Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]=O)[C:3]1=[O:14].[NH2:15][CH2:16][CH:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:15][CH2:16][CH:17]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]1=[O:14]
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(CN)c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)c(CNCC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc21
Reaction time: 16 h

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (0.590 g, 3.15 mmol), tert-butyl 4-(2-amino-1-phenylethyl)piperidine-1-carboxylate (1.2 g crude, 3.94 mmol), and acetic acid (0.677 ml, 11.83 mmol) were combined in CH2Cl2 (20 ml). Sodium triacetoxyborohydride (2.506 g, 11.83 mmol) was added and the reaction stirred for 16 hours. The mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The product was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Reaction time: 16 h
Yield: 68.6 %

Procedure:
To a solution of 4-methoxybenzenesulfonyl chloride (5.0 g, 24 mmol) and 4-chloroaniline (3.1 g, 24 mmol) in dichloromethane (24 mL) at 0° C. was added triethylamine (3.4 mL, 24 mmol) over 10 minutes. The ice bath was removed, and the mixture was stirred for 16 hr. The mixture was diluted with dichloromethane (100 mL) and the combined solution was washed with water (50 mL) and brine (50 mL). The organic solution was dried over MgSO4, filtered, and evaporated, and the crude product was purified by silica gel chromatography (15-60% EtOAc/Hex). Product-containing fractions were pooled, evaporated, and dried under high vacuum to yield 4.9 g (69%) of the product as a tan-colored oil: 1H-NMR (CDC3) δ 10.17 (s, 1H), 7.71 (d, 2H), 7.61 (d, 2H), 7.04 (d, 2H), 6.96 (d, 2H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)(=[O:39])=[O:38])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccn4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and pyridine-2-sulfonyl chloride to give the title compound as a colorless solid. MS: 520.2 ([M+H]+)
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:10]2[S:14][C:13]([NH2:15])=[N:12][N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:10]2[S:14][C:13]([N:15]=[C:1]=[O:2])=[N:12][N:11]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C2CCCC2)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclopentyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cyclopentyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>C([O-])(O)=O.[Na+]>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)cc(O)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(C)nc(O)c1

Procedure:
20.0 g (130.6 mmol) of 2-hydroxy-6-methylisonicotinic acid were dissolved in 200 ml of ethanol and treated with 20 ml of concentrated H2SO4. After the reaction mixture had been refluxed for two hours, it was freed from the solvent. The residue was taken up in saturated NaHCO3 solution and extracted three times with DCM. The combined organic phases were dried with Na2SO4 and concentrated, 20.1 g of the title compound being isolated.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[O-:6].[K+].Br[C:14]1[CH:19]=[C:18]([NH:20][C:21]([CH3:23])=[O:22])[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]=1[O:27][CH3:28]>CN(C=O)C.O>[NH:20]([C:18]1[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]([O:27][CH3:28])=[C:14]([O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[CH:19]=1)[C:21]([CH3:23])=[O:22]
Reactant: [O-]c1cccc(C(F)(F)F)c1
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Oc1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To the above solid 7 under argon, was added a solution of 3.0 g (10.4 mmol) of bromide 6 in 20 mL of DMF via cannula. The resulting solution was stirred at 120° C. for 1 day. TLC and NMR indicated the presence of a small amount of starting material 6. The reaction solution was cooled to room temperature and 2 mmol of compound 7 was added. The solution was stirred at 120° C. for 12 hour, diluted with 200 mL of ice and water, and the solid was collected by filtration, washed with water, dried under vacuum, and crystallized from ethanol to give 3.04 g (79% yield) of compound 8. 1H NMR (CDCl3) δ 10.4 (s, 1 H, NH), 8.39 (s, 1 H), 7.83 (s, 1 H), 7.5 (m, 2 H), 7.3 (m, 2 H), 3.93 (s, 3 H, OMe), 2.23 (s, 3 H, CH3). 13C NMR (CDCl3) δ 174, 155.7, 153.9, 142.4, 141.6, 130.9, 123.0, 121.7, 121.6, (116.9, 116.8, 116.7, 116.6 q for CF3), 108.7, 106.6, 56.7, 21.8.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][NH2:13]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][CH3:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CN
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Br)c(C)c1
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
4-Bromo-3-methylbenzoic acid (20 g) was added to a suspension of 1,1-carbonyldiimidazole (18.1 g) in dry THF (250 ml) at 5° C. and the resulting suspension stirred for 2.5 h at 5° C. Methylamine (33% w/v, solution in methanol 50 ml) was added dropwise over 5 min and the resultant mixture stirred at 23° for 15 h. The solution was evaporated and the residue treated with aqueous 2M-hydrochloric acid (150 ml). The mixture was extracted with ether (4×150 ml) and the combined, dried organic extracts were evaporated. The residue crystallised from hot ethyl acetate (~50 ml) to give the title compound as white crystals (8.7 g),
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28](OB(O)O)=[CH:27][C:26]=1[CH3:36])[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:27][C:26]=1[CH3:36])[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCOCCOc1c(C)cc(OB(O)O)cc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCOc1c(C)cc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(2-ethoxyethoxy)-3,5-dimethylphenylboric acid (0.71 g), cupric acetate (0.27 g) and molecular sieves 4A (0.8 g) suspended in dichloromethane (15 ml) was added triethylamine (1.0 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) as a light yellow oil.
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[C@H:5]([CH2:7][CH2:8][S:9][C:10]([F:13])([F:12])[F:11])[NH2:6]>CO>[F:11][C:10]([F:13])([F:12])[S:9][CH2:8][CH2:7][C@@H:5]([C:4]([NH2:1])=[O:3])[NH2:6]
Reactant: N
Reactant: COC(=O)[C@@H](N)CCSC(F)(F)F
Solvent: CO
Product: NC(=O)[C@@H](N)CCSC(F)(F)F
Temperature: -15 °C
Reaction time: 10 h
Yield: 89 %

Procedure:
5 ml of methanol was placed in an autoclave and cooled to −15° C., and ammonia gas was fed until methanol was saturated with the gas, to thereby prepare a solution of about 7 M ammonia in methanol. Trifluoromethionine methyl ester (50.4 mg, 0.199 mmol) was dissolved in methanol, and the solution was added to the solution of ammonia in methanol. The tube was sealed, and the mixture was stirred at 60° C. for 10 hours. The solvent was distilled off under reduced pressure, and recrystallization was performed with water, thereby 35.8 mg (89%) of trifluoromethionine amide(the general formula (II)) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:12](=[O:17])N(OC)C)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:12](=[O:17])[CH3:19])[CH2:9][CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of [1-(methoxy-methyl-carbamoyl)-cyclobutyl]-carbamic acid tert-butyl ester (11.5 g, 44.6 mmol) in THF (150 mL) at 0° C. was slowly added methylmagnesium bromide as a 3.0M solution in ether (37.2 mL, 111 mmol). The reaction was allowed to slowly warm to 25° C. and stirred for 24 h then quenched by the addition of saturated aqueous NH4Cl (100 mL). EtOAc (200 mL) was added and the layers were separated. The aqueous phase was extracted two more times with EtOAc. The organic layers were combined, washed with brine, dried (Na2SO4), decanted and concentrated to afford a solid. The solid was purified via normal phase flash chromatography on silica gel (10-50% EtOAc-heptane) to afford (1-acetyl-cyclobutyl)-carbamic acid tert-butyl ester as a white solid (6.02 g, 63%).
Reaction SMILES: Cl.N[CH2:3][CH2:4][SH:5].[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([C:24]#[N:25])[C:8]=1[S:26]([CH3:28])=[O:27]>CO>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([CH:24]2[NH:25][CH:3]=[CH:4][S:5]2)[C:8]=1[S:26]([CH3:28])=[O:27]
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: NCCS
Agent: Cl
Solvent: CO
Product: CS(=O)c1c(C2NC=CS2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of 0.297 gram (0.00261 mole) of 2-aminoethanethiol hydrochloride in 2.5 milliliters of methanol was added to 1.0 gram (0.00261 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile, and the mixture was stirred at room temperature for an approximately 17-hour period. The mixture was partitioned between water and dichloromethane and the organic layer was separated, dried over Na2SO4 and filtered. Solvent was evaporated leaving a residue which was purified by preparative thin-layer chromatography to give 0.186 gram (0.00042 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-(dihydro-2-thiazolyl)-4-methylsulfinyl-1H-pyrazole having a melting point of 189.5° C. (with decomposition). This compound is referred to hereinafter as Compound 1.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1.[C-:21]#[N:22].[Na+].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=2[C:21]#[N:22])[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: [C-]#N
Reactant: CCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2C#N)CC1

Procedure:
To a solution of 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-propylpiperidine (1.57 g, 5.4 mmol) in N,N-dimethylformamide (35 ml) was added sodium cyanide (1.0 g, 20 mmol) and 18-crown-6-ether (50 mg). The mixture was heated at reflux for 15 h and then brought to ambient temperature. Aqueous sodium carbonate (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethylacetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound: 0.72 g (45%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 272-274° C. MS m/z (relative intensity, 70 eV) 296 (M+, 4), 268 (16), 267 (bp),204 (3), 184 (3).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4](Br)[N:3]=1.O.[NH2:18][NH2:19]>CCO>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: NN
Reactant: Cc1nc(N2CCN(C)CC2)c(Br)nc1Br
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCN(C)CC2)c(NN)nc1Br
Yield: 53.6 %

Procedure:
A 100 mL round bottom flask was charged with 2,6-dibromo-3-methyl-5-(4-methylpiperazin-1-yl)pyrazine (2.0 g, 5.7 mmol), hydrazine hydrate (3.5 g, 0.065 mol) and absolute EtOH (30 mL). The resulting solution was refluxed under N2 atmosphere overnight. Work-up: the solvent was evaporated. The residue was washed with EtOH (10 mL) and dried, to afford 0.92 g (54%) of the product as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
In a 25 ml round-bottomed flask, 1H-indazole-5-carbonitrile (400 mg, 2.79 mmol) was dissolved in DMF (7 ml). Potassium hydroxide (607 mg, 10.8 mmol) was added followed by iodine (1.42 g, 5.59 mmol). The dark brown suspension was stirred at room temperature for 3 h then was quenched with 10% aqueous NaHSO3 and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 396 mg (53%) of 3-iodo-1H-indazole-5-carbonitrile as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Reactant: Cc1ccc(N)nc1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of (R)-N-(2,3-dichloro-4-chlorosulphonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (200 mg, 0.5 mmol) (Method 1) and 2-amino-5-methylpyridine (81 mg, 0.80 mmol) in pyridine (5 ml) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, poured onto water (50 ml) and extracted with EtOAc (2×25 ml). The organic layer was separated, washed with 1 M aqueous hydrochloric acid, saturated sodium hydrogen carbonate solution, brine, dried and evaporated to give the title compound as a solid (40 mg, 0.08 mmol); NMR: 1.6 (s, 3H), 2.1 (s, 3H), 7.1 (d, 1H), 7.6 (d, 1H), 7.75 (s, 1H), 8.1 (s, 2H); m/z 470.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CN(C=O)C.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>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccccc1
Temperature: 100 °C
Yield: 57.7 %

Procedure:
2-Bromo-4-nitrotoluene (2.16 g, 10.00 mmol) and phenylboric acid (1.46 g, 12.00 mmol) were dissolved in anhydrous DMF (25 mL) under nitrogen. To this mixture was added Pd(Ph3P)4 (0.58 g, 5%). The mixture was heated at 100° C. overnight. The solution was poured onto 1N HCl and extracted with Et2O. The crude product was chromatographed on silica gel using hexanes as eluent. After recrystallization from ethanol, the desired product (1.23 g) was obtained as pale orange needles: m.p. 69-71° C.; 1H NMR (CDCl3) d 2.36 (3H, s), 7.29-7.40 (2H, m), 7.41-7.49 (5H, m), 8.07-8.10 (2H, m); 13C NMR (CDCl3) d 20.68, 121.96, 124.51, 127.78, 128.41, 128.83, 131.06, 139.06, 139.44, 142.97, 143.48, 146.05; Anal. Calc. for C13H11NO2, C: 73.26, H: 5.20, N: 6.57; Found, C: 73.10, H: 5.12, N: 6.50; m/z (EI) 213; HRMS Calc. for C13H11NO2, 213.0790; Found, 213.0793.
Reaction SMILES: Br[C:2]1[N:7]2[C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]3[C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccncc1
Reactant: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(Br)n12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(-c3ccncc3)n12
Temperature: 100 °C
Yield: 19.8 %

Procedure:
Triazolopyridinone 2-4 (40 mg, 0.11 mmol) and pyridin-4-ylboronic acid (27 mg, 0.22 mmol) were placed in a microwave vial and dissolved in dioxane (1 mL). To the mixture was added 1 M aq. Cs2CO3 solution (0.22 mL, 0.22 mmol). The mixture was then sparged with N2 gas for 3 min, and bis(tri-tert-butylphosphine)palladium (5.5 mg, 0.011 mmol) was added. The vial was capped and heated at 100° C. under microwave irradiation for 30 min. After cooling, the reaction mixture was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (12 g cartridge), eluting with 0-10% MeOH/CH2Cl2. The fractions containing the desired product (5-1) were pooled, and after solvent removal in vacuo, 8.0 mg (20%) of a yellow solid were obtained. 1H NMR (400 MHz, CHCl3-d): δ 8.63 (dd, J=4.9, 1.5 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68 (ddd, J=8.4, 6.8, 1.6 Hz, 1H), 7.53-7.48 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.26 (d, J=6.0 Hz, 2H), 7.16 (d, J=9.6 Hz, 1H), 7.08 (dd, J=9.6, 6.4 Hz, 1H), 6.36 (d, J=6.4 Hz, 1H), 4.49 (t, J=7.2 Hz, 2H), 3.51 (t, J=7.2 Hz, 2H). HRMS (ES) 368.1508 (M+H) found, 368.1509 required.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:9]1[CH:10]=C([CH:15]=[CH:16][C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])C(O)=O)#[N:8].CN(C=O)C>C(Cl)Cl>[C:7]([C:9]1[CH:10]=[C:1]([CH:15]=[CH:16][C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])[C:2]([Cl:4])=[O:3])#[N:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.224 ml, 2.56 mmol) was added to a stirred solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (which can be prepared as described in WO2005/58848, 500 mg, 2.437 mmol) in DCM (10 ml), followed by DMF (20 μl) and the resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated to give the title compound (545 mg, 100%) as an olive green solid which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=O)C>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[CH2:31][CH2:32][N:28]([CH3:25])[C:29]4=[O:33])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)c(F)c3)CC2)c(C)c1
Yield: 72.5 %

Procedure:
Using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (839 mg) described in Preparation Example 125 and 1-acetylimidazolidin-2-one (329 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (638 mg) was obtained.