Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:8][C:9](=[O:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH3:20])[CH3:7]>>[CH2:6]([O:8][C:9](=[O:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][C:13]=1[CH2:18][CH2:19][CH3:20])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CCCc1ccccc1OCC(=O)OCC
Product: CCCc1cc(S(=O)(=O)Cl)ccc1OCC(=O)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
Chlorosulfonic acid (36.59 mL, 550.5 mmol) was cooled to 0° C. under argon atmosphere. The cooled chlorosulfonic acid was added dropwise to compound 4.2 (24.5 g, 110.1 mmol) using a dropping funnel. The reaction was stirred at 0° C. for 30 min. and at room temperature for 4 h. The reaction mixture was poured into ice-water and stirred slowly at 0° C. for 20 min. The precipitated crystals were collected and dried in vacuo using oven at 40° C. to give 4.3 (30.8 g) as pale-yellow crystals. 1H NMR (300 MHz) (CDCl3) δ 7.90-7.79 (2H, m); 6.81 (1H, d, J=8.4 Hz); 4.75 (2H, s); 4.28 (2H, q, J=7.1 Hz); 2.79-2.67 (2H, m); 1.77-1.60 (2H, m); 1.30 (3H, t, J=7.1 Hz); 0.97 (3H, t, J=7.3 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[C:31]4[C:27]([C:28]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])=[CH:29][NH:30]4)=[CH:26][CH:25]=3)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[C:31]4[C:27]([C:28]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:29][NH:30]4)=[CH:26][CH:25]=3)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)c[nH]c4c3)no2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1Cl
Reaction time: 1 h
Yield: 79.2 %

Procedure:
Trifluoroacetic acid (1.20 mL) was added to a solution of 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D17) (150 mg) in dichloromethane (2 mL) at RT. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane/ether to afford 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E5) (105 mg) as a pale pink solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.64 (2H, t), 2.97 (2H, t), 4.89 (1H, m), 7.35 (1H, m), 7.45 (1H, d), 7.73 (2H, dd), 8.13 (2H, m), 8.34 (1H, s), 11.22 (1H, s), 12.13 (1H, br s). MS (ES): C22H20ClN3O4 requires 425; found 426.0 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([CH3:10])[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccnc2C=O)cc1
Temperature: 90 °C
Yield: 77 %

Procedure:
To a stirred degassed solution of 3-bromo-2-pyridinecarboxaldehyde (198 mg, 1.06 mmol) and 4-methylbenzene boronic acid (152 mg, 1.12 mmol) in DME/THF (3.5 mL, 2.5:1) were added a 2 M Na2CO3 solution (0.9 mL) and Pd(PPh3)4 (63 mg, 0.055 mmol). The reaction mixture was flushed with Ar and maintained under Ar while being heated at 90° C. overnight. The mixture was then cooled and diluted with EtOAc (40 mL) and brine (30 mL). The organic layer was washed with brine (1×30 mL), dried (Na2SO4), filtered and concentrated. Purification of the resultant oil by column chromatography with silica gel (Hexanes/EtOAc, 2:1) afforded 3-p-tolyl-pyridine-2-carbaldehyde (161 mg, 77%) as a yellow oil. 1H NMR (CDCl3) δ 2.43 (s, 3H), 7.25-7.28 (m, 4H), 7.53 (dd, 1H, J=9, 6 Hz), 7.79 (dd, 1H, J=9, 1 Hz), 8.80 (dd, J=3, 1 Hz), 10.09 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([S:11](Cl)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([S:11]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccc2snc(Cl)c2c1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNS(=O)(=O)c2ccc3snc(Cl)c3c2)cc1
Reaction time: 6 h
Yield: 45.2 %

Procedure:
To a solution of 3-chlorobenzo[d]isothiazole-5-sulfonyl chloride (90 mg, 0.33 mmol) in methylene chloride (2 mL), diisopropylethylamine (142 μL, 0.82 mmol) and 4-methoxybenzylamine (85 μL, 0.65 mmol) were added at room temperature. After stirring for 6 h, the reaction mixture was diluted with methylene chloride (20 mL) and washed with 10% HCl aqueous solution and brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a brown residue. Purification by column chromatography, on silica gel, eluting with 2:8 ethyl acetate:hexanes provided 3-chloro-N-(4-methoxybenzyl)benzo-[d]isothiazole-5-sulfonamide (55 mg). 1H NMR (300 MHz, CDCl3): 8.22 (dd, 1H), 7.82 (dd, 1H), 7.75 (dd, 1H), 7.10 (d, 2H), 6.73 (d, 2H), 5.06 (t, 1H), 4.18 (d, 2H), 3.73 ppm (s, 3H). MW=368 confirmed by LC-MS, tr=13.39 min (Method Y) MH+=369.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:44]([O:43][C:42]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:48])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: CCOC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCCCCNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Yield: 55.9 %

Procedure:
To a solution of ethyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.5 g) in DMF (8 mL) was added tert-butyl 6-bromohexylcarbamate (1.1 g) and K2CO3 (0.9 g). The mixture was heated to 65° C. for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (250 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by recrystallization in MeOH to give ethyl 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.2 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[N:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Br>CC(C)=O>[Br:1][C:2]1[C:3]([O:22][CH2:29][CH:31]2[CH2:32][O:33]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH3:13])[N:8]=[CH:7]2
Reactant: BrCC1CO1
Reactant: C[C@@H](Cn1ncc2ccc(O)c(Br)c21)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@@H](Cn1ncc2ccc(OCC3CO3)c(Br)c21)O[Si](C)(C)C(C)(C)C
Yield: 471.5 %

Procedure:
A suspension of the product from Step C (3.66 g, 9.51 mmol), potassium carbonate (1.92 g, 1.46 mmol), and epibromohydrine (1.32 mL, 1.60 mmol) in acetone (200 mL) was heated at reflux for 30 h. The solid was removed by filtration and the filtrate was concentrated to an oil that was purified by chromatography (silica, 2% to 10% EtOAc/hexane) to afford an oil (3.33 g, 79%): LC/MS (+APCI) m/z 441, 443 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:19](OC)=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccsc2CO)CC1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of 4-(2-methoxycarbonylthiophen-3-yl)piperidine-1-carboxylic acid t-butyl ester (2.4 g, 7.4 mmol, 1.0 eq.) in THF (20 mL) was degassed and purged with nitrogen (2×). Borane dimethyl sulfide complex (35 mL, 70 mmol, 110.8 eq.) was added at room temperature and the mixture was heated to reflux overnight. The mixture was allowed to cool to room temperature and MeOH (20 mL) was slowly added. The mixture was then concentrated under vacuum. The addition of MeOH (20 mL) and concentrating was repeated two additional times. The product was applied onto a silica gel column and purified by chromatography with PE/EtOAc (10:1). The product was then purified by preparative HPLC to yield the title compound (1.5 g) as a yellow oil, which gradually solidified.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]5([C:39]([O:41]CC)=[O:40])[C:38]6[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:44])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+].Cl>CO>[C:39]([C:26]1([CH2:25][CH2:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([C:11]3[CH:10]=[C:9]4[C:14]([CH2:15][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]4=[O:44])=[CH:13][CH:12]=3)[CH2:17][CH2:18]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=2[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([OH:41])=[O:40]
Reactant: CCOC(=O)C1(CCCCN2CCN(c3ccc4c(c3)C(=O)N(C3CCCCC3)C4)CC2)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1c2cc(N3CCN(CCCCC4(C(=O)O)c5ccccc5-c5ccccc54)CC3)ccc2CN1C1CCCCC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
The compound (50 mg) prepared in Example 129 was dissolved in a mixed solvent composed of THF (0.3 ml) and methanol (0.3 ml). 1 N NaOH (0.3 ml) was added to the solution, and the mixture was heated at 65° C. with stirring for 3 hr. The temperature of the reaction solution was returned to room temperature, and 1 N HCl was then added thereto, followed by extraction with chloroform. The extract was dried over anhydrous MgSO4. The solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (chloroform:methanol=5:1) to give the title compound (29 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20](Br)=[C:19]([CH3:27])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:4].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:36]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]([F:34])([F:33])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20]([OH:36])=[C:19]([CH3:27])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:4]
Reactant: Cc1cc2c(cc1Br)c(C#N)c(-c1ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn1)n2C1CCCC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1O)c(C#N)c(-c1ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn1)n2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A mixture of (R)-6-(5-bromo-3-cyano-1-cyclopentyl-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (0.54 g, 0.97 mmol), bis(pinacolato)diboron (0.5 g, 2.0 mmol), PdCl2dppf-CH2Cl2 complex (16 mg, 0.02 mmol) and potassium acetate (0.40 g, 4.0 mmol) in dioxane (5 mL) was stirred at 80° C. overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate and filtered through a silica-celite pad. The filtrate was concentrated, dissolved in acetone (10 mL) and cooled to 0° C. Into this solution was added an aqueous solution of Oxone (10 mL, 1.0 M). The mixture was stirred at room temperature for 15 min and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic extractions were combined and washed with aq. NaHSO3 and brine, dried over Na2SO4, and concentrated. Purification on silica gel eluting with 40% ethyl acetate in hexane gave (R)-6-(3-cyano-1-cyclopentyl-5-hydroxy-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide as a yellow solid (0.40 g, 84%); Melting point: 239-240° C.; MS m/z 493.2 M+H+; 1H NMR (500 MHz, CD3COCD3) δ 9.24 (dd, J=2.30, 0.65 Hz, 1H), 8.50 (dd, J=8.25, 2.35 Hz, 1H), 8.42 (s, 1H), 8.10 (dd, J=8.25, 0.85 Hz, 1H), 7.47 (bs, 1H), 7.54 (s, 1H), 7.15 (s, 1H), 5.30-5.26 (m, 1H), 4.40-4.35 (m, 1H), 2.40 (s, 3H), 2.34-2.31 (m, 2H), 2.16-2.14 (m, 2H), 2.10-2.07 (m, 2H), 1.74-1.72 (m, 2H), 1.21 (d, J=2.25 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=[C:4]([NH:9][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cc(Cl)nc(NC(=O)OCC)n1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A solution of 7.25 g (50 mmol) of 6-chloro-2,4-diaminopyrimidine in 100 ml of dimethylformamide and 20 ml of triethylamine is cooled to 0° and treated dropwise with 10 ml of ethyl chloroformate. The mixture is stirred at room temperature for 70 hours, the precipitated material is filtered off under suction, the filtrate is evaporated and the residue is taken up in methylene chloride. The organic phase is washed with 1N hydrochloric acid, dried over magnesium sulphate and evaporated under vacuum. The crude product obtained is chromatographed on silica gel, there being obtained pure diethyl 6-chloro-2,4-pyrimidinedicarbamate of melting point 153°-154°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:53]=[CH:54][CH:55]=1)[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][OH:24])=[C:15]([Cl:52])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:53]=[CH:54][CH:55]=1)[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:44][C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])([CH2:25][O:26][Si:27]([C:40]([CH3:42])([CH3:43])[CH3:41])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[O:24])=[C:15]([Cl:52])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(CO)(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(C=O)(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.7 %

Procedure:
The compound of Example 191 (940 mg) was dissolved in DMF (10 mL). To this solution, pyridinium dichromate (800 mg) was added and the mixture was stirred for 48 hours at room temperature. Following addition of water, the mixture was extracted with ethyl acetate. The extract was then washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel chlomatography (hexane:ethyl acetate=3:1) to give the desired product as a colorless oil (710 mg).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH:17]([OH:19])[CH3:18])[CH:13]=2)[CH:10]=1)([O-:5])=[O:4]>C(Cl)Cl.O=[Mn]=O>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][N:15]=[C:14]([C:17](=[O:19])[CH3:18])[CH:13]=2)[CH:10]=1)([O-:5])=[O:4]
Reactant: CC(O)c1cc(Cn2cc([N+](=O)[O-])cn2)on1
Agent: O=[Mn]=O
Agent: N#N
Solvent: ClCCl
Product: CC(=O)c1cc(Cn2cc([N+](=O)[O-])cn2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(4-nitro-pyrazol-1-ylmethyl)-isoxazol-3-yl]-ethanol (435 mg, 1.83 mmol) in CH2Cl2 (8.0 mL) was treated at rt with MnO2 (1.32 g, 13.70 mmol) and the reaction mixture was stirred for 16 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound. LC-MS-conditions 02: tR=0.87 min.
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=[N:7]O)[C:4](=[O:6])[CH3:5].[Cl:10][C:11]1[C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=[C:13]([CH3:19])[N:12]=1.O.C>C(#N)C>[Cl:10][C:11]1[C:16]([C:17]2[NH:18][C:2]([CH3:1])=[C:3]([C:4](=[O:6])[CH3:5])[N:7]=2)=[CH:15][CH:14]=[C:13]([CH3:19])[N:12]=1
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: Cc1ccc(CN)c(Cl)n1
Solvent: CC#N
Solvent: O
Product: CC(=O)c1nc(-c2ccc(C)nc2Cl)[nH]c1C
Temperature: 5 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
A mixture of 0.7 g of 2,3,4-pentanetrione 3-oxime and 0.9 g of 2-chloro-6-methyl-3-pyridylmethylamine in 50 ml of acetonitrile was stirred at the reflux temperature for 4 hours. The reaction mixture was evaporated in vacuo to give an oil. The oil was boiled in 50 ml. of water, treated with activated charcoal and filtered. The filtrate was cooled at 5° C. to yield a precipitate. The precipitate was collected, washed with cold water and dried to give 0.25 g of the product of the Example as a white solid, mp 156°-158° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH2:31]O)[CH:30]=1)[C:26]#[N:27]>C(#N)C>[Br:20][CH2:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([Cl:22])[CH:30]=1)[C:26]#[N:27]
Reactant: BrBr
Reactant: N#Cc1cc(Cl)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: N#Cc1cc(Cl)cc(CBr)c1
Reaction time: 0.5 h

Procedure:
(Step 3) Triphenylphosphine (0.94 g) was suspended in acetonitrile (20 ml), bromine (0.19 ml) was added, and the mixture was stirred for 30 min. A solution (10 ml) of 3-chloro-5-(hydroxymethyl)benzonitrile (0.60 g) obtained in Step 2 in acetonitrile was added to the reaction mixture, and the mixture was stirred at 80° C. for 4 hr. The reaction solution was quenched with water, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:2) to give 3-(bromomethyl)-5-chlorobenzonitrile (0.31 g) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15]1)=[O:11]
Reactant: CN=C=O
Reactant: Oc1nsc(-c2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)n1sc(-c2ccccc2)nc1=O
Temperature: 20 °C

Procedure:
0.5 ml of triethylamine and 10 ml of methyl isocyanate were added to a solution of 9 g of 3-hydroxy-5-phenyl-1,2,4-thiadiazole in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C for an hour and then was vacuum filtered. The crystals recovered were crystallized from acetic acid to obtain 10 g of 2-(N-methylcarbamoyl)-5-phenyl-1,2,4-thiadiazole-3-one melting at 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[C:11]([F:13])([F:12])[F:10])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cccc(Cl)c1)C(F)(F)F
Yield: 136.1 %

Procedure:
According to Reference Example 8-12, by use of 3-chlorobenzaldehyde (500 mg, 3.56 mmol), (trifluoromethyl)trimethylsilane (631 μL, 4.27 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 360 μL, 0.360 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 3 hours. Thus, 1-chloro-3-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound DB) (1.02 g, yield: quantitative) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.Cl.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[C:24](Cl)=[O:25]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]([C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH3:18])=[O:25])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1[nH]cnc1C(=O)Cl
Reactant: Cc1ccc(N)cc1Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2nc[nH]c2C)cc1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 740 g (5.22 moles) of 3-chloro-4-methylaniline and 1054.6 g (10.44 moles) of triethylamine in 10 liters of acetone at room temperature and vigorous stirring, there were added slowly 945 g (5.22 moles) of 5-methyl-4-imidazolecarbonyl chloride hydrochloride. After the addition was ended, the mixture was refluxed for 1 hour and then allowed to cool to room temperature and filtered. The liquid filtrate was evaporated until a slight precipitation appeared, it was then poured over 20 liters of cold water with stirring, filtered and the precipitate was dried to give N-(3-chloro-4-methylphenyl)-5-methyl-4-imidazolecarboxamide, a crude yellowish product. Crystallisation from isopropyl alcohol gave 1108 g (85% yield) of the desired pure product having the same characteristics as the one obtained in Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]2[S:12][C:11]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=[N:3]1.O.[NH2:21][NH2:22]>O>[CH3:1][C:2]1([CH2:7][C:8]2[S:12][C:11]([C:13]3[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=3)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=[N:3]1
Reactant: CC1(Cc2ccc(C(=O)CCC(=O)O)s2)N=CC=N1
Reactant: NN
Solvent: O
Product: CC1(Cc2ccc(C3=NNC(=O)CC3)s2)N=CC=N1
Temperature: 100 °C

Procedure:
A mixture of 3 g of 4-[5-(2-methyl-1-imidazolyl-methyl)-thien-2-yl]-4-oxobutyric acid, 0.54 ml of hydrazine hydrate and 50 ml water was heated for 2 hours at 100° C. After cooling the precipitated solid was filtered off, washed with water and dried.