Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1)=[CH:3][C:2]([C:37]1[CH:36]=[C:35]([F:48])[C:34]([OH:49])=[C:33]([Cl:32])[CH:38]=1)=[CH:11][CH:10]=2)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl (trans-4-((6-bromo-3-butyrylquinolin-4-yl)amino)cyclohexyl)carbamate (49 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (36 mg, 64%) as a yellow-brown solid. ESI MS m/z 556 [C30H35ClFN3O4+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N)c3)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(Cl)cc4)c3)cc2s1
Yield: 23.4 %

Procedure:
N-(6-(5-amino-6-chloropyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.040 g, 0.13 mmol) was dissolved in pyridine (1 ml), then 4-chlorobenzene-1-sulfonyl chloride (0.026 g, 0.13 mmol) was added to the mixture while stirring. The mixture was allowed to stir under inert atmosphere for 3 days. The progress of the reaction was monitored by LC/MS, which showed product. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was extracted with DCM (3×20 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography in a gradient of 0-10% Methanol/DCM. The fractions with desired material were combined and concentrated in vacuo. The residue was diluted with ethyl acetate and allowed to stir 10 minutes. The precipitate was collected by filtration and washed with 1:1 ethyl acetate/hexanes to give N-(6-(6-chloro-5-(4-chlorophenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.015 g, 24% yield) as a white crystalline solid. MS (ESI pos. ion) m/z: 494 (MH+). Calc'd exact mass for C20H14Cl2N4O3S2: 493. 1H NMR (400 MHz, DMSO-d6): 2.23 (s, 3H), 5.73 (s, 1H), 7.48-8.17 (m, 7H), 8.84 (s, 1H), 8.62 (s, 1H), 12.45 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([OH:23])=O)=O)=[CH:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21](=[O:23])[C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=2)=[CH:2]1
Reactant: O=C(CCc1c[nH]c2ccccc12)Nc1ccccc1C(=O)O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=c1c2ccccc2nc(CCc2c[nH]c3ccccc23)n1-c1ccccc1
Yield: 31.2 %

Procedure:
To a solution of 3-(3-indolyl)-N-(2-carboxyphenyl)propionamide (6.20 g, 20 mmol) in 50 ml of THF at room temperature was added 1,1-carbonyldiimidazole (3.26 g, 20 mmol). The reaction mixture was stirred under a dry atmosphere for 30 minutes after which aniline (2 ml, 22 mmol) and PPTS (4.03 g, 16 mmol) were added. The resulting reaction mixture was stirred under reflux for two days. The reaction mixture was allowed to cool and evaporated to dryness in vacuo. The product residue was taken up in ethyl acetate and washed (1N HCl, water, saturated NaHCO3, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to a brown oil which crystallized from ethyl acetate/hexanes. The product was recrystallized from methanol/ethyl acetate to provide 2.28 g of 2-[2-(3-indolyl)ethyl]-3-phenyl-4-(3H)quinazolinone as white fluffy needles; m.p. 193°-194° C.; FABMS and EIMS 366 (M+); IR (KBr) 1672 CM--1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:21])=[CH:4][CH:3]=1.[Cl:22]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:14]([Cl:21])=[CH:15][C:16]([NH2:17])=[C:18]([Cl:22])[C:19]=2[Cl:20])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Solvent: c1ccccc1
Product: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1Cl
Yield: 56 %

Procedure:
Into a magnetically stirred solution of 4-(4-chloro-1-naphthoxy)-3,5-dichloroaniline (6.00 grams, 17.72 mmol) prepared in Part B in benzene (50 milliliters) was added solid N-chlorosuccinimide (2.84 grams, 21.20 mmol). The mixture was heated to reflux for 1 hour, cooled and filtered. The solvent was evaporated under reduced pressure and the crude product when subjected to flash column chromatography (3:1 hexane:ethyl acetate) afforded pure 4-(4-chloronaphthoxy)-2,3,5-trichloroaniline (3.70 grams, 9.92 mmol, 56%). Elemental analysis of the product indicated the following:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:14]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:35])[NH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])[CH3:13].C(N(CC)CC)C>>[C:12]([CH:14]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:35])[NH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])(=[O:11])[CH3:13]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1

Procedure:
Analogously to Example 40A, 250 mg (1.94 mmol) of oxalyl chloride, 330 mg (4.2 mmol) of dimethyl sulphoxide, 750 mg (1.61 mmol) of 2-(1-hydroxyethyl)-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenyl-pentanamide and 820 mg (8.07 mmol) of triethylamine are reacted to give 2-acetyl-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenyl-pentanamide.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=1>>[CH3:23][O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: COc1cccc(Br)n1
Product: COc1cccc(C#Cc2c(-c3ccccc3)noc2C)n1
Yield: 67 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-6-methoxypyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 97 mg, 67%) which was obtained as a yellow oil. MS: m/e=291.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>>[C:19]([C:18]1[C:17]([N+:14]([O-:16])=[O:15])=[CH:24][CH:23]=[CH:22][C:21]=1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])#[N:20]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 7 %

Procedure:
Prepared as in Example 215c from tert-butyl 4-hydroxybutylcarbamate and 2,6-dinitrobenzonitrile in 7% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.35 (s, 9H), 1.52-1.55 (m, 2H), 1.72-1.76 (m, 2H), 2.94-2.99 (m, 2H), 4.24 (t, J=6.8 Hz, 2H), 6.86 (brs, 1H), 7.69-7.72 (m, 1H), 7.85-7.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:35])[N:13]([CH2:18][CH2:19][C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22](C4CCCCO4)[N:21]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[CH:9]=1)[C:5]#[N:6].CO>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:35])[N:13]([CH2:18][CH2:19][C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:22][N:21]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1ccn(CCc2nn(C3CCCCO3)c3ncccc23)c(=O)c1Oc1cc(Cl)cc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccn(CCc2n[nH]c3ncccc23)c(=O)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 1 h

Procedure:
3-chloro-5-[(4-methyl-2-oxo-1-{2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]ethyl}-1,2-dihydropyridin-3-yl)oxy]benzonitrile (11.7 mg, 0.023 mmol) was dissolved in TFA (2 mL) and allowed to stand at room temperature for 1 hour. After this time, MeOH (1 mL) was added and the solvent evaporated in vacuo. The residue was purified on Gilson LC using a Luna reverse phase column (10μ, C18, 250×21.2 mm) and eluting with a gradient of 5-95% ACN/water (0.5% TFA). The desired fractions were combined and the solvent evaporated in vacuo to give the title compound. LRMS (M+1): 405.9.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][CH2:14]O)[CH:2]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:37][CH2:38][N:39]([CH2:14][CH2:13][C:12]#[C:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:40][CH2:41]1
Reactant: OCCC#Cc1cnc2ccccc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C(#Cc1cnc2ccccc2c1)CCN1CCN(c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of the alcohol prepared in Step (a) (1.98 g, 0.01 mol), N,N-diisopropylethylamine (3.5 mL, 0.02 mol) and a catalytic amount of 4-dimethylaminopyridine in 100 mL of dichloromethane is cooled to 0° C., and methanesulfonyl chloride (0.8 mL, 0.0105 mol) is added dropwise. The solution is stirred at 0° C. for 18 hours, and then concentrated under reduced pressure. The residue is taken up in dimethylformamide (20 mL), and to this solution is added 1-(2-pyridinyl)piperazine (2.45 g, 0.015 mol) and sodium bicarbonate (3.4 g, 0.04 mol). The mixture is heated at 40° C. for 5 hours and the solvent is removed under reduced pressure. The residue is partitioned between 50 mL of ethyl acetate and 50 mL of water. The aqueous layer is extracted with 50 mL of ethyl acetate and the combined organic layers are dried (sodium sulfate), and the solvent removed in vacuo. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound containing 0.10 mol of water; mp 76.5°-77.0° C.
Reaction SMILES: [F:1][CH2:2][C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])[CH:16]=[CH:17][C:18]=1[F:19].N1C=CC=CC=1.O1CCCC1>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:8]([C:7]2[C:3]([CH2:2][F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Nc1ccccc1-c1ccc(F)c(Cl)c1
Reactant: Cn1cc(C(=O)Cl)c(CF)n1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2ccccc2-c2ccc(F)c(Cl)c2)c(CF)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At room temperature, 0.27 g of 3-fluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride was added dropwise to a solution of 0.33 g of 3′-chloro-4′-fluoro-2-aminobiphenyl and 0.18 g of pyridine in 10 ml of toluene, and the mixture was stirred at room temperature for 16 hours. 10 ml of tetrahydrofuran and 30 ml of methyl tert-butyl ether were added, and the organic phase was washed successively with 2% strength hydrochloric acid, twice with 2% strength aqueous sodium hydroxide solution and then with dilute aqueous sodium chloride solution. The organic phase was dried and concentrated under reduced pressure. The crude product was triturated with 10 ml of diisopropyl ether and the solid that remained was filtered off with suction and dried. This gave 0.46 g of the desired product as a white powder of m.p. 133-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Li]CCCC.[Cl-].[Li+].[S:19]1[C:23]2[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:25]3[CH:26]=[CH:27][C:22]4[N:21]=[CH:20][S:19][C:23]=4[CH:24]=3)[S:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2ccsc2c1
Reactant: O=S(=O)(Oc1ccc2ncsc2c1)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3ccc4ncsc4c3)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-methoxybenzo[b]thiophene (300 mg, 1.82 mmol) in 5 mL of THF was cooled to −20° C. and 2.5 M n-BuLi (0.8 mL, 2.01 mmol) was added dropwise. The reaction was stirred at 0° C. for 0.5 hrs and then warmed to room temperature for an additional 0.5 hrs. Next a 0.5 M solution of anhydrous zinc chloride in THF (4.75 mL, 2.38 mmol) was added and the reaction was stirred at room temperature for 15 minutes followed by the addition of anhydrous lithium chloride (3 equivalents), tetrakis-triphenylphosphine palladium (84 mg, 0.073 mmol) and, by cannula, the product from Example 18, Step 1 (505 mg, 2.01 mmol) dissolved in 2 mL of THF. The reaction was stirred at room temperature for 16 hrs. The THF was removed and the residue diluted in water and extracted three times with Ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was chromatographed on silica gel using 1:20 THF/Hexanes to 1:10 THF/Hexanes as the gradient eluant to yield the title compound.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.O>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[N:14][CH:13]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(OCc2ccccc2)cn1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Sodium hydride (4.76 g, 119 mmol) was added to a dimethylformamide solution (100 ml) of 6-methylpyridin-3-ol (10.0 g, 91.6 mmol) under ice cooling, and this mixture was stirred for 30 minutes, followed by adding benzyl chloride (12.7 ml, 110 mmol) to the mixture and stirring it for 12 hours at room temperature. Water and a saturated saline solution (1:1) and ethyl acetate were added to this reaction solution, and the solution was extracted. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 1:2) to obtain 5-(benzyloxy)-2-methylpyridine (16.4 g, yield: 90%) as an orange-colored product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([C:24]([NH2:26])=O)[CH2:23][CH2:22]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([C:24](=[S:36])[NH2:26])[CH2:23][CH2:22]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1(C(N)=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1(C(N)=S)CC1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a solution of Example 2 (400 mg, 0.99 mmol) in tetrahydrofuran (32 ml), under nitrogen, was added Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disulphide, 240 mg, 0.59 mmol). The reaction mixture was heated at reflux for 3 h, cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate (×3) and the combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (1.2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×30 mm Phenomenex LUNA C18(2) 10 μm column) using an acetonitrile:water gradient [45:55 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (64 mg).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[C:68]([CH3:69])=[CH:67][CH:66]=[C:65]([F:70])[C:61]=1[C:62](Cl)=[O:63]>>[F:59][C:60]1[C:68]([CH3:69])=[CH:67][CH:66]=[C:65]([F:70])[C:61]=1[C:62]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:63]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: Cc1ccc(F)c(C(=O)Cl)c1F
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(F)ccc(C)c4F)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 165 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,6-difluoro-3-methyl benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[OH:18])(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccccc1O
Yield: 92 %

Procedure:
A 193 g (1.0 mole) quantity of p-chlorobenzenesulfonic acid, 188 g (2.0 moles) of phenol and 10 g of 12-molybdophosphoric acid (H3PMol12O40. hydrate) were refluxed with heating and stirring. An azeotropic mixture of the water formed and phenol were cooled and subjected to phase separation to reflux the phenol thus separated to the reaction system. After 6 hours of reaction, the reaction mixture was cooled and the catalyst was separated by filtration. After the mother liquor was washed with water, the phenol was distilled off under reduced pressure, giving 247 g of (4-chlorophenylsulfonyl)phenol in a yield of 92% (melting point 142° to 145° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][CH:10]2[CH3:13])=[CH:5][C:4]=1[OH:16].[K].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([O:16][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])=[N:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2c(cc1O)CC(C)(C)NC2C
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CC(C)(C)N=C2C
Temperature: 55 °C
Yield: 64.8 %

Procedure:
To a solution of 239 (970 mg, 4.4 mmol) in acetone (10 ml) was added potassium C(Ar)bonate (3.06 g, 22.0 mmol), benzyl bromide (1.05 ml, 8.8 mmol) and tetrabutyl ammonium iodide (163 mg, 0.44 mmol). The reaction mixture was heated at 55° C. for 60 h. The reaction mixture was cooled to rt, water (20 ml) was added and the aqueous layer was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography eluting with EtOAc then EtOAc:MeOH:TEA; 10:1:0.1 afforded the title compound (882 mg, 64%) as a pale orange solid. mp=87.9-90° C. 1H NMR (270 MHz; CDCl3) 1.16 (6H, s, 2×CH3), 2.22 (3H, s, CH3), 2.59 (2H, s, CH2), 3.90 (3H, s, OCH3), 5.13 (2H, s, CH2Ph), 6.63 (1H, s, CH), 7.0 (1H, s, CH), 7.27-7.46 (5H, m, 5×CH, phenyl). 13C NMR (67.5 MHz; CDCl3) 23.54 (CH3), 28.15 (2×CH3), 38.70 (CH2), 53.65 (C(CH3)), 56.07 (OCH3), 71.87 (CH2Ph), 111.40 (CH), 112.57 (CH), 121.49 (C), 127.58 (CH), 128.08 (CH), 128.68 (CH), 130.78 (C), 137.15 (C), 146.33 (C), 151.79 (C), 160.65 (C). LC/MS (ES+) tr=2.5 min, m/z 310.05 (M++H). HRMS (ES+) calcd. for C20H24NO2 (M++H) 310.1802, found 310.1801.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([N: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])N=N2)=[CH:6][C:5]=1[CH3:27].[OH-].[K+]>CO.O>[Cl:25][C:23]1[CH:24]=[C:19]([C:13]2([C:15]([F:18])([F:17])[F:16])[CH2:14][N:10]2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[C:5]([CH3:27])[CH:6]=2)[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: COC(=O)c1ccc(N2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)N=N2)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(N2CC2(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Temperature: 80 °C
Yield: 36.9 %

Procedure:
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-[1,2,3]triazol-1-yl]-2-methyl-benzoic acid methyl ester (Example 2.1) (3.6 g, 8.33 mmol) in methanol (10 ml) was added aqueous potassium hydroxide (40% w/v) (35 ml) and the reaction mixture heated at 80° C. for 15 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The aqueous phase was acidified by addition of aqueous hydrochloric acid (1M) and extracted again with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine and concentrated. The residue was purified by column chromatography on silica gel (eluent: 15% v/v ethyl acetate in hexane) to give 4-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-aziridin-1-yl]-2-methyl-benzoic acid as a white solid (1.2 g). 1H-NMR (DMSO-d6, 400 MHz): 12.57 (s, 1H), 7.70 (d, 1H), 7.65 (s, 3H), 6.99 (s, 1H), 6.97 (d, 1H), 3.27 (s, 1H), 3.05 (s, 1H), 2.45 (s, 3H).