Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH2:12][C:13](=[CH:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH2:12][C:13](=[CH:14][C:15]([OH:17])=[O:16])[C:8]2=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 32 mg (0.0627 mmol) of tert-butyl ester (the title compound of Example 15) in 2 mL of CDCl3 at room temperature was added 0.5 mL of TFA, and the progress of the reaction was monitored by 1H NMR. The resulting yellow solution was stirred at room temperature for 1 h and concentrated in vacuo. The crude product was dissolved in a minimum amount of methanol, diluted with methylene chloride, then triturated with ether and hexane at 5° C. to give 27 mg (96%) of the title compound of Example 16 as a solid: mp 154.0°-155.5° C. (decomposed); 1H NMR (CD3OD) δ 0.84 (t, J=7.5 Hz, 3H), 1.2-1.45 (m, 2H), 1.45-1.63 (m, 2H), 2.25-2.55 (m, 3H), 2.60-2.9 (m, 2H), 3.52-3.7 (m, 1H), 5.95 (br s, 1H), 6.59 (s, 1H), 6.99 (d, J=7.5 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 7.50-7.62 (m, 2H), 7.67 (d, J=7.2 Hz, 2H), 8.16 (s, 1H); HRMS. calcd for M+H: 455.2195. Found: 455.2195.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCc2c[nH]c(C(=O)O)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1nc(CCCc2ccc(O)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A solution of the ethyl ester of 13e (1.15 g, 4.0 mmol) in dry dichloromethane (50 ml) was treated with boron tribromide (16 ml, 1.0M solution in CH2Cl2, 16.0 mmol) at 0° C. After 15 min at 0° C., the mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was cooled in an ice bath and quenched with a dropwise addition of water (20 ml). The resulting mixture was briefly stirred at 25° C. then filtered. The filtrate was carefully neutralised by the addition of solid NaHCO3 to afford 13f (700 mg, 71%) as a white solid: m.p. 186-187° C. (decomp.) (recrystallised from MeOH); IR (KBr) 3500-2400, 2935, 1640, 1516, 1396, 1232; 1H NMR (d6-DMSO) δ 9.83 (3H, bs), 7.16 (1H, s), 6.98 (2H, d, J=8.2), 6.66 (2H, d, J=8.2), 2.60-2.40 (4H, m), 1.84 (2H, m). Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 62.96; H, 5.70; N, 11.27.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1([C:11](=[O:25])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:9]1)=[O:7]>CO.C1COCC1.O>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:18][C:13]([NH:12][C:11]([C:8]2([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]2)=[O:25])=[CH:14][CH:15]=1
Reactant: COC(=O)C1(C(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(C(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
LiOH.H2O (21 mg, 0.5 mmol) was added to a solution of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester (100 mg, 0.33 mmol) in methanol (0.5 mL), THF (1 mL) and H2O (0.3 mL) and the resulting mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then concentrated and the residue was diluted with water, acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 55 mg (58%) of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:36]([NH:39][C@@H:40]1[CH2:44][NH:43][C@H:42]([CH2:45][OH:46])[CH2:41]1)(=[O:38])[CH3:37].CS(C)=O.CC#N>C(O)(C(F)(F)F)=O>[C:36]([NH:39][C@@H:40]1[CH2:44][N:43]([C:21]2[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=3)([CH3:33])[CH3:32])=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:22]=2)[C@H:42]([CH2:45][OH:46])[CH2:41]1)(=[O:38])[CH3:37]
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: CC(=O)N[C@@H]1CN[C@H](CO)C1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)N[C@H]1C[C@@H](CO)N(c2cc(-c3ccccc3Cl)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1
Temperature: 130 °C
Yield: 59.8 %

Procedure:
A mixture of 30 mg (0.056 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 200 mg (1.27 mmol) (2S,4S)-4-acetylamino-2-hydroxymethyl-pyrrolidine and 0.2 ml dimethyl sulfoxide was heated at 130° C. for 24 h. After cooling to room temperature, 22 mg (59%) of the title compound were isolated as a white solid by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min). (2S,4S)-4-Acetylamino-2-hydroxymethyl-pyrrolidine can be obtained by the method described by Terry Rosen, Daniel T. W. Chu, Isabella M. Lico, Isabella M. Lico, Prabhavathi B. Fernandes, Kennan Marsh, Linus Shen, Valerie G. Cepa, André G. Pernet, J. Med. Chem. 1988, 31, 1598. MS m/e (%): 657 (M+H+)
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:22]Cl)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]=1[Br:7].[OH-].[Na+].O.O.[CH3:28][N:29]([CH3:33])[C:30](=[S:32])[S-:31].[Na+].CN(C)C=O>O>[CH3:28][N:29]([CH3:33])[C:30](=[S:31])[S:32][CH2:22][N:3]1[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]([Br:7])=[C:2]1[Br:1]
Reactant: CN(C)C(=S)[S-]
Reactant: O=S(=O)(c1c(Br)c(Br)n(CCl)c1-c1ccc(Cl)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=S)SCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.7 %

Procedure:
2,3-Dibromo-1-(chloromethyl)-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00194 mol) is added to a mixture of sodium hydroxide (0.084 g, 0.0021 mol), sodium dimethyldithiocarbamate dihydrate (0.376 g, 0.0021 mol) and dimethylformamide. The reaction mixture is stirred for six hours at room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow gum. The gum is stirred with hexanes overnight and filtered to give the title product as a white solid (0.37 g, mp 185°-187° C.) which is identified by 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15].C(O)C.Cl>[OH-].[Na+]>[C:9]([CH2:8][CH2:7][C:6]1[CH:12]=[CH:13][C:3]([CH:1]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:4][CH:5]=1)([OH:11])=[O:10]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(CCC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 5.34 g of 4-formyldihydrocinnamic acid in 50 ml of 1N sodium hydroxide was added a solution of 3.6 g of acetophenone and 20 ml of ethanol. The reaction mixture was stirred at room temperature for 4 hrs. and then poured onto 300 g of crushed ice. 1N Hydrochloric acid was added and, after stirring at 0° C for 15 min., the precipitate was collected and washed with water. The precipitate was dissolved in 500 ml of ethyl acetate, dried over anhydrous sodium sulfate and the drying agent was collected on a filter. The filtrate was concentrated to about 100 ml and seeded with crystalline product. The solid was collected, washed with 1:4-ethyl acetate-ether followed by ether and dried at 70°-75° C under vacuum to give 8.4 g (72%) of 4-(2-carboxyethyl)benzalacetophenone, as yellow needles, m.p. 159°-160° C.
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20](=O)[CH:21]=[CH:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]=[C:20]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=C(C=CSc1ccccc1)Nc1ccc2c(c1)CCC2
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C(=CC(=Nc1ccc2c(c1)CCC2)Sc1ccccc1)Sc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Thionyl chloride (0.75 mL) and DMF (catalytic amount) were added to a solution of N-(5-indanyl)-3(phenylthio)acrylamide (1.21 g) in toluene (50 mL) at room temperature, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added THF (40 mL), and then a solution (0.62 mol/L, 10 mL) of phenylmercaptan sodium salt in THF was added thereto under ice-cooling. The mixture was stirred at room temperature for 2 hours, and then alkalilized by addition of a 1N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate (250 mL). The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=100:1 to 50:1) to obtain phenyl N-(5-indanyl)-3-(phenylthio)thioacrylimidate (Z-isomer: 0.27 g, E-isomer: 0.94 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.Br[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[N:29][CH:30]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][C:25]5[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][CH:26]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: Cc1ccc(Br)cn1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
A stirred suspension of Example 42 (0.050 g, 0.15 mmol), 5-bromo-2-methylpyridine (0.052 g, 0.30 mmol), palladium(II) acetate (0.010 g), 2-bis(dicyclohexylphosphino)biphenyl (0.030 g) and sodium tert-butoxide (0.044 g, 0.46 mmol) in toluene (5 mL) was heated to 120° C. in a sealed tube, under microwave irradiation, for 5 h. After cooling to r.t., the reaction mixture was concentrated in vacuo. Purification by preparative HPLC (Method 7), gave the title compound (0.0178 g, 28%) as an off-white solid. δH (CDCl3) 8.30 (1H, s), 7.80 (1H, s), 7.30 (1H, dd, J 8.5 and J 3.0 Hz), 7.10 (1H, d, J 8.5 Hz), 6.90 (1H, d, J 8.5 Hz), 6.80 (1H, dd, J 8.7 and J 2.4 Hz), 5.60 (1H, br. s), 5.20 (1H, br. s), 4.40 (1H, m), 4.10 (2H, m), 2.90 (2H, m), 2.50 (3H, s), 1.40 (6H, s). LCMS (ES+) 422.0 (M+H)+, RT 3.10 minutes (Method 2).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:1]=1[CH3:9])[C:7]#[N:8])([O-:12])=[O:11]
Reactant: Cc1ccc(C#N)cc1
Reactant: O=[N+]([O-])O
Product: Cc1ccc(C#N)cc1[N+](=O)[O-]

Procedure:
399 g (2.56 mol) of p-toluonitrile were added over the course of 90 minutes to 1 l of fuming nitric acid at -10° C. 1 h after the addition, the mixture was poured onto 2.5 l of ice/H2O, whereupon a solid precipitated and was removed on a suction filter funnel and washed to neutral pH with water. The yield of the product was 363 g (88%). 1H-NMR (CDCl3 ; δ in ppm): 8.3 (d, 1H); 7.8 (dd, 1H); 7.5 (dd, 1H); 2.7 (s, 3H)
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=O)([F:7])[F:6]>C(O)C.N1C=CC=CC=1.O>[F:4][C:5]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[N:2][OH:3])([F:7])[F:6]
Reactant: NO
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: ON=C(c1cccc(C(F)(F)F)c1)C(F)(F)F

Procedure:
7.8 g of hydroxylamine hydrochloride are dissolved in 250 ml of a mixture of ethanol and pyridine and to this solution 7 g (m-trifluoromethyl phenyl) trifluoromethyl Ketone are added. The mixture is heated to reflux for 16 hours, then cooled and diluted with 100 ml water. The oxime precipitates and is separated by filtration, dried, washed with water many times, and dried again. The yield amounts to 42%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[NH:17]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[NH2:18]>N1C=CC=CC=1.CO>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:16])[CH2:9][C:10]([CH2:11][CH2:12][CH2:13][OH:14])=[N:18]1
Reactant: NNc1nc2ccccc2s1
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CO
Product: OCCCC1=NN(c2nc3ccccc3s2)C(O)(c2ccc(Cl)cc2)C1
Reaction time: 48 h

Procedure:
6-(4-Chlorophenyl)-4,6-diketohexanol (7.2 g, 30 mM) was treated with 2-hydrazinobenzothiazole (4.96 g, 30 mM) in pyridine (5 ml) and MeOH (150 ml) at reflux for 2 hr and then allowed to stand at RT for 48 hr. The solvents were removed in vacuo and the crude residue purified by flash chromatography on silica with Et2O:Et3N (2.5%) as eluent. The title compound (1) was obtained as a pale yellow solid, (3.15 g, mp=132°-134° C.) upon recrystallization from Et2O:hexane. NMR(CDCl3) δ 3.2 (2H, C4 -H); MS, m/e 387 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[CH3:10][N:11]=[C:12]=[S:13]>C(O)C>[CH3:10][NH:11][C:12]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[S:13]
Reactant: CN=C=S
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CCO
Product: CNC(=S)Nc1c(Cl)cccc1Cl

Procedure:
130 g of 2,6-dichloro-aniline, 100 g of methyl isothiocyanate and 300 ml of 95% ethanol are refluxed during 14 hours, with stirring. The resulting solution is cooled in the freezer: the white solid formed is filtered and washed with isopropyl oxide. After recrystallization from isopropanol, 65 g of product (III : R = CH3), m.p. = 184° C, are collected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([NH2:12])=[N:6][NH:7]2.CC(N(CC1C=CC(CN2C3C(=C(OC)C=CC=3)C(NS(C3SC(Cl)=CC=3)(=O)=O)=N2)=CC=1)C(=O)[O-])(C)C.[OH-].[K+].Cl[CH2:53][C:54]1[CH:62]=[CH:61][C:57]([C:58]([NH2:60])=[O:59])=[CH:56][CH:55]=1>CS(C)=O.O>[NH2:12][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[N:7]([CH2:53][C:54]2[CH:62]=[CH:61][C:57]([C:58]([NH2:60])=[O:59])=[CH:56][CH:55]=2)[N:6]=1
Reactant: COc1cccc2[nH]nc(N)c12
Reactant: NC(=O)c1ccc(CCl)cc1
Agent: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CN(C(=O)[O-])C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc2c1c(N)nn2Cc1ccc(C(N)=O)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.816 g, 5 mmol) in DMSO (50 mL) at room temperature under nitrogen was added potassium hydroxide (0.561 g, 10.0 mmol). After stirring the resulting deep red solution for 25 min 4-(chloromethyl)benzamide (0.848 g, 5.00 mmol) was added in one portion. The reaction mixture was stirred for a further 30 min and then poured into water (250 mL), forming an emulsion. The reaction mixture was extracted using chloroform (3×250 mL). The combined organic solutions were washed with water (250 mL) and passed through hydrophobic frit. The solvent was removed in vacuo and the residue was loaded in dichloromethane to a silica (100 g) cartridge and purified by chromatography on Flashmaster eluting with 0-100% ethyl acetate-cyclohexane+0-20% methanol-ethyl acetate over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.18 g, 80%). LCMS: (System A) RT=0.69 min, ES+ve m/z 297 (M+H)+.
Reaction SMILES: N[C:2]1[N:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.N([O-])=O.[Na+].C(Cl)(Cl)Cl.[FH:21].N1C=CC=CC=1>>[F:21][C:2]1[N:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1nc(N)cnc1C(N)=O
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1nc(F)cnc1C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, 0.5 g of 5-amino-3-methoxy-2-pyrazinecarboxamide is dissolved in 9 mL of 70% pyridine hydrofluoride under ice-cooling. Then, 0.23 g of sodium nitrite is added thereto at −70° C., and the resulting solution is heated to a temperature of −10° C. in 30 minutes. Further, the solution is stirred at ambient temperature for 30 minutes. A mixture of 30 mL of ice water and 100 mL of chloroform is added thereto and the resulting mixture is separated into layers. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform:methanol =10:1) to obtain 0.37 q of 5-fluoro-3-methoxy-2-pyrazinecarboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][N:16]1[C:12]([C:10]([NH:9][C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:20]3[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=3)[C:25]([OH:27])=[O:26])[CH:8]=[CH:7][CH:6]=2)=[O:11])=[CH:13][C:14]([CH3:18])=[N:15]1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: O=C(O)c1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)O)c3)c2)n(C)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 11.8 %

Procedure:
In a 50 mL round bottom flask, N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (0.888 g, 3.71 mmol) and 5-bromo nicotinic acid (0.50 g, 2.47 mmol) were dissolved in DMF (15 mL) The mixture was then degassed by bubbling N2(g) through it for ˜20 min. The mixture was then treated sequentially with NEt3 (1.37 mL, 9.90 mmol), Pd(PPh3)2Cl2 (0.173 g, 0.247 mmol) and CuI (0.094 g, 4.95 mmol). The reaction mixture was allowed to stir at 50° C. for 4 h. The reaction mixture was diluted with EtOAc (25 mL) causing a pale yellow precipitate to form. The white precipitate was filtered off giving the title compound (0.105 g, 12%).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([O-:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[K+].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C>[CH:21]1([NH:27][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:19][CH:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C([O-])c1ccc(Cn2cnc3ccccc32)cc1
Reactant: NC1CCCCC1
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
A stirred suspension of crude potassium 4-(1H-benzimidazylmethyl)benzoate (0.49 g, 1.7 mmol) in dry DMF (10 ml) under argon was treated with cyclohexylamine (0.2 g, 2.0 mmol) and triethylamine (0.34 g, 3.4 mmol). The solution was cooled to -5° C. and DPPA (0.53 g, 1.9 mmol) in DMF (10 ml) was added. The solution was allowed to warm to room temperature, stirred overnight and concentrated to give the crude product. Chromatography (silica gel, ethyl acetate) followed by crystallisation from toluene gave N-cyclohexyl 4-(1H-benzimidazylmethyl)benzamide (91 mg, 16%) as a white crystalline solid.
Reaction SMILES: [CH2:1]([N:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH2:1]([N:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)[CH:19]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(c1ccccc1)N(Cc1ccccc1)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)N(Cc1ccccc1)c1cccc(N2CCN(c3ccccc3)CC2)c1
Yield: 79.3 %

Procedure:
A solution of N-benzyl-N-(3-bromo-phenyl)-benzene sulfonamide (25 mg, 0.06 mmol), 1-phenyl-piperazine (0.011 ml, 0.074 mmol), palladium acetate (1 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (2 mg) and sodium tert-butoxide (21 mg, 0.22 mmol) in dioxane (4 ml) were refluxed overnight. The reaction was quenched with water (5 ml) and extracted with dichloromethane (3×6 ml). The organic extracts were combined, filtered then concentrated in vacuo and the residues purified by preparative TLC (SiO2) eluting with dichloromethane to afforded the title compound as a yellow solid (23 mg, 77%) HPLC retention time 9.4 min. Mass spectrum (ES+) m/z 484 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][S:41]([CH:38]([CH3:40])[CH3:39])(=[O:43])=[O:42])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NS(=O)(=O)C(C)C)cc1
Temperature: 65 °C

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 13, Step C) and isopropylsulfonyl chloride according to the procedure of Example 14, except that the mixture was heated overnight at 65° C. Flash chromatography of the crude product on silica gel gave the title compound as a glass; satisfactory purity by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 659 (M+Na)+, 675 (M+K)+.