Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].CC([O-])=O.[Na+].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[C:15]([F:21])[CH:14]=1>O.CO>[Br:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[N:2]/[NH:3][C:4]([NH2:6])=[O:5])=[C:15]([F:21])[CH:14]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)N/N=C/c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of aminourea hydrochloride (2.8 g, 25 mmol) and NaOAc (4.1 g, 49 mmol) in water (50 mL) was added dropwise a solution of 4-bromo-2-fluorobenzaldehyde (5.0 g, 25 mmol) in methanol (50 mL). The resulting solution was stirred at rt for 3 h. The solids formed were collected by filtration to obtain compound 59a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H7BrFN3O: 260.0 (M+H). Found: 260.1.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:42])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH:20]=[CH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4Br)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:30])[C:12]=2[C@H:31]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C>[C:38]([O:37][C@@H:31]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:42])([O:4][CH2:1][CH:2]=[CH:3][C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH:21]=[CH:20]3)[CH2:6][CH2:7]1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:40])([CH3:41])[CH3:39]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(C=CCc4ccccc4Br)nn23)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=Cc1ccccc1CC=C3
Temperature: 120 °C
Yield: 51.8 %

Procedure:
To a pressure tube flushed with N2 were added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-(2-bromophenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.09 g, 0.141 mmol), acetonitrile (4 ml) and triethylamine (0.196 ml, 1.407 mmol). Added to this solution were triphenylphosphine (0.011 g, 0.042 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.013 g, 0.014 mmol). The tube was sealed and stirred at 120° C. After stirring for 20 h, the mixture was cooled, filtered and concentrated to give a yellow residue. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give the title compound (0.0406 g, 0.073 mmol, 51.6% yield) as a sticky yellow oil. LCMS (M+H) calcd for C33H43N4O4: 559.32. found: 559.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:5][C:4]=1[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1CCOc1ccc(C(F)(F)F)cc1
Reactant: O=C1CSC(=O)N1
Product: COc1ccc(CC2SC(=O)NC2=O)cc1CCOc1ccc(C(F)(F)F)cc1

Procedure:
Using 4-methoxy-3-{2-[4-(trifluoromethyl)phenoxy]ethyl}benzaldehyde and 2,4-thiazolidine dione, 5-(4-methoxy-3-2-[4-(trifluoromethyl)phenoxy]ethylbenzyl)-1,3-thiazolane-2,4-dione was obtained in the same method as in Production Example 27c) and then in Example 29).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:30][CH2:29][CH2:28][C@H:10]1[C:11]([NH:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:24])[NH:20][N+]([O-])=O)=[O:12])=[O:8].CO.Cl>[Pd].O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:30][CH2:29][CH2:28][C@H:10]1[C:11]([NH:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:24])=[O:12])=[O:8]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1)C(=O)O
Reaction time: 5 h
Yield: 126.2 %

Procedure:
After 0.60 g (0.87 mmol) of Z-PyroGlu-Pro-Arg(NO2)-CHA was suspended in a solvent mixture of 112.5 ml of MeOH, 35.8 ml of H2O and 1.7 ml of 1N-HCl, 1 g of palladium black was added to the suspension followed by catalytic reduction at 30° C. for 5 hours. After the reaction, the catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was purified through TOYOPEARL HW40F column using MeOH as a developing solvent to give 0.42 g (87.5%) of H-PyroGlu-Pro-Arg-CHA.HCl
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[N:21]=[C:20]4[C:16]([C:14]([NH:13][C:10]([CH3:12])([CH3:11])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]4=[N:24][CH:23]=3)=[N:26][N:27]2[CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:32][CH:31]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a stirred solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 0.042 mmol) in DCM (2 mL) was added trifluoroacetic acid (1 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The residue obtained was dissolved in DCM, washed with NaHCO3 (aq.), and then the organic layer was concentrated and purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; 25% acetonitrile/75% water (doped with 0.1% TFA, v/v) to 42% acetonitrile/58% water (doped with 0.1% TFA, v/v) over 9 min) to give 2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (10 mg, 50%) as a white solid. 1H NMR (300 MHz, DMSO): δ 12.81 (s, 1H), 9.10 (s, 1H), 8.63-8.58 (m, 1H), 8.37 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H, J=8.1 Hz), 7.16 (t, 1H, J=9.2 Hz), 5.08 (t, 1H, J=5.5 Hz), 4.62 (t, 2H, J=6.6 Hz), 3.60 (d, 2H, J=5.4 Hz), 3.18 (t, 2H, J=6.4 Hz), 2.96 (s, 3H), 2.32 (t, 2H, J=7.6 Hz), 1.43 (s, 6H). LC/MS: 489.2 [M+H]+, 487.0 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:18]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH3:21])=[O:19]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])/[CH:22]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC/C(=C\C=O)c1ccc(OC)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-octenal (6 g) was treated with (carbomethoxymethylene)triphenylphosphorane (9.5 g) in carbon tetrachloride (60 mL) for 4 days at room temperature. The ester was isolated in the normal manner and purified by HPLC (ether-hexane; 1:7.5) to furnish 6.1 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][Cl:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCCCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.2 ml (20 mmol) amount of thionyl chloride was added dropwise to a methylene chloride solution (30 ml) containing 3 g (20 mmol) of 4-phenyl-1-butanol and stirred overnight at room temperature. The reaction solution was washed with water, an aqueous 50% sodium hydrogen carbonate solution, water, 1N hydrochloric acid and water in that order, and then the solvent was dried with anhydrous magnesium sulfate. After distillation under reduced pressure, 3.62 g of a crude 4-phenylbutyl chloride was obtained. This material was used in the next reaction without being further purified.
Reaction SMILES: N[C@@H](C)CNC1SC([C:11](OCC)=[O:12])=C(C)N=1.[NH2:17][CH2:18][C@@H:19]([NH:21][C:22]1[S:23][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=1)[CH3:20]>>[CH3:27][C:25]1[N:26]=[C:22]([N:21]2[C@@H:19]([CH3:20])[CH2:18][NH:17][C:11]2=[O:12])[S:23][C:24]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1sc(NC[C@H](C)N)nc1C
Reactant: CCOC(=O)c1sc(N[C@@H](C)CN)nc1C
Product: CCOC(=O)c1sc(N2C(=O)NC[C@@H]2C)nc1C

Procedure:
Following the procedure as described in Preparation 4, making variations as required to replace (S)-ethyl 2-(2-aminopropylamino)-4-methylthiazole-5-carboxylate with (S)-ethyl 2-(1-aminopropan-2-ylamino)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (52%): MS (ES+) m/z 269.7 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1([CH3:19])[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[NH:10][C:9](=[O:18])[CH2:8]1.C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([OH:28])=[O:27]>>[CH3:6][C:7]1([CH3:19])[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[C:14]([N+:26]([O-:28])=[O:27])[CH:15]=2)[NH:10][C:9](=[O:18])[CH2:8]1
Reactant: Cc1cccc2c1NC(=O)CC2(C)C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc2c1NC(=O)CC2(C)C

Procedure:
A mixture of concentrated nitric acid (10 cm3, S.G.=1.42) and 98% w/w sulphuric acid (25 cm3) was added dropwise to a stirred solution of 3,4-dihydro-4,4,8-trimethyl-2-(1H)-quinolone (6 g) in 98% w/w sulphuric acid (25 cm3) cooled to -10°. The temperature was maintained at -10° for a further 30 minutes, the mixture poured onto ice (200 g), basified to pH 9 with saturated sodium carbonate solution and extracted with methanol:chloroform, 1:20 by volume (2×300 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give the title compound (6.46 g) which was characterised spectroscopically and used directly in Preparation 24 without further purification.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[OH2:50]>N1C=CC=CC=1>[C:1]1([S:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[O:50])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Sc2ccccc2)cc1
Reactant: O
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a suspension of 4-(phenylthio)benzoic acid (800 mg, 3.5 mmol) in pyridine (5 mL) and water (5 mL) was added N-phenyl-N,N,N-trimethylammonium tribromide (1.4 g, 3.7 mmol). The mixture was stirred at 20° C. for 12 hours. Then the solvent was evaporated in vacuo to give 4-(phenylsulfinyl)benzoic acid which was used directly without further purification. LRMS (M+H)− m/z: calcd 246.04. found 246.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[C:9]1[C:17]2[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[C-:30]#[N:31].[K+]>CS(C)=O>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:8]([C:9]1[C:17]2[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)[CH2:7][CH2:6][C:30]#[N:31]
Reactant: [C-]#N
Reactant: CSCc1cc(F)cc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1.36 g (2.86 mmol) of the compound from Example 58A and 372 mg (5.71 mmol) of potassium cyanide were dissolved in 65 ml of DMSO and stirred at 120° C. overnight. The mixture was concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 790 mg (68% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19](I)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:22]([NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:10]=3)[CH:20]=2)[CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
N-tert-Butyl-3-{1-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.74) (0.37 g, 0.86 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.33 g, 1.29 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.23 g) which was subsequently deprotected.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:1]1([C:7]2[N:11]=[CH:10][N:9]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2cnc[nH]2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A solution of 5-phenyl-1H-imidazole (504 mg, 3.5 mmol) in DMF (10 mL) was cooled to 0° C., and then NEt3 (530 mg, 5.25 mmol) was added, followed by the addition of (chloromethanetriyl)tribenzene (1.17 g, 4.2 mmol) in small portions. The resulting slurry was stirred at room temperature for 2 hours. The mixture was poured into ice-water (50 mL) and stirred until the ice melted. The resulting precipitate was collected and dissolved in DCM (100 mL). The solution was dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to obtain 4-phenyl-1-trityl-1H-imidazole as a white solid (1.0 g). MS (ESI): m/z 387 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][CH:24]([O:36][CH3:37])[CH2:25][C:26]1[N:31]=[C:30]2[CH2:32][O:33][C:34](=O)[C:29]2=[CH:28][CH:27]=1.OS(O)(=O)=O>C1COCC1>[CH3:37][O:36][CH:24]([O:23][CH3:22])[CH2:25][C:26]1[N:31]=[C:30]2[CH2:32][O:33][C:34](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:29]2=[CH:28][CH:27]=1
Reactant: COC(Cc1ccc2c(n1)COC2=O)OC
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (141 mg, 0.93 mmol.) in THF (4 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.9 mL of a 1 M solution in THF, 1.9 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 2-(2,2-dimethoxy-ethyl)-7H-furo[3,4-b]pyridin-5-one (104 mg, 0.47 mmol in THF (1 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 1.5 h and is then poured into cold aqueous 2N H2SO4 solution (10 mL) at 0° C. The resulting mixture is heated at 45° C. for 30 min and then cooled to room temperature and stirred overnight. The reaction mixture is poured into ice water (150 mL) and stirred for 2 h. The solid which formed is collected to give the title compound as a brown solid (76 mg, 46%).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:8]=2[CH:7]=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:30])C=1.O.[OH-].[Na+]>C(Cl)Cl>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([CH2:3][OH:30])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:8]=2[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)c(Cl)cc2c(-c3ccccc3F)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Temperature: 0 °C
Yield: 65 %

Procedure:
To the ice-cooled solution of 7-allyl-5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (9.5 g) in methylene chloride (200 ml), m-chloroperbenzoic acid (16.4 g) was added in small portions under agitaiton, and the solution was subsequently refluxed for 3 hours. After cooling the solution, water and 100 ml of an aqueous solution of 2N sodium hydroxide were added and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 6.5 g of 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 136°-139° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 319.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].NC1C=CC=CC=1>CO>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][N+:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: Cl
Solvent: Nc1ccccc1
Solvent: CO
Product: NC(=O)c1cc[n+](-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 125.7 %

Procedure:
A suspension of 30.0 g 4-Carbamoyl-1-(2,4-dinitro-phenyl)-pyridinium hydrochloride and 22.4 g aniline in 600 ml methanol was stirred at room temperature for four days. The suspension was warmed to 55° C. and stirred at this temperature for one hour. The resulting solution was cooled and the solvent removed in vacuo. The resulting residue was suspended in 300 ml propan-2-one and stirred at room temperature. The insoluble residue was filtered and dried in vacuo to obtain 27.3 g 4-Carbamoyl-1-phenyl-pyridinium hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([Cl:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>>[ClH:31].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Agent: Cl
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(15.0 mg, 44%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-fluorophenylsulfonyl chloride (20.8 mg, 0.107 mmol). HRMS-FAB+ for C21H18N2O2SF4.HCl, calculated MH+ (--HCl): 439.11035; found: 439.10807.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:21][O:22][C:23](=[O:27])[C:24](Cl)=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:27])[C:24]([NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:25]
Reactant: Nc1cccc2ccccc12
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
In a round bottom flask containing 1-naphthyl amine (0.1 g, 0.68 mmol) stirring in DCM (5 mL) was added DIEA (0.18 mL, 1.02 mmol) and chloro-oxo-acetic acid methyl ester (0.068 mL, 0.748 mmol). The mixture was allowed to stir at room temperature for 1 h. The reaction mixture was poured over saturated sodium bicarbonate and the layers separated. The aqueous layer was extracted twice more with 3×15 mL DCM. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to afford a brown solid. The crude material was purified by flash chromatography (0-50% EtOAc:Hexanes on silica gel) to yield the desired product (0.14 g, 90%) as an off-white solid. Expected mass=229. Observed mass=230.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: Cc1ccc(-c2cnn3c(=O)[nH]nc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc3c2Cl)cc1
Temperature: 55 °C
Yield: 59.6 %

Procedure:
To a stirring suspension of 8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (2.2 g, 8.4 mmol) and 5-(chloromethyl)-2-(trifluoromethyl)pyridine (2.1 g, 11 mmol) in DMF (15 mL) at room temperature under argon was added K2CO3 (1.74 g, 12.6 mmol). The resulting mixture was heated at 55° C. for 2 h. HPLC/MS analysis indicated complete reaction. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (10 mL×2) to obtain a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes/EtOAc/CH2Cl2. Desired product (2.1 g) was obtained as a brown solid. Washing with MeOH (10 mL×2) and drying provided pure title compound, 8-chloro-7-p-tolyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (1.76 g, 56%) as a light yellow solid. MS [M+H]+ 420; HPLC retention time=3.53 min; 1HNMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.13 (s, 1H), 8.00 (d, 1H), 7.70 (d, 1H), 7.30-7.50 (m, 4H), 5.36 (s, 2H), 2.45 (s, 3H).