Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1.FC1C=[CH:27][C:26]([C:29](=[O:41])CC2C=CC(C(F)(F)F)=CN=2)=[CH:25]C=1.[OH-].[Na+].Cl.NO.C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:29](=[O:41])[CH:26]([CH3:27])[CH3:25])=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CO
Product: CC(C)C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Yield: 59 %

Procedure:
1-(4-fluorophenyl)-2-(5-(trifluoromethyl)pyridin-2-yl)ethanone oxime. To a solution of 1-(4-fluorophenyl)-2-(5-(trifluoromethyl)pyridin-2-yl)ethanone (8.00 g, 28.2 mmol) in methanol (100 ml) at room temperature was added 15% NaOH (29 ml, 109 mmol). The resulting solution was stirred vigorously as solid hydroxylamine hydrochloride (9.8 g, 140 mmol) was added portionwise. The mixture was heated to reflux for 1 hour, treated with charcoal while hot, and then quickly filtered through Celite before being allowed to cool. The filtrate was concentrated to one-half of its original volume and then cooled to 0° C. for 1 hour. The resultant solids were collected by filtration, washed with water, and dried under vacuum at 50° C. overnight to provide 5.00 g (59%) of the title compound as a dark yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[C:12](O)(=[O:17])[CH2:13][C:14](O)=[O:15].C(OC(=O)C)(=O)C.O>C(O)(=O)C.CO>[CH3:1][N:2]1[C:12](=[O:17])[CH2:13][C:14](=[O:15])[N:5]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]1=[O:4]
Reactant: CNC(=O)NC1CCCCC1
Reactant: O=C(O)CC(=O)O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Temperature: 70 °C
Yield: 96.1 %

Procedure:
In 15 ml of acetic acid is dissolved 5 g of N-methyl-N'-cyclohexylurea together with 5 g of malonic acid under heating. Then, at 70° C., 15 ml of acetic anhydride is added dropwise over a period of 30 minutes. The mixture is further heated at 80°-90° C. for 2 hours, after which time 5 ml of water is added. The mixture is heated at 70° C. for 30 minutes and, then, concentrated to dryness. By the above procedure is obtained a pale-yellow oil. This oil is dissolved in methanol and allowed to stand in a refrigerator, whereupon needles separate out. These crystals are collected by filtration and washed with ethanol. The above procedure provided 6.9 g of 1-methyl-3-cyclohexylbarbituric acid as colorless crystals, melting point: 81°-82° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:13]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:22]([N:26]([C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:21]2[CH:45]=[C:46](Br)[CH:47]=[CH:48][C:20]1=2)=[O:18])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.ClCCl.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:42]([N:26]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:40])([F:39])[F:41])[CH:29]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][CH:13]([CH3:15])[CH3:14])=[O:18])[C:20]2[CH:48]=[CH:47][C:46]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:45][C:21]1=2)(=[O:44])[CH3:43]
Reactant: C1COCCN1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N3CCOCC3)cc21
Temperature: 80 °C
Yield: 64.3 %

Procedure:
Combine tris(dibenzylideneacetone)dipalladium (0) (0.031 g, 0.034 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphyl (0.064 g, 0.102 mmol) and sodium t-butoxide (0.045 g, 0.470 mmol) in toluene (2 mL) and purge this suspension with nitrogen at room temperature for 5 min. Add morpholine (0.033 mL, 0.369 mmol) followed by isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.200 g, 0.336 mmol) and heat this mixture at 80° C. under nitrogen for 1 h. Cool the reaction mixture to room temperature, dilute the mixture with dichloromethane, filter through Celite, and concentrate under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (20:1 to 1:2), to provide the title compound as an off-white solid (0.130 g, 64%): APCI MS 603 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.C(Cl)[Cl:32].CN(C=O)C.CS(Cl)(=O)=O>O.CCN(CC)CC>[Cl:32][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
N-{4-{2-[4-(Hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (539.5 mg), CH2Cl2 (5 ml) and DMF (5 ml) were combined under N2 atmosphere. Then, Et3N (0.211 ml) and MsCl (0.108 ml) were added to the suspension at 0° C. The reaction mixture was stirred at r.t. for 3.5 hours. The reaction mixture was poured into water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid was washed with ethyl ether to give N-{4-{2-[4-(chloromethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (537.5 mg) as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:10][C:11]1[N:12]=[C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]([C:21]2[CH:22]=[CH:23][C:24](=[O:30])[N:25]([CH:27]([CH3:29])[CH3:28])[N:26]=2)=[N:15][C:16]=1S(C)(=O)=O.Cl>CC(N(C)C)=O.C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:12]=[C:13]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:14]([C:21]2[CH:22]=[CH:23][C:24](=[O:30])[N:25]([CH:27]([CH3:29])[CH3:28])[N:26]=2)=[N:15][C:16]=1[O:9][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: OC1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)n1nc(-c2nc(OC3CCCCC3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (31.1 mg) in DMA (0.6 ml) was added cyclohexanol (0.081 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml) was added to the mixture and an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane (60:40 v/v) to give 6-[5-amino-6-(cyclohexyloxy)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (55 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[C:37](O)=[O:38]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:37]([C:28]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:35]=[CH:36][C:27]=4[CH3:26])=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1ccc2ccccc2c1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(C)ccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methylnaphthalene-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[OH-:24].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O>O1CCOCC1.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]>[CH:19]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([OH:24])[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: [OH-]
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(O)ccc1-2
Temperature: 100 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27, see FIG. 4 (1.06 g, 2.70 mmol), pulverized potassium hydroxide (303 mg, 5.4 mmol), tris(dibenzylideneacetone)di palladium(0) (24.8 mg, 0.027 mmol), 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl (26.0 mg, 0.054 mmol) were combined in a sealed tube. The mixture was then taken up in 1,4-dioxane (2.4 mL), water (2.4 mL), and sealed. The reaction mixture was placed in a pre-heated bath and stirred at 100° C. overnight. Added an additional 2.0 eq of pulverized potassium hydroxide, 1 mol % tris(dibenzylideneacetone)di palladium(0), 2 mol % 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl, and 0.2 mL of water and 1,4-dioxane and heated at 100° C. for 2 h. The reaction mixture was filtered through a plug of celite and concentrated in vacuo and the residue purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in heptane) to afford 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-hydroxyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as a yellow solid (480 mg, 54%). 1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 6.61 (dd, J=8.8, 2.4 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.90 (hept, J=6.6 Hz, 1H), 4.51-4.38 (m, 4H), 1.47 (d, J=6.6 Hz, 6H).
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1(C)C(C)=CC=CC=1>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: CN(C)CCNc1cc([N+](=O)[O-])cc2ccoc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
Xylene (75 mL) was added to 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), N,N-dimethylethane-1,2-diamine (0.37 g, 4.15 mmol), Pd2(dba)3 (0.08 g, 0.87 mmol), Xantphos (0.20 g, 0.35 mmol) and Cs2CO3 (1.59 g, 4.84 mmol). The mixture was stirred at 120° C. overnight, filtered through Celite and the solvent was removed in vacuo. The crude product was purified by flash chromatography [eluent: DCM:MeOH (6:1) and DCM:MeOH:Et3N (9:1:0.1)] to afford 0.378 g (44%) of the title compound. HPLC 90%, RT: 1.430 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 2.44 (d, J=3.22 Hz, 6H) 2.81 (t, J=6.56 Hz, 2H) 3.52 (t, J=6.56 Hz, 2H) 6.97 (d, J=2.23 Hz, 1H) 7.40 (d, J=2.23 Hz, 1H) 7.89 (t, J=1.98 Hz, 2H). LC-MS 250 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]2[N:15]=[C:16]([I:21])[C:17]([C:18](O)=[O:19])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:25](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:18]([C:17]1[C:16]([I:21])=[N:15][N:11]2[CH2:12][CH:13]([CH3:14])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)(=[O:19])[NH2:25]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1Cn2nc(I)c(C(=O)O)c2CN1C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cn2nc(I)c(C(N)=O)c2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a stirred solution of Intermediate 340E (0.65 g, 1.596 mmol) in DMF (3.0 mL) was added NH4Cl (0.427 g, 7.98 mmol), HATU (1.214 g, 3.19 mmol) and DIPEA (0.836 mL, 4.79 mmol) and the resulting solution was allowed to stir at RT for 3 h. It was diluted with ethyl acetate (10 mL), washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 340F as a colorless liquid (0.38 g, 59%). MS(ES): m/z=407 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 8 ppm 6.79-7.56 (m, 2H), 5.01 (d, J=18.51 Hz, 1H), 4.66 (br. s., 1H), 4.39 (d, J=18.13 Hz, 1H), 3.96-4.20 (m, 2H), 1.44 (s, 9H), 1.07 (d, J=6.80 Hz, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Br[C:40]1[C:41]([C:46]([F:49])([F:48])[F:47])=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[CH3:38][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[C:41]([C:46]([F:49])([F:48])[F:47])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: FC(F)(F)c1ncccc1Br
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5C(F)(F)F)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.3 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-2-trifluoromethyl pyridine (339 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was partially purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 40:60, gradient). This partially purified product was dissolved in a solution of 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (135 mg, 32%) as a colorless solid.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([N+:8]1[C:12]2=[N:13][C:14]3[C:19]([N:20]=[C:11]2[N:10]([CH2:21][CH3:22])[C:9]=1[C:23]#[C:24][CH:25]=[C:26]1[N:38]([CH2:39][CH3:40])[C:29]2=[N:30][C:31]4[C:36]([N:37]=[C:28]2[N:27]1[CH2:41][CH3:42])=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:7].[CH2:43]([N:45]1[C:52](=[O:53])[CH2:51][C:49](=[O:50])[N:48]([CH2:54][CH3:55])[C:46]1=[S:47])[CH3:44].C(N(CC)CC)C.O>CN(C)C=O>[CH2:54]([N:48]1[C:49](=[O:50])[C:51](=[C:24]([CH:25]=[C:26]2[N:27]([CH2:41][CH3:42])[C:28]3=[N:37][C:36]4[C:31]([N:30]=[C:29]3[N:38]2[CH2:39][CH3:40])=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:23]=[C:9]2[N:10]([CH2:21][CH3:22])[C:11]3=[N:20][C:19]4[C:14]([N:13]=[C:12]3[N:8]2[CH2:6][CH3:7])=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:52](=[O:53])[N:45]([CH2:43][CH3:44])[C:46]1=[S:47])[CH3:55]
Reactant: CCN1C(=CC#Cc2n(CC)c3nc4ccccc4nc3[n+]2CC)N(CC)c2nc3ccccc3nc21
Reactant: CCN1C(=O)CC(=O)N(CC)C1=S
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(=C(C=C2N(CC)c3nc4ccccc4nc3N2CC)C=C2N(CC)c3nc4ccccc4nc3N2CC)C(=O)N(CC)C1=S

Procedure:
A mixture of 1,3-diethyl-2-[(1,3-diethyl-1H-imidazo[4,5-b]quinoxalin-2-(3H)-ylidene)-1-propynyl]imidazo[4,5-b]quinoxalinium perchlorate) 0.33 g, 0.0005 mol) of Example 1, 1,3-diethyl-2-thiobarbituric acid (0.11 g, 0.0005 mol) and triethylamine (0.10 g, 0.001 mol) in dimethylformamide (5 ml), is heated at reflux for 30 seconds. After cooling the solution is diluted to 20 ml. with water. The dye is collected and washed with water. After recrystallization from acetonitrile, the yield of purified dye is 0.27 g (79%) - mp. indistinct.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S(C)(=O)=O)cc1

Procedure:
250 ml of a desiccated methanol solution containing 50 g (0.25 mol) of p-methylsulfonylbenzoic acid and 10 ml of concentrated sulfuric acid was refluxed by heating for 8 hours. The reaction mixture was then cooled with ice and the crystals thus precipitated were collected by filtration and washed with methanol to obtain 48.2 g (0.225 mol) of the above described compound.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+].[N:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[CH:35][CH:34]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[N:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:4][C:40]=2[C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)=[CH:35][CH:34]=1
Reactant: Fc1ccc(C#Cc2ccncc2)cc1
Reactant: Nc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2[nH]c3ccccc3c2-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
2-Iodoaniline (2) (525 mg, 2.40 mmol) was added to palladium acetate (26.9 mg, 0.120 mmol), triphenyl phosphine (31.5 mg, 0.120 mmol), potassium acetate (1.18 g, 12.0 mmol), tetrabutylammonium chloride (547 20 mg, 2.40 mmol), 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1) (1.0 g, 4.8 mmol), and DMF (20 mL). The reaction was warmed to 100° C. for 17 h under argon. After cooling to 23° C., the reaction was poured into water (200 mL), extracted with ethyl acetate (3×100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography on silica gel (methanol:ethyl acetate 1:19) to afford indoles (3) and (4) as a mixture of regioisomers (4:1): Mass Spectrum (CI) 289 (MH+).
Reaction SMILES: FC1C=C(F)C=CC=1N1C=CC=N1.C(OCCO)C.CC(C)([O-])C.[K+].[C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)(=[O:28])[CH3:27].[F:35][C:36]([F:43])([F:42])[C:37](OCC)=[O:38].OS(O)(=O)=O>C1COCC1.O>[O:38]=[C:37]([C:36]([F:43])([F:42])[F:35])[CH2:27][C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: Fc1ccc(-n2cccn2)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CCOCCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)C(F)(F)F)c1ccccn1
Reaction time: 24 h
Yield: 79.6 %

Procedure:
2-(2′,4′-difluorophenyl)pyrazole (3.6 g, 20 mmol) and K3IrBr6 (6.3 g, 8 mmol) were added to a flask containing 90 ml 2-ethoxyethanol and 30 ml water. The reaction mixture was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the pale yellow precipitate was vacuum filtered and washed first with ethanol followed by heptanes. The product [2-(4′,6′-diflouorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-diflouorophenyl)pyrazole]2 was dried in vacuum oven (4.2 g, 81%). Step 2 To a 60 ml THF suspension of potassium t-butoxide (7.9 g, 59 mmol) and 2-acetylpyridine(7.1 g, 59 mmol) was added dropwise ethyl trifluoroacetate (10 g, 70 mmol) at 10° C., and the mixture was stirred at room temperature for 15 h. After the PH value of the mixture had been adjusted to 6-7 with 10% H2SO4, the solution was extracted with Et2O. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 followed by recrystallization from ethanol to give 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (10.2 g, 81%). Step 3 Hydrazine hydrate (1.44 g, 27.7 mmol) was added dropwise to 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (5 g, 23 mmol) in 250 ml diethyl ether, and the mixture was stirred at ambient temperature for 3.5 h. Most of the solvent was evaporated and the mixture was extracted with water. The organic layer was dried (MgSO4) and evaporated to give 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 78%). Step 4 Compound 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 24 mmol) was boiled under reflux in 300 ml ethanol in the presence of conc. sulfuric acid (1.85 ml) for 30 min. The reaction mixture was then extracted with water. Evaporation and chromatography (ethyl acetate/heptanes 1:5) gave 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (4.2 g, 85%). Step 5 [2-(4′,6′-difluorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-difluorophenyl)pyrazole]2 (0.15 g, 0.12 mmol), 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (70 mg, 0.3 mmol) and 0.2 g of K2CO3 were refluxed under an nitrogen atmosphere in 2-ethoxyethanol for 18 h. After cooling to room temperature, water was added and a white precipitate was filtered and washed with water. The crude product was chromatographed on a silicon column with dichloromethane/methanol (9:1 v/v) as the mobile phase (110 mg, 60%).