Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:48])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]4[N:34]=[CH:33][C:32]5=[CH:35][CH:36]=[C:37]([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=6[O:44][CH3:45])[N:31]5[N:30]=4)=[C:24]([O:46][CH3:47])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:47][O:46][C:24]1[CH:23]=[C:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:48])[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[NH:28][C:29]1[N:34]=[CH:33][C:32]2=[CH:35][CH:36]=[C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[N:31]2[N:30]=1
Reactant: COc1cc(C2CCN(CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2CCN(CC(=O)N3CCNCC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into an 8-dram vial Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (170 mg, 0.46 mmol), 4-{2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester (223 mg, 0.516 mmol), N,N-Diisopropylethylamine (250 uL, 1.4 mmol) and 1-Methoxy-2-propanol (2 mL, 20 mmol). The reaction mixture was heated at 100° C. overnight. After 18 h, the mixture was cooled to RT and the product was purified by flash chromatography (ISCO, 40 g column, EtOAC-MeOH 95:5). The product was obtained as a syrup (156 mg, 52%). MS: 656 (M+H). The product was subjected to the BOC deprotection step. 4-[2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.23 mmol) was treated with trifluoroacetic acid (0.5 mL, 6 mmol) in methylene chloride (10 mL, 200 mmol). The mixture was stirred at RT. After 3 days, solvent was removed and the product, 2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-1-piperazin-1-yl-ethanone, was purified by reverse phase liquid chromatography (Gilson) as a brown solid (61 mg, 48%, —85% pure). LCMS (E/I+) 556 (M+H). NMR 1H (DMSO-d6)-9.6 (br s, 1H), 9.02 (br s, 2H), 8.95 (s, 1H), 7.07 (d, 1H, J=8.27 Hz), 7.82 (d, 1H, J=6.44 Hz), 7.64 (s, 1H), 7.46 (m, 1H), 7.21 (d, 1H, J=8.37 Hz), 7.10 (m, 1H), 6.96 (m, 2H), 6.90 (s, 1H), 6.71 (d, 1H, J=8.34 Hz), 4.35 (m, 2H), 4.2-3.0 (series of m and s along with water peak, 18H), 2.84 (m, 1H), 2.08-1.99 (m, 4H).
Reaction SMILES: [C:1]([CH2:3][C:4](=S)[NH2:5])#[N:2].BrCC.[O-]CC.[Na+].[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[O:19]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=[C:4]([CH2:3][C:1]#[N:2])[NH:5]1
Reactant: N#CCC(N)=S
Reactant: Nc1ccccc1C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCBr
Product: N#CCc1nc2ccccc2c(=O)[nH]1
Reaction time: 6 h
Yield: 47.1 %

Procedure:
2-Cyanoethanethioamide (1.00 g, 10.0 mmol) and bromoethane (821 μL, 11.0 mmol) were added to an ethanolic solution of sodium ethoxide (11.5 mmol, 5.3 mL). The resulting mixture was stirred for 6 hours, 2-aminobenzoic acid (1.50 g, 10.9 mmol) was added, and the reaction was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with ethanol, water, ethanol, and diethyl ether. The solid was then dried to yield 2-(4-oxo-3,4-dihydroquinazolin-2-yl)acetonitrile (872 mg, 47%). 1NMR (400 MHz, DMSO-d6) δ ppm 4.17 (s, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 8.10 (dd, J1=7.9 Hz, J2=1.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[S:14][C:13]([NH:15][C:16](=[O:18])[CH3:17])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][C:27](N1C=CC=N1)=[N:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C)C=O>O1CCCC1>[C:16]([NH:15][C:13]1[S:14][C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH:27]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:26][C:24](=[O:25])[O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:3][CH:4]=2)=[CH:11][N:12]=1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(=O)Nc1ncc(CCc2ccc(N)cc2)s1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)s1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 48.5 %

Procedure:
N-{5-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (100 mg), —N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (119 mg), N,N-dimethylformamide (1 ml) and tetrahydrofuran (2 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at 50° C. for 5.5 hours. After cooled to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by preparative silica gel column chromatography with n-hexane/ethyl acetate (1:2) as an eluent to give di-tert-butyl {[(4-{2-[2-(acetylamino)-1,3-thiazol-5-yl]ethyl}phenyl)amino]-methylidene}biscarbamate (93.9 mg) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[S:17][CH:16]=[N:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[S:17][CH:16]=[N:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cncs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2cncs2)cc1
Temperature: 0 °C
Yield: 78 %

Procedure:
A stirred solution of 5-[(4-nitrophenyl)sulfonyl]thiazole (1.72 g, 6.4 mmol) and stannous chloride dehydrate (7.17 g, 31.8 mmol) in absolute ethanol (25 mL) was heated at reflux for 1 hour. The reaction mixture was poured into ice water, the aqueous solution basified with solid sodium bicarbonate and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed to yield an orange solid. Flash chromatography (eluted with 10% ethyl acetate in methylene chloride) and evaporation of the solvent yielded the title thiazole (1.20 g, 78%) as a pale yellow solid; mp 158°-160° C. 1H--NMR (250 MHz, d6 --DMSO): 6.35 (br s, 2H, NH2), 6.65 (d, 2H, J=8.9 Hz, aromatic), 7.61 (d, 2H, J=8.7 Hz, aromatic), 8.39 (s, 1H, aromatic), 9.38 (s, 1H, aromatic). MS (CI, CH4): 241(M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[NH:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1Br
Solvent: CCO
Product: Cc1ccccc1Nc1ccccc1

Procedure:
2-Bromotoluene (2 mmol) is heated to 230° C. for 6 hours with aniline (20 mmol) in the presence of [(C6H5)2PCH2]2Ni(CO)2 (0.2 mmol) using ethanol (1.2 mL) as the solvent in a sealed tube to form 2-anilinotoluene. 2-Anilinotoluene is oxidized with potassium permaganate in water to form 2-anilinobenzoic acid. (See Cramer, et al., J. Org. Chem. (1975), 40:2267).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].CCN(C(C)C)C(C)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[O:24][CH3:25]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of 2-fluoro-5-nitroaniline (500 mg, 3.20 mmol) in THF (20 mL) was treated with DIEA (0.84 mL, 4.8 mmol) followed by methyl chloroformate (0.25 mL, 3.20 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, 40 g column, 30 min. gradient) to afford Intermediate 59A (450 mg, 65.6%). HPLC: Rt=2.868 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.94 (1H, s), 8.72 (1H, dd, J=6.80, 2.77 Hz), 7.87-8.09 (1H, m), 7.52 (1H, t), 3.72 (3H, s).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH:12]=[CH2:13].Cl[Sn]Cl.O.CC(=O)OCC>O>[C:1]1([CH2:7][CH:8]([OH:9])[CH2:13][CH:12]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: C=CCBr
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCC(O)Cc1ccccc1
Yield: 54.3 %

Procedure:
To a mixture of phenylacetaldehyde 30a (7.84 g, 65.3 mmol) and 3-bromoprop-1-ene (11.1 g, 91.5 mmol) in water (50 mL), KI (3.25 g, 19.6 mmol) and NiCl2.6H2O (3.1 g, 13 mmol) were added. After the mixture was stirred for several minutes, SnCl2.H2O (29.5 g, 13 mmol) was added. The mixture was vigorously stirred at rt overnight and then extracted with EA. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, evaporated in vacuo. The residue was purified by CC using PE:EA=5:1 as mobile phase to give the desired product (5.75 g, 54% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]=O>CO.C(O)(=O)C>[CH3:14][CH:10]1[N:11]([CH3:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: C=O
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CC(=O)O
Solvent: CO
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C
Temperature: 80 °C

Procedure:
tert-Butyl-3-methylpiperazine carboxylate (1.49 g, 7.45 mmol) and paraformaldehyde (1.12 g, 37.2 mmol) were dissolved in a mixture of MeOH and acetic acid (5:1) on molecular sieves. NaBCNH3 (1.88 g, 29.8 mmol) was added to the suspension at 25° C. The slurry was subsequently heated to 80° C. for 10 hr. Then the mixture was cooled, filtered, and concentrated. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The organic solution was dried over Na2SO4, and concentrated to give a white oily (1.2 g, 90%). LC-MS (ESI) m/z: 215 (M+1)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH2:27](Br)[CH3:28]>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH3:28])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCBr
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2Cl)c1OC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C#N)(CC)c1cccc(Oc2ccccc2Cl)c1OC
Yield: 91 %

Procedure:
Sodium hydride (50%, 920 mg), ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetate (6 g) and ethyl bromide (2.84 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]butyrate (5.9 g).
Reaction SMILES: Cl.[CH:2]1([C:5]2[C:6]([N:25]([C:30]3[CH:35]=[CH:34][C:33]([B:36]([OH:38])O)=[C:32]([CH2:39][O:40]COC)[CH:31]=3)[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[C:10]([C:20](=[O:23])[NH:21][CH3:22])[C:9]=3[CH:24]=2)[CH2:4][CH2:3]1>O1CCCC1.CO>[CH:2]1([C:5]2[C:6]([N:25]([C:30]3[CH:35]=[CH:34][C:33]4[B:36]([OH:38])[O:40][CH2:39][C:32]=4[CH:31]=3)[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)=[C:10]([C:20]([NH:21][CH3:22])=[O:23])[C:9]=3[CH:24]=2)[CH2:3][CH2:4]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc4c(c3)COB4O)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C
Yield: 96.7 %

Procedure:
HCl (1.0 mL, 1.000 mmol) was added to a solution of (4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-((methoxymethoxy)methyl)phenyl)boronic acid (53 mg, 0.089 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.2 mL). The mixture was heated to 70° C. under N2 overnight. Cooled down to room temperature, it was then evaporated to dry under reduced pressure to give the desired product (46 mg, 97%) as light-yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[N:8]=1)(=O)=O.CC1(C)COB([C:36]2[C:37]([CH3:44])([CH3:43])[O:38][C:39]([CH3:42])([CH3:41])[CH:40]=2)OC1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[N:8]=[C:7]([C:36]3[C:37]([CH3:44])([CH3:43])[O:38][C:39]([CH3:42])([CH3:41])[CH:40]=3)[CH:11]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)COB(C2=CC(C)(C)OC2(C)C)OC1
Reactant: COc1ccccc1-n1nc(OS(=O)(=O)C(F)(F)F)cc1-c1ccc(Cl)cc1
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: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-n1nc(C2=CC(C)(C)OC2(C)C)cc1-c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
To a solution of 5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl trifluoromethanesulfonate (Example 65, (c)) (337 mg, 0.78 mmol, 1 eq) in DMF (5 mL) was added 5,5-dimethyl-2-(2,2,5,5-tetramethyl-2,5-dihydro-furan-3-yl)-[1,3,2]dioxaborinane (223 mg, 0.93 mmol, 1.2 eq), sodium carbonate (198 mg, 1.87 mmol, 2.4 eq), and Pd(Ph3P)4 (90 mg, 0.078 mmol, 0.1 eq). Ar was bubbled through and the solution was heated to 100° C. for 5 hrs. Added water, extracted with EtOAc, dried over MgSO4 and conc. Purification by column chromatography (24 g) eluting with 5 to 10% EA/hexanes gave the title compound (249 mg, 78%).
Reaction SMILES: [CH3:1][SH:2].C(=O)([O-])[O-].[K+].[K+].[N+]([C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])([O-])=O>CC(C)=O>[CH3:1][S:2][C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: CS
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1cc(C(F)(F)F)ccc1C#N
Temperature: 20 °C
Reaction time: 23 h
Yield: 88.5 %

Procedure:
Methanethiol (278 g, 5.78M) was added during 20 minutes to a stirred mixture of acetone (5 litres) and potassium carbonate (593 g, 4.29M) at −15° C. A solution of 2-nitro-4-trifluoromethylbenzonitrile (618 g, 2.86M) in acetone (500 ml) was added during 10 minutes. The mixture was allowed to warm to 20° C. with stirring for 23 hours and then heated at 55° C. for 2 hours to remove most of the methanethiol and then flushed with nitrogen for 4 hours. The mixture was poured onto ice/water, the solid filtered off, washed and dried to give 2-methylthio-4-trifluoromethylbenzonitrile (550 g). The yield of product was 89%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.[CH3:36][S:37]([O-:39])=[O:38].[Na+]>CN1C(=O)CCC1.[Cu](I)I>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([S:37]([CH3:36])(=[O:39])=[O:38])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: CS(=O)[O-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(S(C)(=O)=O)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
{3-[4-Bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester (0.1 g, 0.19 mmol), sodium methanesulfinate (0.087 g, 0.84 mmol), and copper iodide (0.159 g, 0.84 mmol) were combined in NMP (2 mL) and degassed with N2 for 10 minutes. The reaction was then stirred at 150° C. for 3 hours, until no starting material was seen by analytical tlc. The mixture was filtered through Celite and worked-up with brine and EtOAc, and the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (0.1 g).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:19]=O>C(O)=O>[CH2:1]([N:6]([CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CCCCCCCCCCCCNCCC(C)C
Reactant: C=O
Solvent: O=CO
Product: CCCCCCCCCCCCN(C)CCC(C)C

Procedure:
To 30 g of N-isoamyldodecanamine in 100 ml of formic acid was added 30 ml of formalin (40% formaldehyde) and the reaction mixture was refluxed for 8 hrs. Most of the solvent was removed under vacuum and the remaining material was made alkaline with 3 N sodium hydroxide solution and the amine extracted into hexane. The hexane phase was washed with water, and then dried over sodium hydroxide pellets. Removal of the hexane under vacuum gave 28 of N-isoamyl-N-methyldodecanamine, ND20 1.4507.
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[NH:19][C:20]2[N:28]=[C:27]3[C:23]([NH:24][C:25](=[O:35])[N:26]3[CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:21]=2)C(C)=CC=1.Cl.NO>C(O)C.O>[NH2:3][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:10][C:9]=1[NH:19][C:20]1[N:28]=[C:27]2[C:23]([NH:24][C:25](=[O:35])[N:26]2[CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:22]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[N:21]=1
Reactant: Cc1ccc(C)n1-c1ccc(OC(F)(F)F)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Nc1ccc(OC(F)(F)F)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1

Procedure:
2-(2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethoxy)phenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (0.018 mmol) was reacted with hydroxylamine hydrochloride (5 equiv.) in a mixture of ethanol and water (1.6 mL/0.6 mL) at reflux for 20 h. Upon completion of the reaction (monitoring by HPLC and MS), the solvent was removed in vacuo, the material thoroughly dried and used in the next step without further purification. MS (EI) m/z 488.4 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[CH2:27](I)[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[NH2:7][C:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:27][CH3:28]
Reactant: CCI
Reactant: Nc1c(C(=O)c2ccccc2O)oc2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccccc1C(=O)c1oc2ccc(Cl)cc2c1N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of potassium carbonate (0.056 g, 0.4 mmol), 3-amino-5-chloro-2-(2-hydroxybenzoyl)-benzofuran (0.05 g, 0.4 mmol) and ethyl iodide (0.05 g, 0.34 mmol) in dry DMF is stirred at 60° C. for 2 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 114-115° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=[C:20]([Br:24])[Br:21])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of triphenylphosphine (119.6 g) in methylene chloride (420 mL) at 0° C. was added a solution of carbon tetrabromide (75.72 g) in methylene chloride (90 mL). After completion of the addition, the mixture was stirred for 10 min. Then a solution of 3-(benzyloxy)benzaldehyde (J.A.C.S., 99, 2571 (1977)) (40 g) in methylene chloride (150 ml) was added. The mixture was stirred for 16 hrs at -5° C. After warming to room temperature, the organic layer was washed with saturated sodium bicarbonate (2×150 ml) and brine (1×150 ml), then dried over magnesium sulfate, filtered and the mixture was concentrated. Ether (300 ml) was added, causing the formation of a precipitate which was filtered. The filtrate was concentrated and the process repeated 2 times. Finally, the filtrate was concentrated and chromatographed using 10% ethyl acetate in hexane, affording the title compound as a solid.
Reaction SMILES: O[C:2]([CH3:9])(C)[C:3]([O:5][CH2:6][CH3:7])=O.CS(C1C=C[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=1)(=O)=O.[H-].[Na+]>CN(C=O)C>[CH2:6]([O:5][C:3]1[CH:2]=[CH:9][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=1)[CH3:7]
Reactant: CCOC(=O)C(C)(C)O
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(C)(=O)=O)cn1
Temperature: 80 °C

Procedure:
A mixture of ethyl 2-hydroxyisobutyrate (0.41 mL, 3.0 mmol), 2,5-bis(methylsulfonyl)pyridine (J. Heterocycl. Chem. 1985, 22, 1583) (0.70 g, 3.0 mmol) and sodium hydride (60% dispersion in mineral oil, 0.14 g, 3.6 mmol) in 30 mL of anhydrous DMF was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, and was partitioned between saturated aqueous ammonium chloride (200 mL) and ether (200 mL). The organic layer was separated and was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluting with 0 to 80% ethyl acetate in hexane to give the title compound as a 1:1 mixture with 2-ethoxy-5-methylsulfonylpyridine. LC-MS: m/e 288 (M+H)+ (0.70 min).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:27])[C:25]=1[F:26])[C:20]([OH:22])=O>>[F:27][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([F:16])[C:25]=1[F:26])[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(F)c(F)c(F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3,4,5-trifluorobenzoic acid (CAS RN 121602-93-5) after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). The product-containing fractions were pooled and evaporated. The resulting brown solid was chromatographed a second time by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (22%). MS (ESI): m/z=357.12 [M+H]+.