Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)=[C:17]([NH:19][C:20]([C:22]2[O:23][C:24](Br)=[CH:25][CH:26]=2)=[O:21])[CH:18]=1)=[O:12].C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C>C(#N)C.[Cu]I>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)=[C:17]([NH:19][C:20]([C:22]2[O:23][C:24]([C:45]#[CH:46])=[CH:25][CH:26]=2)=[O:21])[CH:18]=1)=[O:12]
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccc(Br)o2)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1ccc(C(=O)Nc2cc(C(=O)NCCCN3CCCC3=O)ccc2N2CCN(c3ccccc3C)CC2)o1
Temperature: 80 °C
Reaction time: 4 h
Yield: 14.1 %

Procedure:
In a 20 mL scintillation vial, 5-bromo-furan-2-carboxylic acid [5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (0.1 g, 0.231 mmol) was taken in acetonitrile (5.0 mL). Trimethylsilyl acetylene (0.045 g, 0.462 mmol), CuI (0.009 g, 0.046 mmol), triethylamine (0.116 g, 1.155 mmol) and PdCl2(Ph3P) (0.032 g, 0.046 mmol) were added to this, and the solution was evacuated for 5 min and nitrogen purged and stirred at 80° C. for 4 h. LC-MS indicated the completion of the reaction. It was diluted with acetonitrile and filtered through celite and concentrated. The crude was dissolved in THF and stirred with TBAF (2.0 mL of 2 M solution in THF) at room temperature for 16 h. The reaction was concentrated and dissolved in methanol and purified on preparative HPLC using methanol/water as eluent to give the desired product (0.018 g, 14% yield).
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:26])[C:23](=[NH:25])[NH2:24])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[S:34](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O>C(Cl)Cl>[NH2:25][C:23]1[C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:10][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[N:16]=2)=[N:26][S:34][N:24]=1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1nsnc1NCCCOc1cccc(CN2CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the crude product prepared in Step B in 80 ml of CH2Cl2 and containing 7.69 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (7.35 g; 18.5 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 50 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 100 g of silica gel (230-400 mesh) using ethyl acetate-methanol (95:5) as the eluent to give 3.63 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate salt of the title compound, mp 125.5°-131° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:16]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:17]=2[N:18]=[C:19]([C:21]([O:23]CC)=[CH2:22])[CH:20]=1)=[O:14].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[C:21]([C:19]1[CH:20]=[C:15]([C:13]([NH:12][CH2:11][C:4]2[C:5](=[O:10])[NH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH3:2])=[O:14])[C:16]2[CH:28]=[N:27][N:26]([CH:29]([CH3:30])[CH3:31])[C:17]=2[N:18]=1)(=[O:23])[CH3:22]
Reactant: C=C(OCC)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
35% HCl (4 mL) was added to the N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(1-ethoxyvinyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.12 g, 0.293 mmol) at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, saturated NaHCO3 solution was added to it and extraction was carried out by using 5% MeOH/DCM, the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired compound (90% yield). LCMS: 382.10 (M+1)+; HPLC: 99.55% (@ 254 nm) (Rt; 6.316); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.09 (bs, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 5.89 (s, 1H), 5.35-5.29 (m, 1H), 4.36 (d, 2H, J=4.0 Hz), 2.75 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.56 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1)[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH:22]=O.[CH2:33]([NH2:36])[CH2:34][CH3:35].C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:22][NH:36][CH2:33][CH2:34][CH3:35])[CH:24]=[CH:25][C:26]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1
Reactant: Cc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C=O)ccc1-c1noc(=O)[nH]1
Reactant: CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCNCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
100 mg 5-[3-Methyl-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde and 12.8 mg propylamine were suspended in 3 ml methanol. 30.0 μl triethylamine were added upon the reaction mixture became a clear solution. 400 mg molecular sieves four angstrom were added and the reaction mixture stirred at room temperature for two hours. Then 8.2 mg sodium borohydride were added and the reaction mixture stirred at room temperature for thirty minutes. The reaction mixture was filtered through a celite pad. The filtrate was evaporated in vacuo and then evaporated in vacuo. The residue was purified by RP-HPLC to obtain 45.7 mg 3-{2-methyl-4-[4-propylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as its trifluoroacetate salt.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CN(C)CCO
Solvent: CCO
Product: CN(C)CCOB(c1ccccc1)C(OC(B(OCCN(C)C)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (10 mg) was obtained by allowing 25 mg of bis(3,3′-(phenylhydroxyboryl)benzyl) ether and 12 mg of N,N-dimethylethanolamine to act in 0.4 mL of ethanol.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[C:3]=1[NH2:4].C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.Cl>O1CCOCC1>[NH2:4][C:3]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1cc(F)cc(Br)c1N
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(F)cc(C(C)=O)c1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 2-bromo-4-fluoro-6-methoxy aniline (4.80 g, 21.8 mmol), which had been obtained in Reference example 3(3a), in 1,4-dioxane (200 mL), tributyl (1-ethoxy vinyl) tin (11.1 mL, 32.7 mmol) and tetrakistriphenyl phosphine palladium (2.52 g, 2.18 mmol) were added, and the mixture was stirred for 16 hours at 100° C. After cooling the reaction solution to room temperature, 1 N aqueous hydrogen chloride solution (100 mL) was added and stirred further for 2 hours. The reaction solution was concentrated under reduced pressure, neutralized by adding 1 N aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a yellow solid substance (2.80 g, yield 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.[CH3:33]COCC.C(O)(=O)CC>C1COCC1>[CH3:33][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: CCOCC
Reactant: O=C(O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Temperature: 70 °C
Yield: 40.4 %

Procedure:
A solution of 6-[4,5,6,7-tetrahydro-1-(4-nitrophenyl)-1H-inda-zol-3-yl]hexanoic acid (1.11 g, 3 mmol) in THF (10 ml) was treated with sodium borohydride (0.175 g) and boron trifluoride etherate (4.7 mmol) in THF (11 ml) during 0.5 hour. The solution was reacted for 18 hours at ambient temperature, treated with propionic acid (2 ml), and heated at 70° C. for 2 hours. The solution was cooled, dilution with water and the precipitate was extracted into ethyl acetate. Drying and evaporation of solvent gave crude title compound (1.69 g) as a viscous residue. Polar impurities were removed by filtration through silica gel (100 g) to yield pure title compound (0.45 g), m.p. 60°-61° C., after methanol crystallization.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)CCC>[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: COCCN1CCNCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(c2cc(N)ncn2)CC1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.3 g, 2.32 mmol) and diisopropylethylamine (0.30 g, 2.32 mmol) were suspended in n-butanol and then 1-(2-methoxyethyl)piperazine 5-2 (0.334 g, 2.32 mmol) was added. The reaction was stirred at 125° C. for 18 hours. The butanol was removed under reduced pressure, diluted with DCM and loaded onto a silica column eluted with DCM (100 mL), DCM:MeOH (99:4) and then DCM:MeOH:NH4OH (9:1:0.1). The product 5-3 was isolated after evaporation. 1H-NMR (DMSO): 7.95 ppm (s, 1H); 6.23 ppm (s, 2H); 5.59 ppm (s, 1H); 3.43 ppm (m, 4H); 3.33 ppm (m, 2H); 3.25 ppm (s, 3H); 2.59 ppm (m, 2H); 2.54 ppm (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCO.O.[NH2:16][NH2:17]>>[C:5]1([CH2:4][C:3]([NH:16][NH2:17])=[O:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: COC(=O)Cc1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1ccccc1

Procedure:
Phenyl-acetic acid methyl ester (5 g, 33.3 mmol) was dissolved in hydrazine hydrate (25 mL) and EtOH (50 mL) and the reaction was heated in a sealed tube to 80° C. overnight. After cooling the reaction was concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[F:11][C:12]([F:14])([F:13])[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[OH:5]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.25 h
Yield: 117.9 %

Procedure:
2,4-Difluorobenzaldehyde (1.1 mL, 10.0 mmol) and (trifluoromethyl)trimethylsilane (1.77 mL, 12.0 mmol) were dissolved in THF (25 mL) and then cooled to 0° C. To this, 1M TBAF in THF (76 μL, 76 μmol) was added and the reaction mixture was allowed to warm to room temperature. After 3.25 h, 2.5M HCl (25 mL) was added. The reaction was stirred for 1 h and then extracted with ether. The organic layer was washed with brine and dried with Na2SO4. The solvent was removed under the reduced pressure to give 2,2,2-trifluoro-1-(2,4-difluoro-phenyl)ethanol (2.5 g) as a racemic mixture.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:45])=[C:15]([N:17]2[C:24](=[O:25])[C:23]3[CH:22]=[C:21](B4OC(C)(C)C(C)(C)O4)[N:20]([CH:35]([CH3:37])[CH3:36])[C:19]=3[CH:18]2[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[CH:16]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:45])=[C:15]([N:17]2[C:24](=[O:25])[C:23]3[CH:22]=[C:21]([C:2]4[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=4)[N:20]([CH:35]([CH3:37])[CH3:36])[C:19]=3[CH:18]2[C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[CH:16]=1
Reactant: COc1cccnc1Br
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(B3OC(C)(C)C(C)(C)O3)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1cccnc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-3-methoxy-pyridine [24100-18-3] and 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Step 113.1) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a light brown solid. tR: 6.54 min (HPLC 2); ESI-MS: tR=1.27 min, [M+H]+ 506/508/510 (LC-MS 1); TLC: Rf=0.21 (98:2 CH2Cl2/MeOH).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Br:10][C:11]1[N:12]=[N:13][C:14](Br)=[CH:15][CH:16]=1.C(N(CC)CC)C>C1COCC1>[Br:10][C:11]1[N:12]=[N:13][C:14]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]2)=[CH:15][CH:16]=1
Reactant: Brc1ccc(Br)nn1
Reactant: CN(C)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc(Br)nn2)CC1
Temperature: 70 °C
Yield: 89.7 %

Procedure:
N,N-dimethylpiperidin-4-amine (0.505 g, 3.94 mmol), 3,6-dibromopyridazine (0.511 g, 2.15 mmol), and triethylamine (0.599 mL, 4.30 mmol) were combined in 5 mL of THF. The solution was heated at 70° C. for 17 hours. The solution was cooled to room temperature and then purified on CombiFlash column (dry loaded), eluting with 10% methanol/0.5% NH4OH (˜28% in water)/DCM isocratic. The fractions containing the product were combined and concentrated under vacuum to give compound 201 (0.550 g, 89.8% yield) as an off white solid. 1H NMR (500 MHz, MeOD-d3) δ 7.51 (1 H, d, J=9.8 Hz), 7.24 (1 H, d, J=9.8 Hz), 4.45 (2 H, d, J=13.7 Hz), 2.98 (2 H, td, J=13.0, 2.2 Hz), 2.61 (1 H, tt, J=11.5, 3.8 Hz), 2.38 (6 H, s), 1.99-2.07 (2 H, m), 1.45-1.58 (2 H, m, J=12.5, 12.2, 12.2, 4.2 Hz) ppm; LCMS-ESI (POS), M/Z, M+1: Found 285.0.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1.[CH3:18]O>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:18])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (31.5 ml; 0.432 mol) was slowly added dropwise at 0° C. to a solution of 4-fluoro-2-nitrobenzoic acid (16.0 g; 86.4 mmol) in methanol (240 ml). After warming to RT, stirring overnight and boiling under reflux for 4 h, the reaction solution was concentrated in vacuo and partitioned between ethyl acetate and potassium hydrogencarbonate solution. Drying and concentration of the organic phase afforded a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][N:11](C)C=O.[Cu](C#N)C#N>>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: CN(C)C=O
Agent: N#C[Cu]C#N
Product: Cc1cc(Br)cnc1C#N
Temperature: 120 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To a solution of 2,5-dibromo-3-methylpyridine (5.0 g, 20. mmol) in N,N-dimethylformamide (20.0 mL, 259 mmol) was added copper cyanide (1.8 g, 20. mmol) and the reaction was stirred at 120° C. for 12 h. The reaction was partitioned between EtOAc and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by combi-flash chromatography to afford 1.94 g (49% yield) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][OH:20])=[O:18].[N+](C1C=CC(OC(=O)CC2C=CC=CC=2NC2C(C)=CC=CC=2[Cl:46])=CC=1)([O-])=O>>[Cl:46][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][OH:20])=[O:18]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)NO
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)NO

Procedure:
[o-(3-chloro-o-toluidino)-phenyl]-acetohydroxamic acid, M.P. 135°-136° (from ether/petroleum ether), starting with [o-(3-chloro-o-toluidino)-phenyl]-acetic acid-p-nitrophenyl ester.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>O1CCOCC1.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>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)=[C:3]([CH3:17])[CH:4]=2)[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: Cc1cc(N2CCN(C(C)C)CC2)ncc1Br
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2cnc(N3CCN(C(C)C)CC3)cc2C)c1
Temperature: 100 °C

Procedure:
To a solution of 1-(5-bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine (0.59 g, 2 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added 3-acetylamino-phenylboronic acid (430 mg, 2.4 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol) and TEA (404 mg, 4 mmol). The resulting mixture was degassed and heated at 100° C. for 4 h under a nitrogen atmosphere. The mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with CH2Cl2/MeOH (100:1). This afforded 138 mg (15%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:19]([NH:18][CH3:17])=[O:20])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Yield: 96.2 %

Procedure:
5.0 g of 2-(3,3,3-trifluoro-1-propen-1-yl)phenysulfonamide and 1.7 g of methyl isocyanate are suspended in 25 ml of methylene chloride and 3.0 g of triethylamine are added dropwise for 10 minutes, whereupon a clear solution forms. The solution is concentrated, the residue is dissolved in a 5% sodium carbonate solution, and insoluble constituents are removed by filtration. The clear solution is acidified with 10% hydrochloric acid, to give 5.9 g of N-[2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonyl]-N'-methylurea as a colorless precipitate with a melting point of 190°-192° C.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[C:5]([CH3:10])[N:4]=1.[Cl:11][C:12]1[C:13]([O:35][CH3:36])=[CH:14][C:15]([O:33][CH3:34])=[C:16]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:25][C:24](=[O:26])[CH2:23][C:22](=[O:27])[CH2:21]2)[CH:17]=1>>[Cl:11][C:12]1[C:13]([O:35][CH3:36])=[CH:14][C:15]([O:33][CH3:34])=[C:16]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:25][C:24](=[O:26])[C:23]([CH2:2][C:3]3[NH:8][C:7](=[O:9])[CH:6]=[C:5]([CH3:10])[N:4]=3)=[C:22]([OH:27])[CH2:21]2)[CH:17]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1cc(=O)[nH]c(CCl)n1
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc(C)cc(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 19 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)-6-methylpyrimidin-4(3H)-one (Example B(54), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 19%. 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.75 (m, 8H), 1.87 (s, m overlap, 4H), 2.05 (m, 1H), 2.36 (m, 1H), 2.43-2.50 (m, 2H, overlap with DMSO-d5), 2.56 (d, J=17.5 Hz, 1H), 2.67 (d, J=17.5 Hz, 1H), 3.48 (m, 2H, overlap with H2O), 3.77 (s, 3H), 3.84 (s, 3H), 5.98 (s, 1H), 6.71 (s, 1H), 7.09 (s, 1H). LC-MS (APCI) calcd for C26H31ClN2O6: 502.19; found (M+H+) 503.0 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14]O)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.C(N(S(F)(F)[F:24])CC)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14][F:24])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2
Reactant: CC(C)(CO)c1cc(F)c2c(=O)[nH]ccc2c1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(CF)c1cc(F)c2c(=O)[nH]ccc2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
8-fluoro-6-(1-hydroxy-2-methylpropan-2-yl)isoquinolin-1(2H)-one (114 mg, 485 μmol) was dissolved in DCM (dry) and cooled to −78° C. under argon. To this solution was added the diethylaminosulfur trifluoride (90 μl, 678 μmol) and the reaction was stirred for about 10 min before removal of the cooling bath. The reaction was warmed to ambient and stirred at this temperature for 2 hrs. To the reaction mixture was added 25 ml water and 20 ml DCM. The mixture was shaken and the organics collected. The organics were washed with 25 ml brine. The aqueous phase was extracted (2×20 ml DCM). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by preparative tlc (2 plates, eluted with 4.5% MeOH/DCM) to afford 92 mg of the desired product as an off-white powder. (M+H)+=238 m/e.