Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:13][C:11]([C:9]1[CH:8]=[N:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([F:14])[CH3:12]
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Reactant: CC(F)(F)c1cnn2c(Br)cnc2n1
Product: CC(F)(F)c1cnn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1
Yield: 44 %

Procedure:
This compound was prepared in 44% yield as described in the final paragraph of Example 2, step d, but using 7-bromo-3-(1,1-difluoroethyl)imidazo[1,2-b][1,2,4]triazine instead of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine, and using 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine (prepared as described in Example 3, step f) instead of 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile: 1H NMR (360 MHz, CDCl3) δ 2.19 (3H, t, J 18.8 Hz), 7.36-7.47 (2H, m), 7.98 (1H, m), 8.08 (1H, m), 8.22 (1H, dd, J 2.3, 7.2 Hz), 8.45 (1H, s), 8.78 (1H, d, J 11.2 Hz), 8.85 (1H, s), 8.88 (1H, s); MS (ES+) m/z 356 [M+H]+. Anal. Found: C, 60.85; H, 3.45; N, 19.69%. Required for C18H12F3N5: C, 60.85; H, 3.40; N, 19.71%.
Reaction SMILES: O.NN.C1(=O)[N:8]([O:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])=[CH:25][CH:26]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCCON3C(=O)c4ccccc4C3=O)cc2)S1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
0.32 ml of hydrazine monohydrate was added to a suspension of 2.64 g of 5-[4-(2-phthalimidooxyethoxy)benzyl]thiazolidine-2,4-dione [prepared as described in step (d) above] in 30 ml of ethanol, and the resulting mixture was stirred at 80° C. for 2 hours. At the end of this time, the reaction mixture was cooled and the precipitated phthalhydrazide was filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:20 by volume mixture of methanol and methylene chloride as the eluent, to give 1.93 g of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione as a syrup.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]([O:14]CC)=O.[N+:17]([CH3:20])([O-])=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:20][NH:17][C:12](=[O:14])[CH2:11]1
Reactant: CCOC(=O)C=Cc1cc(F)cc(F)c1F
Reactant: C[N+](=O)[O-]
Product: O=C1CC(c2cc(F)cc(F)c2F)CN1

Procedure:
4-(2,3,5-trifluorophenyl)pyrrolidin-2-one x38 is synthesized from nitromethane and ethyl 3-(2,3,5-trifluorophenyl)acrylate according to the methodology described in Kenda B. et al., J. Med. Chem. (2004), 47, 530-549.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][OH:15])[CH:9]1[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>[K]>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][O:15][S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:9]1[C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(CO)C(c2c(Cl)cccc2Cl)N1Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K]
Product: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(Cc3ccccc3)C2c2c(Cl)cccc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To 40 g of 1-benzyl-2-(2,6-dichlorophenyl)-3-hydroxymethyl-pyrrolidine-5-one in 67 ml of potassium dried pyridine at 5°-10° was added 23.3 g of tosyl chloride over 30 minutes. After the addition, the mixture was stirred for 3 hours at 15° and then for 13 hours at ambient temperature. The reaction mixture was added dropwise to a stirred ice-water solution and then set at ambient temperature for 72 hours. The light yellow solid was collected by filtration and then air dried. Trituration with ether followed by filtration provided 44.5 g of colorless crystals, m.p. 110°-114°.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:30]=[O:31])[CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C=O)CC3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(rac)-5,7-Difluoro-6-[1-(6-piperazin-1-yl-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Example 6, 50 mg, 0.127 mmol) and 4-nitrophenyl formate (29.7 mg, 0.177 mmol) were dissolved in DCM (1.27 mL) and triethylamine (0.021 mL, 0.152 mmol) was added. The RM was stirred at RT for 0.5 h. The mixture was concentrated and the residue was purified by flash chromatography and afforded the title compound as a white foam (tR 3.25 min (conditions 1), MH+=423).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@@H:22]12[O:29][C@@H:26]([CH2:27][CH2:28]1)[CH2:25][NH:24][CH2:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:23][C@@H:22]4[O:29][C@@H:26]([CH2:27][CH2:28]4)[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1C[C@H]2CNC[C@@H]1O2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@H]2CC[C@@H](C1)O2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (54745-74-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.5 [MH+].
Reaction SMILES: [CH:1]1[C:14]2[S:13](=[O:16])(=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:21])CCC>O1CCCC1.CCCCCC>[Li:21][C:1]1[C:14]2[S:13](=[O:15])(=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: O=S1(=O)c2ccccc2Oc2ccccc21
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]c1cccc2c1S(=O)(=O)c1ccccc1O2
Temperature: -40 °C

Procedure:
A mixture of phenoxathiin 10,10-dioxide (50.5 g) in dry tetrahydrofuran (500 mL) under nitrogen was cooled in an acetone/dry ice bath. To this slurry was added a 1.6 M solution of n-butyllithium in hexane (144 mL) at a rate which maintained the reaction temperature at -40° C., resulting after 30-45 min. in an orange solution of 1-lithiophenoxathiin 10,10-dioxide. To this solution was added ethyl iodide (35 mL), after which the reaction mixture was allowed to warm to room temperature. After about 3-4 hr the yellow solution was partially evaporated under reduced pressure and was then partitioned between methylene chloride and water. The methylene chloride phase was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to a yellow residue which was purified by column chromatography on Silica Gel 60 (E. Merck, Darmstadt, Germany) eluting with toluene. The desired fractions were combined and evaporated, and the residue was crystallized from ethyl acetate/pentane to give 1-ethylphenoxathiin 10,10-dioxide, mp. 112°-114° C. (del. 102°-104° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1([NH:37][C:38]([C:40]2[N:41]=[C:42](Br)[S:43][CH:44]=2)=[O:39])[CH2:36][CH2:35]1.C([O-])(O)=O.[Na+].CN(C=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:42]2[S:43][CH:44]=[C:40]([C:38](=[O:39])[NH:37][CH:34]3[CH2:36][CH2:35]3)[N:41]=2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(NC1CC1)c1csc(Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1csc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)n1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (90 mg, 0.2 mmol), 2-Bromo-thiazole-4-carboxylic acid cyclopropylamide (1 eq., 49 mg), Pd[P(Ph)3]4 (5 mol %, 10 mg), in methanol (4 mL), NaHCO3 (sat. aq., 600 uL) and DMF (800 uL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the products. Yield 11.1 mg. MS: 491.3 (M+H). H1-NMR (DMSO-d6): δ (ppm) 10.2 (s, 1H), 8.4-8.2 (m, 2H), 7.8-7.0 (m, 10H), 6.5 (m, 2H), 5.1-4.9 (m, 2H), 4.4 (m, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 1.9 (m, 3H), 0.7-0.6 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.BrN1C(=[O:18])CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH:10]=[O:18])[C:6]=2[CH:11]=1
Reactant: Cc1csc2ccc(Cl)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1csc2ccc(Cl)cc12
Yield: 87.9 %

Procedure:
A stirred mixture of 5-chloro-3-methylbenzothiophene (39 g, 0.214 mole, (D22)) and recrystallized N-bromosuccinimide (77 g, 0.432 mole) in carbon tetrachloride (700 ml) was illuminated with a 100 W lamp, while heating at reflux temperature for 4 hours. The reaction mixture was allowed to cool, the solid was filtered off and the filtrate was evaporated to dryness to leave a yellow oil. This residue was treated with 10% sodium carbonate solution (450 ml) and heated under rflux, with vigorous stirring, for 5 hours. The mixture was allowed to cool and extracted with chloroform (3×200 ml). The organic solution was washed with brine (2×200 ml), dried (MgSO4) and evaporated to dryness to give the title compound as a red solid (37 g, 88%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[F:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[C:25]([NH:31][C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:24]=1>>[F:22][C:23]1[N:24]=[C:25]([NH:31][C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:26]=[CH:27][C:28]=1[CH2:29][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reactant: COc1ccc(Nc2ccc(C=O)c(F)n2)cn1
Product: COc1ccc(Nc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1

Procedure:
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine P-3019 is prepared in two steps from 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 and 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde 56 as shown in Scheme 11.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:22][CH:21]=2)[C:16](=[O:33])[CH:15]=1)C1C=CC=CC=1>[Pd].CO>[OH:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:24][CH:25]=2)[C:16](=[O:33])[CH:15]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OC2CCCCO2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1cc(O)ccn1-c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Into a THF (25 mL)-MeOH (25 mL) mixed solvent solution of 4-benzyloxy-1-{4-[(2-tetrahydropyranyl)oxy]phenyl}-1H-pyridin-2-one (Step (1) of Example 12, 2.05 g, 5.4 mmols), 10% palladium-on-carbon (600 mg) was added. The atmosphere was hydrogen-substituted, and the reaction system was stirred at room temperature for 3.5 hours. The reaction liquid was filtered, the solvent was concentrated under reduced pressure, methanol was added to the resulting residue and the precipitate was recovered by filtration. Drying the same, the title compound (1.25 g, 80%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]=[C:28]=[S:29])=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:28]([NH:27][C:25](=[O:26])[CH2:24][C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[S:29])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
4-Fluorophenylacetylchloride (Aldrich, 0.072 mL, 0.525 mmol, 2.5 eq) was added to a solution of sodium thiocyanate (0.056 g, 0.695 mmol, 3.3 eq) in ethyl acetate (2.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to afford a solution of 2-(4-fluorophenyl)ethanoyl isothiocyanate (0.263 M). A solution of 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (0.050 g, 0.21 mmol, 1.0 eq) in CH2Cl2 (1.0 mL) was added dropwise to the 2-(4-fluorophenyl)ethanoyl isothiocyanate solution and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 3/1 hexane/ethyl acetate) to afford the title compound (0.058 g, 64%) as a solid. 1H NMR (DMSO-d6) δ 12.46 (s, 1H), 11.84 (s, 1H), 8.35-8.33 (m, 1H), 8.02-8.33 (m, 1H), 6.99-7.52 (m, 8H), 3.84 (s, 2H); MS (ESI+) m/z 434 (M+H)+; HRMS (ESI+) calcd.: 434.0542. found: 434.0547.
Reaction SMILES: [F:1][C:2]([F:59])([F:58])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:20][C@H:21]([OH:50])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:26]([N:38](C(OC(C)(C)C)=O)[S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].ClCCl>FC(F)(F)C(O)=O>[F:58][C:2]([F:1])([F:59])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([N:19]([CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:20][C@H:21]([OH:50])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:26]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=3)[CH2:17][CH2:18]2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)ccc1OCc1ccccc1)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)ccc1OCc1ccccc1

Procedure:
A solution of 1.4 g of trans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(tert-butoxycarbonyl)(methylsulfonyl)amino]phenoxy)-2-hydroxy-propyl)amino]cyclohexyl}phenyl trifluoromethanesulfonate (1.62 mmol) in a mixture of trifluoroacetic acid (5 ml) and of dichloromethane (45 mol) is stirred for 3 h 20. The solvents are evaporated under reduced pressure and then water, ethyl acetate and an aqueous ammonium solution are added. The organic phase is washed once with water and dried over sodium sulfate. trans-4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenyl trifluoromethanesulfonate is obtained in the form of an oil (1.27 g, 98%) after evaporation of the solvents under reduced pressure. [M+H+]=763.5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:14]([O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19](=[O:20])[CH:21]=[CH:12][CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(CC=O)cc2cn[nH]c12
Solvent: C1CCOC1
Product: Cc1cc(CC=CC(=O)OC(C)(C)C)cc2cn[nH]c12
Reaction time: 15 h
Yield: 51.5 %

Procedure:
Tetrahydrofuran (8 mL) was added to a flask containing (7-methyl-1H-indazol-5-yl)-acetaldehyde (1.94 mmol, 1.0 equiv) and (tert-butoxycarbonyl-methylene)triphenylphosphorane (1.46 g, 3.88 mmol, 2.0 equiv) at room temperature under nitrogen. The resulting yellow solution was stirred overnight (15 h). LCMS indicated completion. The mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to afford the desired product as a yellow oil (272 mg, 51.5% for two steps). MS (ESI) [M+H]+=273; 1H NMR (400 MHz, CDCl3) δ 12.3 (br., 1H), 8.06 (s, 1H), 7.36 (s, 1H), 7.04 (m, 1H), 6.96 (s, 1H), 5.74 (dd, J=15.6 and 1.6 Hz, 1H), 3.54 (d, J=6.8 Hz; 2H), 2.57 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[C:3]=1[C:4]#[N:5].Cl.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>O.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C:9]([CH2:10][Br:16])=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: CC(=O)Nc1ccc(C)c(C)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(CBr)c(C)c1C#N
Reaction time: 1 h
Yield: 42.3 %

Procedure:
In a carefully dried Pyrex reaction vessel were combined 10 g of 2,3-dimethyl-6-acetamidobenzonitrile, 300 ml of CCl4, and 200 ml of HCl-free CHCl3 under argon. To this solution was added 10.8 g of N-bromosuccinimide (recrystallized from H2O) and 0.5 g of azo bisisobutyronitrile (AIBN). The reaction was heated to reflux and irradiated with an external General Electric sunlamp. The initially yellow reaction turned red-brown after 1 h when an additional 0.5 g of AIBN was added. After another 2 h, the reaction mixture was poured into H2O, separated, and the aqueous layer reextracted with CHCl3. The combined CHCl3 layers were washed with H2O, saturated NaHCO3 solution, and brine. The dried organic solution was evaporated at reduced pressure and the residue was crystallized from ethyl acetate to yield 6 g (42%) of the title compound, m.p. 152°-153° C. NMR (CDCl3) 2.30 (3H, s, CH3CON), 2.60 (3H, s, CH3), 4.50 (2H, s, --CH2Br), 7.40 (1H, d, ArH), 8.10 (1H, d, ArH), Anal. Calc'd for C11H11BrN2O: C, 49.5; H, 4.15; N, 10.5. Found: C, 50.3, H, 4.31; N, 10.6.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[O:6][CH:7]=1.ClC1C=C(C(OO)=[O:29])C=CC=1>ClCCl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([C:17]([F:20])([F:19])[F:18])=[O:29])=[CH:14][CH:15]=2)[O:6][CH:7]=1
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A mixture of 17.6 g (55 mmol) 4-chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole and 14.93 g (60 mmol) 3-chloro-benzenecarboperoxoic acid in 200 ml dichloromethane was stirred at room temperature over night. After filtration, the filtrate was washed three times with sodium hydroxide solution, then with water, dried over sodium sulfate, filtered and evaporated. Purification on silica, after elution with heptane/ethyl acetate 5:1, yielded 5.78 g (31%) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole as off-white solid melting at 102-104° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[NH2:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:15](=[O:16])[O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)CN
Solvent: Cc1ccccc1
Product: CC(C)(N)CNC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
To a 65 g sample of 1,2-diamino-2-methylpropane dissolved in 650 mL of toluene cooled to -5° C. was added dropwise over 45 minutes a toluene solution (200 mL) of benzylchloroformate (52 g, 1.18 mmol). The reaction was warmed to room temperature and stirred for 2 hours before it was filtered and the filtrate was stripped of all solvent under reduced pressure. The residue, dissolved in CH2Cl2 (100 mL), was filtered and the filtrate again was stripped of all solvent to produce the title compound (54 g) as a viscous oil.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23]O)[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].C(Br)(Br)(Br)[Br:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][Br:43])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCO)c2)c2cccnc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCBr)c2)c2cccnc21
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-hydroxy-1-propynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (90 mg, 0.16 mmol) in methylene chloride (1.5 ml) were added carbon tetrabromide (81 mg, 0.245 mmol) and triphenylphosphine (51 mg, 0.196 mmol) under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane: 1:5) to give the title compound (53 mg, 0.086 mmol).