid).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].O.[I:16]Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([I:16])[C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClI
Reactant: CC(C)(C)c1cc([N+](=O)[O-])ccc1O
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(I)c1O
Reaction time: 2 h
Yield: 96 %

Procedure:
To the product from Example 1, Part A (4.5 g, 23.05 mmol) dissolved in MeOH (120 ml) and water (30 mL) was added iodine monochloride (1.155 ml, 23.05 mmol) drop wise over a period of 10 min. The mixture was stirred for 2 h and diluted into 1 L of water and allowed to stand overnight. The solid material was collected by filtration and washed 3×50 mL with water and dried under vacuum overnight to give a tan solid (7.14 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[Cl:12].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([Cl:12])=[CH:6][C:7]([Br:11])=[CH:8][C:9]=1[CH2:10][Br:14]
Reactant: COC(=O)c1c(C)cc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cc(Br)cc1CBr

Procedure:
A mixture of 4-bromo-2-chloro-6-methyl-benzoic acid methyl ester (2.447 g, 9.27 mmol,), N-bromosuccinimide (1.815 g, 10.2 mmol), and benzoyl peroxide (0.051 g, 0.22 mmol) in carbon tetrachloride (30 mL) was refluxed until most of the starting materials were consumed (as analyzed by GC/MS). The resulting mixture was filtered and the filtrate concentrated to afford 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[Cl:18]>C(O)(C(F)(F)F)=O.Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:9]=2[Cl:18])=[CH:6][C:5]2[NH:19][C:11]([C:14]([F:17])([F:16])[F:15])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2Cl)cc1N
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)F)nc3cc2Cl)c(Cl)c1
Yield: 174.3 %

Procedure:
To a solution of [2-chloro-4-(trifluoromethyl)phenyl]boronic acid (4.5 g, 20.06 mmol) in water (30 mL) and dioxane (200 mL) was added K3PO4 (5.7 g, 26.85 mmol), 5-chloro-4-iodo-2-nitroaniline (4 g, 13.40 mmol) and Pd(PPh3)4 (800 mg, 0.69 mmol) maintained with an inert atmosphere of nitrogen and stirred overnight at 95° C. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-4-[2-chloro-4-(trifluoromethyl)phenyl]-2-nitroaniline as a yellow solid (3 g, 32%). Next, to a solution of 5-chloro-4-[2-chloro-4-(trifluoromethyl)phenyl]-2-nitroaniline (3 g, 8.54 mmol) in ethanol (80 mL) was added hydrochloric acid (2 mL) and Zn powder (3.4 g, 52.3 mmol) in portions. The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum and dissolved in water (100 ml) adjusted to pH 8 with sodium carbonate and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was purified by a silica gel column with 20% ethyl acetate in petroleum ether to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (1 g, 36%). Finally, the solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol) in TFA (5 mL) and hydrochloric acid (conc, 1 mL) was stirred overnight at 80° C. and quenched with water (100 ml), adjusted pH to 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenyl]-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (107.8 mg, 87%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9]C(=O)[C:7]2=[O:14].[OH:17]O.Cl>[OH-].[Na+]>[NH2:9][C:10]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:16])[F:15])=[CH:5][C:6]=1[C:7]([OH:14])=[O:17]
Reactant: OO
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: 17 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
5-Trifluoromethoxy-1H-indole-2,3-dione (3.48 g, 15.0 mmol) was dissolved in 2N aqueous sodium hydroxide (90 ml) and cooled to 17° C. before adding 30% aqueous hydrogen peroxide solution (2.75 ml, 27 mmol) dropwise over 20 minutes. The mixture was stirred at room temperature for 1 hour before adding concentrated hydrochloric acid (7 ml). The resulting brown precipitate was filtered off and dried in vacuo at 50° C. for 66 hours to give the title compound (1.83 g) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:28].C([Li])CCC.CCCCCC.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>O1CCCC1>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[C:19]([F:27])[CH:18]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH:7]([CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:6]1=[O:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CCC(=O)N2Cc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CC(CC(=O)OC(C)(C)C)C(=O)N2Cc1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (14 mg, 0.03 mmol) in anhydrous tetrahydrofuran (1 mL) at −78° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (40 μL, 0.06 mmol) with stirring. The reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was re-cooled to −78° C., a solution of tert-butyl bromoacetate (98 mg, 0.50 mmol) in anhydrous tetrahydrofuran added (0.5 mL), and the reaction mixture stirred overnight, allowing it to warm up to room temperature. The reaction was followed by LCMS, and stirring was continued as needed until the starting material was consumed. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (10 mL) and diluted with aqueous ammonium chloride (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL), and the combined organic phase was successively washed with 2N spdium carbonate (10 mL), 30% ammonium chloride (10 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford tert-butyl 2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (12 mg, 0.02 mmol, 67%). LCMS m/z 524.0 (M-tBu), 602.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; acetone-d6) δ7.77 (t, J=8.0 Hz, 1H); 7.60 (m, 2H); 7.38 (m, 2H); 7.11 (m, 1H); 7.00 (m, 1H); 6.81 (s, 1H); 5.35 (s, 2H); 3.80 (s, 3H); 2.70-3.30 (m, 3H); 2.40-2.60 (m, 2H); 1.48 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=[C:10]2[CH:9]=1)(C)(C)C.O.C(OCC)(=O)C>Cl>[C:17]1([C:15]2[N:16]=[C:10]3[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][N:11]3[N:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A suspension of (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (8.5 g, 27.4 mmol) in hydrochloric acid (6 N in diethyl ether, 175 ml) is stirred overnight at room temperature. The suspension is diluted under cooling with water (ca 2 l) and ethyl acetate, the aqueous layer is washed once with ethyl acetate, made alkaline with 32% aqueous sodium hydroxide and extracted twice with ethyl acetate. The combined organic layers are dried with magnesium sulfate and the solvent is removed in vacuo affording 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (5.52 g, 95.9%) as a light pink solid. mp.: 212-213° C. MS: m/z=211.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:8]=O)[NH:5][C:6]=1[CH3:7].[CH2:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>[Pt](=O)=O.C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH2:8][NH:15][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1nc(C=O)[nH]c1C
Reactant: CC(C)CCN
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1nc(CNCCC(C)C)[nH]c1C
Reaction time: 24 h
Yield: 98 %

Procedure:
A mixture of 3.35 g (27 mmol) of 4,5-dimethyl-2-imidazolecarboxaldehyde, 9.0 mL (77 mmol) of isoamylamine, 200 mL of ethanol, and 0.20 g of platinum dioxide is hydrogenated under 50 psi of pressure at 22° C. for 24 h. The solution is filtered, and the volatiles are evaporated under reduced pressure to give 5.17 g (98%) of N-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine. Mass Spec m/z (M++1) 196.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC)c1
Reaction time: 48 h
Yield: 52.3 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol) in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes ethanesulfonylchloride (0.131 ml, 177 mg, 1.38 mmol). The mixture was stirred for 48 hours, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with ethyl acetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (140 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][N:4]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[CH:6]=[CH:5][N:4]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2ncc(C(F)(F)F)cn2)ccn1
Yield: 17 %

Procedure:
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.66 g, 7.06 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (1.3 g, 7.1 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (307 mg, 16%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 2H), 8.34 (d, J=5.3 Hz, 1H), 7.89 (dd, J=5.3, 1.4 Hz, 1H), 7.81 (s, 1H), 4.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](O)=[O:6].C([N:16](CC)CC)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:16])=[O:6]
Reactant: CCN(CC)CC
Reactant: COc1cccc(OC)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cccc(OC)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
5.0 of 2,6-dimethoxybenzoic acid suspended in 200 ml of anhydrous methylene chloride are added with 7.65 ml of triethylamine and then with 3.6 ml of oxalyl chloride. The mixture after being stirred at room temperature for three hours is concentrated under reduced pressure, cooled with ice, added with 10 ml of concentrated ammonia, then stirred for half an hour, then again evaporated under reduced pressure, taken with water and filtered. The solid so obtained, after crystallization from methanol, gives 2,6-dimethoxybenzamide with melting point 208°-209° C.; yield is 54%.
Reaction SMILES: N([C:4]([C:6]1[N:7]=[CH:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][CH:11]=1)=[O:5])=[N+]=[N-].[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([O:21][C:4]([C:6]1[N:7]=[CH:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][CH:11]=1)=[O:5])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cnc(C(=O)N=[N+]=[N-])cn1
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A mixture of ethyl 5-(azidocarbonyl)pyrazine-2-carboxylate (1.00 g, 4.52 mmol), tert-butanol (1.5 mL, 20.2 mmol) and toluene (15 mL) was heated to reflux for 1 hour. After cooling to room temperature, the solid precipitate was collected to afford the title compound (0.75 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:21][CH:23]2[O:25][CH2:24]2)[CH:9]=1
Reactant: ClCC1CO1
Reactant: Cc1ccc(-c2cccc(O)c2)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cccc(OCC3CO3)c2)n1C

Procedure:
While stirring, a mixture of 10 g of the resulting crude 1,5-dimethyl-2-(3-hydroxyphenyl)-pyrrole, 50 ml of epichlorohydrin and 15.2 g of potassium carbonate is heated at boiling point for 3 hours. The reaction mixture is cooled, filtered and concentrated by evaporation. The residue is divided between 200 ml of ether and 20 ml of 2N sodium hydroxide solution; the ether phase is separated off, dried over magnesium sulphate and concentrated by evaporation. The crude 1,5-dimethyl-2-[3-(2,3-epoxypropoxy)-phenyl]-pyrrole is obtained in the form of an oil and is further used in that form.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[OH:1][C@@H:2]([CH2:3][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NC(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Solvent: CCO
Product: NC(=O)Nc1ccc(OC[C@@H](O)CN2CCN(c3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 70.8 %

Procedure:
A mixture of 0.1 g of (S)-1-(4-(oxiran-2-ylmethoxy)phenyl)urea, 0.14 g of N-phenyl-piperazine, and 6 mL of absolute ethanol was heated to 70° C. for 20 hrs. The reaction was cooled, and the resulting precipitate collected by filtration. The solids were washed three times with ethanol, and dried. 0.126 g of the title compound was obtained as a fluffy white powder was obtained. 1H NMR (d6-DMSO): δ 2.36 (dd, 1H, J=6 Hz, J=13 Hz), 2.48 (m, 1H), 2.55 (m, 4H), 3.08 (t, 4H, J=5 Hz), 3.78 (dd, 1H, J=6 Hz, J=9 Hz), 3.89 (m, 1H), 3.93 (m, 1H), 4.84 (d, 1H, J=5 Hz), 5.68 (s, 2H), 6.73 (t, 1H, J=8 Hz), 6.78 (d, 2H, J=9 Hz), 6.88 (d, 2H, J=8 Hz), 7.16 (t, 2H, J=8 Hz), 7.24 (d, 2H, J=9 Hz), 8.27 (s, 1H); MS: 371 (M+H); HRMS: Observed: 371.20723; HPLC: 100% peak area composition; retention time=6.64 min.
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:13].C[Si]([C:18]#[N:19])(C)C.CCN(CC)CC.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([C:18]#[N:19])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(C(F)(F)F)c[n+]([O-])c1Cl
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)c(C#N)nc1Cl
Temperature: 25 °C
Yield: 56.5 %

Procedure:
A mixture of 6-chloro-5-methyl-3-trifluoromethyl-pyridine-1-oxide (1.03 g, 5.30 mmol), trimethylsilyl cyanide (1.57 g, 16.0 mmol) and Et3N (1.34 g, 13.3 mmol) in dry CH3CN (30 mL) was heated at reflux for 64 h. The reaction mixture was then cooled to room temperature, and saturated aqueous NaHCO3 (20 mL) was added. After concentrated under reduced pressure the mixture was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (6:1 hexanes/EtOAc) to afford 6-chloro-5-methyl-3-trifluoromethyl-pyridine-2-carbonitrile as a colorless oil (0.660 g, 56%). 1H NMR (CDCl3) δ 2.56 (s, 3H), 7.95 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[S:14](=[O:16])(=[O:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:17][C:18]([F:23])([F:22])[C@@H:19]1[CH2:21][O:20]1>ClCCl>[F:17][C:18]([F:23])([F:22])[C@@H:19]([OH:20])[CH2:21][N:11]1[CH2:12][CH2:13][S:14](=[O:16])(=[O:15])[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10]1
Reactant: COc1cccc(C2CNCCS2(=O)=O)c1
Reactant: FC(F)(F)[C@@H]1CO1
Solvent: ClCCl
Product: COc1cccc(C2CN(C[C@H](O)C(F)(F)F)CCS2(=O)=O)c1
Reaction time: 8 h
Yield: 65.3 %

Procedure:
In a 25 mL round-bottomed flask was placed 2-(3-methoxyphenyl)-thiomorpholine-1,1-dioxide (252 mg, 1.04 mmol), followed by (S)-2-(trifluoromethyl)oxirane (129 mg, 1.15 mmol). The reaction mixture was stirred overnight. Reaction was not complete. An additional 100 mg of the (S)-2-(trifluoromethyl)oxirane was added followed by a small amount of dichloromethane. Reaction mixture was stirred at room temperature for an additional 2 h. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 40% EtOAc in hexanes) afforded (S)-1,1,1-trifluoro-3-[2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholin-4-yl]-propan-2-ol (240 mg) as a white foam. (M+H)+=354 m/e.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]([Br:16])=[C:13]([Br:15])[CH:14]=1)=[O:9])C.[OH-].[K+]>O1CCOCC1.O>[Br:15][C:13]1[CH:14]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])=[O:9])[NH:11][C:12]=1[Br:16]
Reactant: CCOC(=O)CCNC(=O)c1cc(Br)c(Br)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCNC(=O)c1cc(Br)c(Br)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-propionic acid ethyl ester (7.80 g, 21.1 mmol) in 160 mL of 1:1 mixture of dioxane-H2O is added KOH (4.72 g, 84.2 mmol). The mixture is stirred at room temperature overnight. The solution is extracted with Et2O (100 mL) and the aqueous layer is then acidified with HCl to a pH of less than 2 followed by extraction with EtOAc (80 mL×3). The EtOAc layers are combined, washed with brine, and dried with Na2SO4. After removal of solvent, 3-[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-propionic acid is obtained. It was used without further purification; 1H NMR (DMSO-d6) δ 2.47 (t, 2H, J=7.2 Hz), 3.39 (q, 2H, J=6.0 Hz), 6.90 (s, 1H), 8.17 (t, 1H, J=4.8 Hz); m/z [M++1] 340.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20](O)[N:15]2[N:14]=1)(=[O:12])=[O:11].P(Cl)(Cl)([Cl:26])=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20]([Cl:26])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1

Procedure:
A suspension of 10.0 g (27.0 mmol) of N-(2,6-dichlorophenyl)-7-hydroxy-5-methyl-1,2,4-triazolo-[1,5-a]-pyrimidine-2-sulfonamide and 100 ml (1.1 mol) of phosphorous oxychloride in 700 ml of acetonitrile (dried over 4A Molecular Sieves) was heated at reflux for 24 hr. As the reaction progressed the mixture became homogeneous. After cooling the solution was concentrated by rotary evaporation in vacuo and the resulting residue was diluted with 300 ml of methylene chloride and 10 ml of water. The methylene chloride solution was decanted off and the solid that had formed was triturated with 100 ml of hexane and 5 ml of water. The resulting yellow solid was collected. Recovered 9.0 g (85 percent) of the desired product; mp 217°-220° C. An analytical sample could be prepared by recrystallization from methanol (mp 218°-221° C.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cc(F)cc(F)c2)s1
Yield: 34.3 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 3,5-difluorophenylboronic acid (9 mg, 0.06 mmol) giving 7.2 mg (34%) of the title compound. MS (ESI+) calcd for C17H11F2N5O2S2 419.032222, found 419.032222.