Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][S:11][C:10]2[S:15][C:16]([C:18](=O)[NH2:19])=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1.O>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][S:11][C:10]2[S:15][C:16]([C:18]#[N:19])=[CH:17][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc2c(s1)SCC(=O)N2Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cc2c(s1)SCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of 1-benzyl-6-carbamoyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine (0.18 g) and p-toluenesulfonyl chloride (0.17 g) in pyridine (5 ml) was stirred for 24 hours at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, and adjusted to pH 1.5 with concentrated hydrochloric acid. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform. The fractions containing the object compound were collected and evaporated in vacuo to give 1-benzyl-6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine (0.11 g)
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:15])([CH3:3])=[CH2:2].C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.[I-]>CN(C=O)C.C(OCC)(=O)C>[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N:6]2[C:7]3[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=3[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]2=[O:15])=[CH:24]1
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: C=C(C)n1c(=O)[nH]c2cc(C)c(C)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-Isopropenyl-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.25 g, 1.2 mmol) in DMF (10 mL) was added K2CO3 (0.51 g, 3.7 mmol). The reaction mixture was heated to 90° C. and stirred for 20 min. (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium; iodide (0.64 g, 1.8 mmol) was then added to the reaction mixture and stirred for another 3 h. The reaction mixture was treated with ethyl acetate and washed with water. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate as an eluent to afford 0.35 g the desired product as an off-white solid. LCMS (ESMS): m/z 360.33 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].Br[Si:8]([CH3:11])([CH3:10])[CH3:9]>C[Si](C)(C)N[Si](C)(C)C>[NH2:1][CH:2]([CH2:5][O:6][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][O:4][Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)Br
Reactant: NC(CO)CO
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)OCC(N)CO[Si](C)(C)C
Reaction time: 16 h

Procedure:
A stirred solution of 1.84 g (20.0 mmol) of serinol in 4.25 mL (20.1 mmol) of hexamethyldisilazane containing 1 drop of bromotrimethylsilane was heated to 180° C. under argon. After 16 h, the reaction mixture was partially cooled and distilled at 0.6 Torr, collecting the fraction with bp 44-47° C. to give title compound as a colorless liquid, 4.05 g, 86%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Cl:11])=[N:6][CH:5]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH3:15])[C:7]([Cl:11])=[N:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cnc(Cl)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-chloro-5-hydroxynicotinic acid methyl ester (1.8 g, 9.6 mmol), methyl iodide (2 M solution in Et2O, 5.8 mL, 11.6 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in acetone (190 mL) was refluxed for 6 h. The reaction was then concentrated via rotavap and H2O was added (100 mL). The resulting white precipitate was filtered and rinsed with additional H2O to furnish the product 6-chloro-5-methoxynicotinic acid methyl ester as a white solid (1.33 g, 68%); mp=83-85° C.; 1H NMR (400 MHz, CDCl3) δ 8.60 (d, 1H), 7.77 (d, 1H), 3.98 (s, 3H), 3.96 (s, 3H): GC-MS: Exact mass calcd for C8H8ClNO3 [M]+, 201. Found 201.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[CH:17]([NH2:20])([CH3:19])[CH3:18].Cl>C(O)(C)C>[CH:17]([NH:20][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4])([CH3:19])[CH3:18]
Reactant: CC(C)N
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NCC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Yield: 47.1 %

Procedure:
12.6 g of the 5-chloroacetyl-8-hydroxycarbostyril (IV) obtained in Example 4 or 8 was suspended in 130 ml of isopropanol, and 2515 g of isopropylamine (III) was added dropwise to the resulting suspension while stirring. The reaction mixture was then stirred at 55° to 60° C. for 3 hours. After cooling, concentrated hydrochloric acid was added to the mixture to adjust the mixture to a pH of 2 to 3, and the precipitated crystals were filtered, washed with acetone and recrystallized from methanol-dimethylformamide (1:1 by volume) to obtain 6.5 g of 5-isopropylaminoacetyl-8-hydroxycarbostyril (II) hydrochloride having a melting point of 286° - 288° C. (with decomposition as pale yellow crystals.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Hg](C#N)C#N.[C:15]([O:18][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:22][S:21][C@@H:20]1Br)(=[O:17])[CH3:16]>>[C:15]([O:18][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:22][S:21][C@H:20]1[S:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1cccc(S)c1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2cccc(C#N)c2)SC[C@H]1OC(C)=O

Procedure:
If the procedure described in Preparation I is followed starting from 9.3 g (67.10-3 mol) of 3-mercaptobenzonitrile, 18 g (73.10-3 mol) of mercuric cyanide, Hg(CN)2, and 26.14 g (73.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 8.55 g of the expected product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].Cl.[CH3:15][O:16][NH2:17].O.Cl>N1C=CC=CC=1>[CH3:15][O:16][NH:17][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: CON
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 87.5 %

Procedure:
2-nitrobenzene sulfonyl chloride (28.8 g, 130 mmol) was added within 30 min to a solution of O-methylhydroxylamine hydrochloride (11.7 g, 141 mmol) in pyridine (100 ml) accompanied by stirring and water cooling. After the addition the mixture was stirred for a further 30 min at room temperature (RT), mixed with ice (200-300 g) and acidified with concentrated HCl to pH 2-3. The still-cold suspension was sucked out, the precipitate carefully washed with ice water and dried. 26.4 g (87%) of the sulfamide 1 was obtained as a yellowish solid with a melting point of 133-136° C. 1H-NMR (DMSO-D6, 300 MHz): δ=3.67 (s, 3H), 7.92-8.06 (m, 4H), 11.05 (s, 1H) ppm.
Reaction SMILES: [Si](C([O:17][CH:18]([Si](C(C)(C)C)(C)C)[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)C1C=C(Cl)C=C(Cl)C=1)(C(C)(C)C)(C)C.C([Li])CCC.[Cl:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1.Cl>CCCCCC.O1CCCC1>[Cl:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([Cl:26])[C:22]=1[C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([Cl:39])=[CH:41][CH:42]=1)[CH2:18][OH:17]
Reactant: CC(C)(C)[Si](C)(C)C(OC(c1cc(Cl)cc(Cl)c1)[Si](C)(C)C(C)(C)C)c1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CO)cc1Cl

Procedure:
React t-Butyldimethylsilyl-3,5-dichlorobenzyl ether (858.A1) (1 mole) with n-Butyllithium 1.6M solution in hexane followed by 4-Chlorobenzoyl chloride, (1.01 mole), in Tetrahydrofuran, while cold and treat the intermediate with aqueous Hydrochloric acid to give 3,5-dichloro-4-(4-chlorobenzoyl)benzyl alcohol (858.B).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[CH3:24][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10](=[O:11])[CH3:24])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(Cc2ccc(Br)cc2)C(=O)N(C)OC)cc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(C(Cc2ccc(Br)cc2)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
3-(4-bromophenyl)-2-(4-methoxyphenyl)propanoic acid (3.0 g, 8.95 mmol), Weinreb amine (1.05 g, 10.7 mmol) were dissolved in DMF (90 ml) and diisopropylethylamine (1.88 ml, 10.7 mmol) was added in one portion. EDC (2.06 g, 10.7 mmol) and HOAt (0.122 g, 0.895 mmol) were added to the resulting solution portionwise. The resulting solution was allowed to stir at 25° C. for 1 hour. After one hour the reaction was diluted with EtOAc, washed with 10% KHSO4, saturated NaHCO3, and LiCl (×3). The organic layer was dried over sodium sulfate and concentrated in vacuo, which afforded 3.2 g of 3-(4-bromophenyl)-N-methoxy-2-(4-methoxyphenyl)-N-methylpropanamide as a colorless oil. 3-(4-bromophenyl)-N-methoxy-2-(4-methoxyphenyl)-N-methylpropanamide (1.0 g, 2.64 mmol) was dissolved in anhydrous THF (26.4 ml) and the resulting solution was cooled to 0° C. MeMgBr (1.32 ml, 3.97 mmol) was added dropwise to the cooled solution, and the resulting solution was allowed to stir for 30 min. at 0° C. The solution was then warmed to 25° C. for one hour, at which point the solution was filtered over a pad of celite and concentrated in vacuo. The resulting crude oil was purified using silica gel chromatography (0-40% EtOAc in hexanes gradient to afford 627 mg of 4-(4-bromophenyl)-3-(4-methoxyphenyl)butan-2-one as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][NH:4][N:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.CCOC(C)=O>[CH3:16][N:4]1[CH:5]=[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)[C:2]([CH3:1])=[N:3]1.[CH3:16][N:3]1[C:2]([CH3:1])=[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)[CH:5]=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Product: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 166.7 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.3 g, 1.442 mmol) and potassium carbonate (0.996 g, 7.21 mmol) were suspended in acetonitrile (10 ml) and stirred overnight at RT. Additional iodomethane (0.5 ml) was added and the mixture was stirred overnight at RT. The mixture was diluted with EtOAc and the inorganic salts were removed by filtration. The filtrate was evaporated to yield an inseparable mixture (2:1) of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.267 g, 83% yield). MS (ESI) m/z: 223.1 (M+H+).
Reaction SMILES: C1[C:6]([CH2:7][CH2:8][NH2:9])=[CH:5]C=C(S(F)(=O)=O)C=1.[OH:14]CC(CO)O.C1[N:25]([CH2:26][CH2:27][OH:28])CCN(CCS(O)(=O)=O)C1>>[NH2:25][C@H:26]([C:27]([OH:28])=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: NCCc1ccc(S(=O)(=O)F)cc1
Reactant: OCC(O)CO
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 0.25 h

Procedure:
smegmatis or M. bovis BCG cultures with an optical density measured at 600 nm (OD600) of 0.5 were centrifuged at 10000 g for 15 min. The pellet was re-suspended in 10 ml of 50 mM Hepes buffer (pH 7.4) containing 1 mM of AEBSF (Pefabloc Sc, Roche) and 15% (v/v) of glycerol (buffer A). The cells then underwent continuous sonication for 10 minutes at 4° C. using a Branson type sonicator, the outlet power being adjusted to 5. The total cell lysate was centrifuged at 4° C. at 20000 g for 15 min. For the methylation tests, 300 μl of total clarified lysate containing 1 mg of protein per ml was mixed with 40 μl of [methyl-14C]AdoMet (60 mCi/mmol, Amersham Pharmacia Biotech), 100 μl of recombinant HBHA purified on a heparin column to 0.5 mg/ml, 5 μl of 1M MgCl2 and 55 μl of buffer A. The methylation tests were carried out at 25° C. 100 μl samples were removed at intervals to verify the degree of methylation of the recombinant HBHA by autoradiography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:31][C:32](=[O:34])[CH3:33]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:31][C:32](=[O:34])[CH3:33])[C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(Nc2nccc(-c3ccc(NC(=O)OC(C)(C)C)s3)n2)c1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2ccnc(Nc3cccc(C)c3)n2)s1
Temperature: 60 °C
Reaction time: 0.13 h

Procedure:
[5-(2-m-Tolylamino-pyrimidin-4-yl)-thiophen-2-yl]-carbamic acid tert-butyl ester (30 mg, 0.078 mmol) was dissolved in DMF (0.8 mL) and 60% NaH (4.7 mg, 0.117 mmol) was added. After 8 min., KI (12.9 mg, 0.078 mmol) and chloroacetone (9.4 uL, 0.117 mmol) were added and the reaction was heated to 60° C. for 15 h. The reaction was ˜60% converted and an additional aliquot of 60% NaH (3.1 mg, 0.078 mmol) and chloroacetone (6.2 uL, 0.078 mmol) were added and reaction heated at 60° C. for another 18 h. The reaction was concentrated in vacuo and taken to the next step crude.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].[OH-].[Na+].C(O)(=O)CCC(O)=O>C(Cl)Cl>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: COC(CN)OC
Reactant: O=C1CCC(=O)O1
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(CNC(=O)CCC(=O)O)OC
Reaction time: 0.5 h

Procedure:
50.04 g (0.5 mol) of freshly distilled succinic anhydride are dispersed in 100 ml of methylene chloride. 52.75 g (0.5 mol) of aminoacetaldehyde dimethyl acetal are added, and the mixture is boiled under reflux. After 30 minutes, the homogeneous solution is evaporated in vacuo and freed from solvent at 60° C. under a high vacuum, giving a viscous oil which, according to titration with sodium hydroxide solution, has a purity of 99.4%. NMR data: 2.63 ppm (m) 4 methylene protons of succinic acid, 3.42 ppm (s) 6 methoxy protons, 4.42 ppm (t) 1 acetal proton, 3.6 ppm (d) 2 methylene protons, 6.60 ppm (t) 1 amide proton, 9.79 ppm 1 acid proton ##STR23##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[CH:34]=[CH2:35].C(N1C(C2C=CC(S(C)(=O)=O)=CC=2)=C(C2C=CC(F)=CC=2)C(C(F)(F)F)=N1)C=C>CN(C=O)C>[CH2:35]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[CH:34]=[CH2:33]
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: C=CCBr
Agent: C=CCn1nc(C(F)(F)F)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 40.8 %

Procedure:
Reaction of 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) (0.1 g) with 0.08 g of potassium carbonate and 2.0 g of allyl bromide in 5 mL of DMF gave a crude mixture of 1-allyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole and 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-5 (trifluoromethyl)-1H-pyrazole. HPLC purification with 50% ethyl acetate-hexane and recrystallization from ether-hexane gave 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (45 mg, 41%): mp 115.5-119° C.
Reaction SMILES: C1C=CC=CC=1.C=C.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]C)=[CH:13][CH:12]=1)[CH3:10].C(C1C=CC=CC=1)C>C1(C)C=CC=CC=1>[CH2:10]=[CH:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(CC)cc1
Agent: C=C
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCc1ccccc1
Product: C=CCCCCCC
Product: CCc1ccc(C)cc1

Procedure:
For example, benzene and ethylene at a mole ratio of 1:2 to 10:1 yield p-diethylbenzene besides ethylbenzene. (p=400 psig, Temp.=800° F.); toluene and 1-octene yield p-ethyltoluene and a mixture of n- and isopropyl toluene rich in p-isomer.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:4]=1[NH2:5].[N:11]([O-])=[O:12].[Na+].[O:15]=[C:16]1[O:22][C@H]([C@H](CO)O)C(O)=[C:17]1[OH:18]>O>[C:17]([OH:12])(=[O:18])[C:16]([OH:22])=[O:15].[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:4]=1[NH:5][NH2:11]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=N[O-]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Cl)ccc1Cl
Product: O=C(O)C(=O)O
Temperature: -1 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a 500 ml flask under a nitrogen atmosphere, concentrated HCl (180 ml, 32%, 10.17 M, 1.83 moles) was charged and cooled down to −2 to 0° C. 2,5-Dichloroaniline (30 g, 185 mmoles) was added in one portion as a solid. The acidic suspension was re-cooled to −2 to 0° C. and sodium nitrite (15.3 g, 222 mmoles) dissolved in water (30 ml) was added dropwise to the acidic mixture through an addition funnel over a period of 1 hour at −2 to 0° C. The resulting mixture was kept with stirring for 1 hour at −2 to 0° C. Next, L-ascorbic acid (34.2 g, 194 mmoles) was added portionwise as a solid at −2 to 0° C. The reaction mixture was allowed to come to room temperature (18-20° C.). A thick orange suspension was formed. The reaction mixture was diluted with concentrated HCl (50 ml, 32%, 0.51 moles, 2.7 eq) and water (150 ml) and then filtered. The wet solid was triturated in water (650 ml) at 20-25° C. for 16 hours, filtered, washed with water and dried to constant weight to afford 34 g of crude oxalic acid derivative as a red crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=O)[O:10]C1C=CC([N+]([O-])=O)=CC=1.[CH:22]1([CH2:25][NH2:26])[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[CH:22]1([CH2:25][NH:26][C:9]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[O:10])[CH2:24][CH2:23]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC1CC1
Reactant: Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
4-Aminophenol (18.33 mmol, 2 g) and 4-nitrophenyl carbonochloridate (18.33 mmol, 3.69 g) in dichloromethane (10 mL) were stirred at room temperature for 30 minutes. Cyclopropylmethanamine (36.7 mmol, 3.72 mL, 2.61 g) was added followed triethylamine (55.0 mmol, 7.66 mL, 5.56 g). The reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with dichloromethane/saturated sodium hydrogen carbonate solution and filtered through a hydrophobic frit. The organic layer was concentrated and the residue was purified by silica column chromatography (eluent: 2-8% methanol in dichloromethane) to give the title compound (1.4 g). MS (ESI) m/z 207.1 [M+H]+
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[Br:32])S(C2C=CC(C3C=CC=CC=3)=CC=2)(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1>[Br:32][C:27]1[C:28]([CH3:31])=[N:29][O:30][C:26]=1[NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][CH:5]=1)(=[O:8])=[O:9]
Reactant: Cc1noc(N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
N-(4-biphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide (0.150 g, 0.233 mmol) was dissolved in tetrahydrofuran (THF). Sodium hydroxide (0.120 g, 3.0 mmol) was added and the solution was warmed to 45° C. to dissolve the sodium hydroxide. Stirring was continued for 20 min. Tetrahydrofuran was removed under reduced pressure. The residue was dissolved in water, cooled to 0° C. and acidified to pH 3-4 with concentrated HCl. The solid precipitate was filtered off and dried in vacuo to give N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide (94% yield), which was further purified by recrystallization from chloroform/hexanes, m.p. 133°-135° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[O:10]=[C:11]([C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:11]([C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)([OH:10])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C(CCCCc1ccccc1)c1c[nH]cn1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCCCc1ccccc1)(c1ccc(F)cc1)c1c[nH]cn1
Temperature: 25 °C

Procedure:
0,52 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. Then a solution of 1-bromo-4-fluorobenzene (3,8 g) in 60 ml of dry tetrahydrofuran is added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 4-(1-oxo-5-phenylpentyl)-1H-imidazole (3,8 g) in 40 ml of tetrahydrofuran at 60° C. After the addition is complete, the reaction mixture is refluxed for 3 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and conc. hydrochloric acid is added to the solution. The product is extracted as hydrochloric salt into methylene chloride. Combined methylene chloride extracts are then evaporated to dryness.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]([CH2:16][C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2F)([OH:15])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)C=O.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]2([CH2:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:15]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC1(Cc2cc(Cl)ccc2F)CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)CC1(CCN(Cc3ccccc3)C1)O2
Temperature: 25 °C
Yield: 46 %

Procedure:
To a suspension of sodium hydride (NaH) (55%, 612 mg, 14.0 mmol) in toluene (10 mL) was added a solution of 1-benzyl-3-(5-chloro-2-fluorobenzyl)pyrrolidin-3-ol (1.3 g, 4.06 mmol) in toluene (20 mL) and the reaction mixture was kept on stirring at reflux, after 5 minutes dimethylformamide (10 mL) was added and the reaction mixture was refluxed for 90 minutes, cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% ammonium hydroxide, NH4OH) to give the subtitled compound (560 mg).