Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(F)(F)F)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (74 mg, 77%), MS (ISP) m/z=384.6 [(M+H)+], mp 252° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1[C:21]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])=[CH:22][S:23][CH:24]=1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl>C1COCC1>[F:33][C:34]([F:36])([F:35])[CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:21]1[C:20]([CH3:19])=[CH:24][S:23][CH:22]=1)[OH:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cscc1-c1ccccc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cscc1-c1ccccc1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
Tetrabutylammonium fluoride (0.013 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-(4-methylthiophen-3-yl)-benzaldehyde (260 mg, 1.29 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (228 μl, 1.54 mmol) in 5 ml of THF at 0° C. The formed mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 5 ml of 1N HCl and stirred at room temperature overnight. The product was extracted with ethyl acetate (3×50 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 340 mg of 2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethanol, yield 97%.
Reaction SMILES: [CH:1]1([S:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C([NH2:19])=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[O-2].[Mg+2].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2].O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[NH:19])=[O:5])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)C2CC2)cc1
Reactant: NC(=O)C(F)(F)F
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: Ic1ccccc1
Product: N=S(=O)(c1ccc([N+](=O)[O-])cc1)C1CC1
Reaction time: 0.08 h

Procedure:
6.6 g (31.24 mmol) (RS)-1-(cyclopropylsulfinyl)-4-nitrobenzene, 7.77 g trifluoroacetamide (68.74 mmol), 16.6 g (51.55 mmol) iodobenzene diacetate and 5.54 g (137.5 mmol) magnesium oxide are placed in 350 ml dichloro-methane. The mixture is stirred for 5 minutes, treated with 0.69 g (1.56 mmol) rhodium(II) acetate dimer and stirred at room temperature for 12 hours. The suspension is diluted with 235 ml methanol, treated with 23.75 g potassium carbonate and stirred at room temperature for 4 hours. Next the mixture is treated with 400 ml water, and the organic phase is separated and filtered at the pump through Celite®. The aqueous phase is extracted several times with dichloromethane. The combined organic phases are washed with half-saturated sodium chloride solution and stirred with 100 ml 2N hydrochloric acid for 30 minutes. The aqueous phase is adjusted to pH 9 with concentrated sodium hydroxide solution with ice cooling. The crystallised product is aspirated dry, washed with water and dried. 4.7 g (66.5% of theor.) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2cc3c(s2)CCCC3(O)c2ccc(Cl)cc2)ccn1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2cc3c(s2)CCCC3c2ccc(Cl)cc2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 100 mL round bottomed flask was placed crude N-{4-[4-(4-chlorophenyl)-4-hydroxy-4,5,6,7-tetrahydro-1-benzothien-2-yl]pyridin-2-yl}acetamide (410 mg, 1.0 mmol) prepared above and 1,2-dichloroethane (10 mL). The mixture was refluxed for 30 min to obtain a yellow solution. To the refluxing mixture were added triethylsilane (1 mL, 6 mmol) and trifluoroacetic acid (2 mL, 20 mmol), and refluxing was continued for an additional 3 hr. The mixture was allowed to cool to rt then concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) then washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.OO.NC(N)=[O:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][N+:3]=1[O-:16]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Reaction time: 22 h

Procedure:
Cool a DCM (500 mL) solution of 2-chloro-5-trifluoromethylpyridine (96 g, 529 mmol) to 0° C. in an ice bath. Add urea hydrogen peroxide (105 g, 1111 mmol), followed by dropwise addition of trifluoroacetic anhydride (147 mL, 1058 mmol), and allow the reaction mixture to reach room temperature. After 22 hours, TLC (50% EtOAc/Hexanes) shows only a trace amount of starting material. Quench the reaction with sat. aqueous Na2S2O3 and stir for 15 minutes to destroy any residual peroxides. Then, pour the mixture into 0.5 M HCl (300 mL) and extract with CH2Cl2 (2×200 mL). Wash the combined organic extracts with sat. NaHCO3 (3×100 mL), dry over Na2SO4, filter, and concentrate under vacuum to give the title product as a pale yellow solid, which is used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.64 (d, 1H, J=8.4 Hz), 7.38 (d, 1H, J=8.0 Hz). Mass spec. (481.11, M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)=[S:4].C(OCC)(=O)C.[CH3:20][N:21]=[C:22]=[O:23]>CCCCCC>[CH3:1][N:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:22](=[O:23])[NH:21][CH3:20])[CH:7]=1)=[S:4]
Reactant: CN(C)C(=S)Nc1cccc(O)c1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC(=O)Oc1cccc(NC(=S)N(C)C)c1
Temperature: 20 °C

Procedure:
1,1-dimethyl-3-(meta-methylcarbamoyloxyphenyl)-2-thiourea is prepared by charging to a suitable equipped reaction vessel about 32.7 parts by weight of 1,1-dimethyl-3-(meta-hydroxyphenyl)-2-thiourea, about 100 parts by weight of ethyl acetate, about 12 parts by weight of methyl isocyanate and about 1 part by weight triethylamino, refluxing for about 1 hour with stirring, diluting the resulting slurry with about 100 parts by weight of hexane, cooling to about 20°C., recovering the precipitate from the remainder by filtration, washing the recovered solid with ethyl acetate and hexane and air drying.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)[CH:6]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3,4-dichlorophenyl)-6-methyl-pyrimidine (example E.61) (0.16 g, 0.42 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g, 0.54 mmol) according to the general procedure VI. Obtained as a yellow solid (0.06 g, 36%). MS (ISP) 397.1 [(M+H)+]; mp 213° C.
Reaction SMILES: C[O:2][C:3]([CH:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][C:9]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].O[Li].O>CO.O>[CH2:17]([O:16][P:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:3]([OH:4])=[O:2])=[CH:7][CH:8]=1)([O:13][CH2:14][CH3:15])=[O:19])[CH3:18]
Reactant: CCOP(=O)(OCC)c1ccc(C(C(=O)OC)c2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A mixture of Diethyl 4-((methoxycarbonyl)(phenyl)methyl)phenylphosphonate, 14-e, (1.7 g, 5.0 mmol) and LiOH.H2O (0.3 g, 7 mmol) in methanol (10 mL) and H2O (10 mL) was stirred overnight. The resulting mixture was concentrated and extracted by EA. The aqueous layers were added HCl (1 M) until pH 1˜2. The mixture was extracted by EA. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford the title compound, 14-f, as colorless oil (1.18 g, 72%). 1H NMR (300 MHz, CDCl3) δ1.22-1.31 (m, 6H), 4.03-4.14 (m, 4H), 5.05 (s, 1H), 7.25-7.31 (m, 5H), 7.38-7.42 (m, 2H), 7.68-7.75 (m, 2H); LC-MS: (M+H)+ 349.
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.Cl.O1CCOCC1>C(OCC)C.C(O)(=O)C>[CH3:1][C:2]1[N+:6]([O-:7])=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([C:9]([F:8])([F:18])[F:19])=[CH:17][CH:16]=2)[O:5][C:3]=1[CH3:4]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)C(C)=NO
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 0 °C
Yield: 34.3 %

Procedure:
A 100 mL pear-shaped flask was charged with butane-2,3-dione monooxime (2.1 g, 20.4 mmol), 4-(trifluoromethyl)benzaldehyde (3.0 mL, 22.4 mmol), and acetic acid (20 mL). The mixture was cooled to 0° C. A solution of 4N HCl in dioxane (7.0 mL, 28.0 mmol) was added dropwise to the reaction and the resultant mixture was stirred at 0° C. for 20 minutes. Diethyl ether (30 mL) was added to the reaction and the mixture was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the resulting residue was taken up in water (300 mL). Conc. NH4OH(aq) was added to adjust the pH to 9.0. The mixture was extracted with ethyl acetate (2×75 mL), and the combined organic layers were washed with water (100 mL), followed by saturated brine (100 mL). The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure. The resulting residue was purified via radial chromatography (3% MeOH in DCM) to yield 1.8 g (35%) of 4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole-3-oxide as a white solid. LC/MSD m/e: 258.1 (M+H); 1H NMR (400 MHz) (Acetone-d6) δ 8.68 (d, 2H, J=8.0 Hz), 7.89 (d, 2H, J=8.0 Hz), 2.45 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.CN(C)C.C1(C)C=CC=CC=1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([OH:37])[CH:33]=[CH:34][C:35]=1[F:36]>C1(C)C=CC=CC=1.O>[F:39][C:29]([F:28])([F:38])[C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[F:36])[O:37][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([Cl:16])=[CH:4][N:3]=1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: Clc1ncc(Cl)c(-c2ccc(Cl)c(Cl)c2)n1
Agent: CN(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Oc2ncc(Cl)c(-c3ccc(Cl)c(Cl)c3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
To a solution of 0.5 g (1.7 mmol) of 3B in 10 mL of toluene was added 4.0 mL of 10% trimethylamine/toluene solution and the mixture stirred at room temperature for 20 min. To the resulting mixture was added 0.36 g (20 mmol) of 3-trifluoromethyl-4-fluorophenol and the mixture stirred overnight. The reaction mixture was diluted with H2O and transferred to a separatory funnel and extracted with 40 mL of methylene chloride. The organic layer was washed sequentially with 5% NaHCO3 solution and water, dried and evaporated to yield 0.52 g (70.3%) of 2-(3-trifluoromethyl-4-fluorophenoxy)-4-(3,4-dichlorophenyl)-5-chloropyrimidine (m.p. 90-92)
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][OH:20]>C[O-].[Na+]>[CH2:1]([S:8][C:9]1[N:18]=[C:12]2[CH:13]=[N:14][CH:15]=[C:16]([O:20][CH3:19])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Brc1cncc2nc(SCc3ccccc3)nn12
Agent: C[O-]
Agent: [Na+]
Product: COc1cncc2nc(SCc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Benzylthio-5-bromo[1,2,4]triazolo[1,5-a]pyrazine (0.71 g) was dissolved in 20 mL of methanol and to this 1.20 mL of 25 percent by weight solution of sodium methoxide in methanol was added by means of a syringe with stirring at ambient temperature. The mixture turned pale yellow and the reaction was complete in 4 hours. The mixture was quenched with 0.5 mL of glacial acetic acid and the volatiles were removed by evaporation under reduced pressure. The oily residue was triturated with water and the solid that formed was recovered by filtration to obtain 0.31 g (50 percent of theory) of the title compound as a light brown solid melting at 114°-116° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][O:20]S(C)(=O)=O)[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][O:20][C:32]3[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[O:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc(COS(C)(=O)=O)n2)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COc3ccc(S(C)(=O)=O)cc3)n2)CC1
Temperature: 50 °C

Procedure:
A mixture of 4-(5-methanesulfonyloxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.33 mmol), 4-methanesulfonyl-phenol (86 mg, 0.5 mmol) and Cs2CO3 (0.33 g, 1 mmol) in acetonitrile (5 mL) was heated at 50° C. for 2 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 7.9 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.2˜4.05 (2H, m), 3.03 (3H, s), 3.04˜2.85 (3H, m), 2.05˜1.96 (2H, m), 1.8˜1.7 (2H, m), 1.45 (9H, s).
Reaction SMILES: [IH:1].N[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOCC>[I:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: I
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(I)cc1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
A solution of 57% aqueous HI (3.29 ml, 25 mmol) dissolved in DMSO (25 ml) was added dropwise to a solution of 4-aminobenzophenone (0.986 g, 5 mmol) in a mixture of 25 ml of DMSO and KNO2 (0.851 g, 10 mmol) at 35° C. with agitation. The added mixture was stirred at 35° C. for 10 minutes and then was transferred to a solution containing K2CO3 (5 g) in 100 ml ice-water. The reaction mixture was then taken up in ether, and then the ethereal extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the crude 4-iodobenzophenone. The crude product was further purified by column chromatography to obtain 4-iodobenzophenone. The yield determined by gas chromatography was 88% (based on decane as an internal standard).
Reaction SMILES: [OH-:1].[Na+].BrBr.[F:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])C)=[CH:11][CH:10]=1>O.O1CCOCC1>[F:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:1])=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: CCCCCCCCC(F)COc1ccc(C(C)=O)cc1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCC(F)COc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A solution of 11.3 g of sodium hydroxide in 75 ml of water was charged in a 300 ml-three necked flask and cooled to 0° C., and 12.3 g of bromine was added thereto in 15 minutes under stirring, followed by addition of 30 ml of dioxane. The resultant mixture solution was added dropwise in 40 minutes to a solution which was obtained by dissolving 5.2 g of p-(2-fluorodecyloxy) acetophenone in 170 ml of dioxane followed by addition of 10 ml of water, and subjected to reaction for 3.5 hours while being kept below 10° C. Thereafter, the excessive hypobromite was removed by addition of a hydrosulfite aqueous solution, followed by acidification with addition of 6N-hydrochloric acid aqueous solution, and addition of 500 ml of water to precipitate a crystal, which was then recovered by filtration. The crystal was recrystallized from isopropyl ether to obtain 4.1 g of p-(2-fluorodecyloxy)benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH2:39][NH:40][CH2:41][CH2:42][C:43]#[N:44])[CH:36]=[N:37][CH:38]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O.CO>[C:43]([CH2:42][CH2:41][NH:40][CH2:39][C:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:38]=[N:37][CH:36]=1)#[N:44]
Reactant: CC1(C)OB(c2cncc(CNCCC#N)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCCC#N)c4)cc23)CC1
Yield: 17.4 %

Procedure:
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.072 mmol) was added 3-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amino)propanenitrile (24.8 mg, 0.086 mmol). To this mixture was added dioxane (0.75 mL), followed by a solution of potassium carbonate (60 mg, 0.434 mmol) in water (0.25 mL) and SK-0002-A (4.4 mg, 0.007 mmol). The vials were capped and reacted in a CEM microwave at 150° C. for 30 min. The reaction was loaded onto a 2 g SCX SPE cartridge primed with 3 mL of methanol. The cartridge was then sequentially eluted with water (3 mL), methanol (9 mL), and 2M NH3 in MeOH (6 mL). The NH3 in MeOH fractions were dried under a stream of N2 at 40° C. The crude product was purified on the Agilent MDAP with UV (230 nm) and MS detection. The desired fractions were passed thru a 5 g CHQAX cartridge primed with 4 mL of methanol and 4 mL of water. The solvents were evaporated under a stream of N2 at 65° C. to give 6.2 mg of the title compound (17.4%).
Reaction SMILES: COC[O:4][C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:15][C:16]=2[CH3:17])=[CH:8][N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:6]=1.[ClH:30]>CO>[ClH:30].[CH3:17][C:16]1[S:15][C:14]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:13][C:12]=1/[CH:11]=[CH:10]/[C:9]1[C:5]([OH:4])=[N:6][N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=1
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCOCC2)sc1C
Agent: Cl
Solvent: CO
Product: Cc1sc(N2CCOCC2)nc1/C=C/c1cn(-c2ccccc2)nc1O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 4-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)morpholine (1.0 g) in methanol (20 mL) was added concentrated hydrochloric acid (0.4 mL) at room temperature, and stirred at 50° C. for 1.5 hrs. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethyl acetate-methanol to give 4-{(E)-2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-ol.hydrochloride (0.98 g, yield 100%) as gray crystals. melting point: 278-279° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[C:3]=1I.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]([CH3:35])=O.CN(C1CCCCC1)C1CCCCC1>CC(N(C)C)=O.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:11]([O:10][C:9]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26])[C:6]1[N:7]=[C:2]2[NH:1][C:33]([C:32]([O:37][CH2:38][CH3:39])=[O:36])=[CH:35][C:3]2=[C:4]2[N:29]([CH3:30])[CH:28]=[N:27][C:5]=12)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)C(C)=O
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)c(I)c3c2ncn3C)c(OC)c1
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc2c(nc(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)c3ncn(C)c32)[nH]1
Temperature: 60 °C
Yield: 85.8 %

Procedure:
To a flask charged with tert-butyl 6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1E, 3.49 g, 6.47 mmol) in DMA (43.1 mL) was added Pd2(dba)3 (0.474 g, 0.518 mmol), ethyl pyruvate (7.22 mL, 64.7 mmol), and N-methyldicyclohexylamine (2.77 mL, 12.94 mmol). The reaction mixture was sparged with argon for 10 min and heated at 60° C. 6 h. The reaction was complete by LCMS. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and saturated aqueous NaHCO3. The resultant emulsion was vacuum filtered through a pad of Celite and transferred to a separatory funnel The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 10% aqueous LiCl solution (2×). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The brown residue was purified by flash chromatography using an Isco 120 g column eluting with 40-80% ethyl acetate/hexane to yield ethyl 4-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylate (2.830 g, 86% yield)